Nanomedicine: Nanotechnology, Biology, and Medicine
12 (2016) 1663 – 1701
nanomedjournal.com
Ultrasmall inorganic nanoparticles: State-of-the-art and perspectives for
biomedical applications
Kristof Zarschler, PhD a,⁎, Louise Rocks, PhD b , Nadia Licciardello, PhD a, c, d ,
Luca Boselli, PhD b , Ester Polo, PhD b , Karina Pombo Garcia, MSc a , Luisa De Cola c, d ,
Holger Stephan, PhD a , Kenneth A. Dawson b
a
Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden - Rossendorf, Bautzner Landstraße 400, Dresden, Germany
Centre For BioNano Interactions (CBNI), School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
c
Laboratoire de Chimie et des Biomatériaux Supramoléculaires, Institut de Science et d’Ingénierie Supramoléculaires (ISIS), 8 allée Gaspard Monge, Strasbourg, France
d
Institut für Nanotechnologie (INT), Karlsruher Institut für Technologie (KIT) Campus North, Hermann-von-Helmholtz-Platz 1,
Eggenstein-Leopoldshafen, Germany
Received 26 October 2015; accepted 15 February 2016
b
Abstract
Ultrasmall nanoparticulate materials with core sizes in the 1-3 nm range bridge the gap between single molecules and classical, largersized nanomaterials, not only in terms of spatial dimension, but also as regards physicochemical and pharmacokinetic properties. Due to
these unique properties, ultrasmall nanoparticles appear to be promising materials for nanomedicinal applications. This review overviews the
different synthetic methods of inorganic ultrasmall nanoparticles as well as their properties, characterization, surface modification and
toxicity. We moreover summarize the current state of knowledge regarding pharmacokinetics, biodistribution and targeting of nanoscale
materials. Aside from addressing the issue of biomolecular corona formation and elaborating on the interactions of ultrasmall nanoparticles
with individual cells, we discuss the potential diagnostic, therapeutic and theranostic applications of ultrasmall nanoparticles in the emerging
field of nanomedicine in the final part of this review.
© 2016 Elsevier Inc. All rights reserved.
Key words: Ultrasmall nanoparticles; Nanomedicine; Pharmacokinetics; Protein corona; Active targeting; Cancer; Renal excretion
Since few decades, the immense potential of nanoparticles (NPs)
especially in the field of nanomedicine leads to widespread interest
and attention together with knowledge and expertise about
nanosized objects. Despite the growing interest, the understanding
that nanoparticles could have clearance problems for in vivo
This article is part of the “Targeted Nanosystems as Therapeutic and
Diagnostic Tools” papers.
The financial support by the Helmholtz Virtual Institute Nano-Tracking
(Agreement Number VH-VI-421) is gratefully acknowledged. This study is
part of a research initiative “Technologie und Medizin – Multimodale
Bildgebung zur Aufklärung des in vivo Verhaltens von polymeren
Biomaterialien” of the Helmholtz-Portfoliothema. Financial support through
European Union’s Horizon 2020 Research and Innovation Programme
(Nanofacturing, grant agreement No 646364) is gratefully acknowledged.
There are no conflicts of interest.
⁎Corresponding author at: Helmholtz-Zentrum Dresden - Rossendorf
(HZDR), Institute of Radiopharmaceutical Cancer Research, Bautzner
Landstr. 400, Dresden, Germany.
E-mail address: k.zarschler@hzdr.de (K. Zarschler).
http://dx.doi.org/10.1016/j.nano.2016.02.019
1549-9634/© 2016 Elsevier Inc. All rights reserved.
application or being limited in the crossing of biological membranes,
spins off the growth of ultrasmall nanoparticles (USNPs) of
dimensions of small biological objects. 1
By definition, the core size of USNPs ranges from 1 to 3 nm with
the majority of its atoms located at the surface. 2-4 Both, the specific
surface area and the number of atoms at the surface increase
drastically when the core diameter decreases towards the ultrasmall
range (Figure 1). For instance, more than 70% of the atoms forming a
2-nm USNP will be located on its surface. This increased surface/
volume ratio leads to unique properties that diverge from their
microscopic species or from the bulk material itself. 4 As a
consequence, USNPs fill the gap between small molecules and
conventional, larger-sized NPs, not only in terms of size, but also as
regards physicochemical and pharmacokinetic properties. Their core
size in the low single-figure nanometer range represents a necessary,
but by no means sufficient precondition for their rapid elimination
via the renal pathway upon intravenous administration. 5 In other
words, not all USNPs can per se be cleared renally, as their surface
1664
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
Figure 1. The specific surface area as well as the number of atoms at the
surface increases drastically when the core diameter decreases towards the
ultrasmall range.
charge, shape and surface composition influences their pharmacokinetics in addition to their size. 6-8 The widely used term “ultrasmall
nanoparticles” originating from the field of material science is
therefore in no way synonymous with the pharmacological term
“renal excretable nanoparticles”. In fact, their biodistribution as well
as blood clearance depends primarily on their in vivo hydrodynamic
diameter that can be substantially larger than their in vitro diameter
due to the unspecific adsorption of serum component including
proteins and lipids. 9 This formation of a biomolecular corona has
been observed for a wide range of different NP platforms. As a result,
many nanosized objects are scavenged by the mononuclear
phagocyte system (MPS) and adequate surface modifications need
to be made to counter this issue and to render NPs more suitable for
nanomedical applications. 10
This review will focus specifically on inorganic USNPs and
attempts to summarize comprehensively the relevant literature
regarding metallic and non-metallic USNPs (e.g. gold and carbon),
oxide USNPs (e.g. iron oxide and silica) as well as ultrasmall
semiconductor quantum dots (QD) and rare earth based USNPs
including upconverting nanophosphors. These different NP species
will be successively discussed, describing in detail their synthesis and
properties as well as their characterization, surface modification and
toxicity. Subsequently, the current state of knowledge regarding
pharmacokinetics and biodistribution of USNPs with a main focus on
their elimination pathways is summarized and targeting strategies for
USNPs are examined. Before the potential diagnostic, therapeutic and
theranostic applications of USNPs in the emerging field of
nanomedicine are discussed in the final part of this review, the
issue of biomolecular corona formation is addressed and the very
limited knowledge about the interactions of USNPs with individual
cells is specified.
Metallic nanoparticles
Gold nanoparticles
Due to the high chemical inertness, broad variety of surface
functionalization and facile synthesis, gold NPs have been
considered for a long period as ideal candidates for many
biological and medical applications, e.g. cell imaging, ultrasensitive detection, transfection, drug transport and delivery
systems, antiviral agents and efficient materials for photothermal
ablation. 11-13 Particularly, in recent years considerable effort has
been directed towards ultrasmall gold particles (AuNPs). 14-20
AuNPs can be synthesized by the cluster beam method in the
gas phase 21 or in solution. Typically, the reduction of a dissolved
Au(III) salt or Au(I) complex to Au(0) is performed by a suitable
reducing agent in presence of Lewis base ligands. The most
common ligands are carboxylic acids, amides, phosphines and
thiols. Reducing agents are mainly sodium borohydride or
diborane, but also citrate or hydroquinone, depending on the
polarity of the solvent as well as the intended size range.
Modestly monodisperse AuNPs about 10 nm can be obtained by
the Turkevich method using citrate as reducing agent for
chloroauric acid in boiling water. 22,23 One of the most feasible
routes to achieve ultrasmall AuNPs (b 5 nm) was developed by
Brust and Schiffrin. HAuCl4 is reduced by NaBH4 in a biphasic
water/toluene system containing an alkylthiol for stabilization and
tetraoctylammonium bromide as phase transfer catalyst. 24 By
variation of thiols, uniform-sized AuNPs can be tailor-made.15 The
thiol-containing tripeptide glutathione provides highly stable AuNPs
b 3 nm. 25 Colloidal stable 3-6 nm-sized AuNPs can be also obtained
in aqueous solution by reduction of chloroauric acid with NaBH4
dissolved in NaOH. These particles are suitable precursors for
subsequent hydrophobic and hydrophilic coating as well. 26 Monodisperse ultrasmall AuNPs are meanwhile also available by ATP
capping 27, stabilization with polymers 28, fabrication in aminecontaining ionic liquids 29 and template synthesis using dendrimers 30.
Biodistribution and toxicity studies of gold NPs are recently
summarized in an excellent review. 31 Many of AuNPs investigated
in vitro and in vivo have hydrodynamic diameters larger than 10 nm.
However, ultrasmall materials are gaining more and more in
importance. To stabilize AuNPs in biological systems, thiolterminated poly(ethylene)glycol (PEG-SH) is very often applied.
Furthermore, peptides (glutathione), proteins, carbohydrates, hydrophilic phosphine and thiol ligands are used. Interestingly, in vivo
experiments reveal that AuNPs b 10 nm, even 1.4 nm, were mainly
found in the liver of rats. This finding is probably arisen from
insufficient colloidal stability. 32-34 On the other hand, the X-ray
contrast agent Aurovist™ (1.9 nm) is rapidly cleared from the blood
via the renal pathway and ultimately found in the bladder. 35
The synthesis of luminescent Au-thiolate nanoclusters with a
size below 2 nm was described by Xie and colleagues in 2012, 36
and in later in vitro and in vivo studies similar materials showed
good biocompatibility, strong radiosensitizing effects, passive
tumor accumulation and efficient renal clearance. 37,38
Zheng and co-workers synthesized renal clearable ∼ 2 nm
glutathione coated Au-NPs and demonstrated that this particular
zwitterionic coating minimizes nonspecific MPS uptake in balb/c
mice. Further pharmacokinetics studies showed that these
particles rapidly distribute in this animal model and circulate
with a blood-elimination half-life of 12.7 h. Due to this long
blood retention time, these ultrasmall GS-AuNPs possess the
ability to passively target tumors in MCF-7 tumor-bearing nude
mice. 39-41 By direct comparison of these zwitterionic Au-NPs
with their PEGylated counterparts, differences in renal clearance,
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
1665
Figure 2. Pharmacokinetics and biodistribution of 2, 6, and 15 nm gold nanoparticles. (A) Blood elimination profiles of gold following a single intravenous injection of
gold nanoparticles at a dose of 5 mg gold/kg in tumor-bearing mice. Data represent mean ± SD (n = 3). (B) Gold content in tumor, heart, liver, spleen, lung, brain, and
kidney 24 h after iv injections of gold nanoparticles at 5 mg gold/kg. Data represent mean ± SD (n = 3) (C) representative TEM micrographs of tumor tissue taken 24 h
after the administration of gold nanoparticles. Reprinted with permission from ACS Nano, Size-dependent localization and penetration of ultrasmall gold nanoparticles in
cancer cells, multicellular spheroids, and tumors in vivo. Volume 6, Issue 5, 2012, pp 4483-4493, K. Huang, H. Ma, J. Liu, S. Huo, A. Kumar, T. Wei, X. Zhang, S. Jin, Y.
Gan, P. C. Wang, S. He, X. Z., and X. J. Liang, Fig. 5.44 Copyright (2012) American Chemical Society.
pharmacokinetics and passive tumor targeting in nude mice
became apparent. 42
Passive tumor targeting in athymic BALB/c nude mice was
also observed for ultrasmall Au nanoclusters stabilized with
BSA. These non-toxic materials with a hydrodynamic size
of ∼ 2.7 nm emitted an intense red fluorescence can therefore be
utilized for in vivo tumor NIR fluorescence imaging. 43
Recently, it was demonstrated that ultrasmall AuNPs (2 nm)
coated with N-(2-mercaptopropionyl)glycine are superior over 6
and 15 nm particles with respect to cancer cell penetration and in
vivo tumor accumulation (Figure 2). 44 PET studies of
64
Cu-labeled Cu-Au alloy clusters stabilized with PEG-SH
permit reliable information of pharmacokinetic properties. It was
shown that smaller particles (5 nm) are significantly faster
cleared into the bladder and feces than larger ones (7 nm). 45
In vitro and in vivo nanotoxicity screening has shown that
surface functionalization as well as particle size remarkably
influences the cytotoxicity and cellular response. 46-48 For
example, recent studies, using a zebrafish model, have shown
that 1.4 nm AuNPs coated with triphenylphosphine exhibit
hepatotoxicity, but GSH-coated did not. 47 Notably, AuNPs with
zwitterionic surfaces are low-toxic. 49 Zero serum protein adsorption
can be achieved for AuNPs equipped with amino acids cysteine and
lysine or sulfobetaines on the surface. 50,51 Very recently, pH
responsive zwitterionic AuNPs have been developed, showing high
cellular uptake and cytotoxicity at pH b 6.6. 52
Silver nanoparticles
Over the last decade, efficient synthetic methods for the
fabrication of other noble metals such as silver, palladium and
platinum have been developed. 4 Ultrasmall AgNPs show high
antimicrobial activity and unique fluorescent properties. 15,53-56
However, investigations with respect to biocompatibility and
particularly biodistribution studies are in its infancy. 1-2
nm-sized AgNPs capped with dihydrolipoic acid (DHLA) are
prone to bind proteins on the surface. AgNPs covered with
human serum albumin showed lower cellular uptake and reduced
cytotoxicity compared to the pristine particles in HeLa cells. 57
GSH-capped AgNPs (2 nm) were used for fluorescence imaging
1666
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
of epithelial lung cancer cells (A549), achieving quantum yields
N 65%. 58 Near-infrared emitting silica-coated silver sulfide NPs
(1.5 and 9 nm) equipped with integrin-targeting peptides show
specific uptake into cancer cells and high tumor accumulation
in vivo. 59
Copper-based ultrasmall nanoparticles
Ultrasmall copper-based NPs have recently received attention
for biomedical applications. Metallic CuNPs (4 nm) can be
prepared in aqueous solution by EDTA-assisted reduction of
Cu(OH)2 with KBH4. Polyvinylpyrrolidone (PVP) is used for the
stabilization of the CuNPs. 60 Reduction of copper citrate with
N,N,N’,N’-tetramethyl-p-phenylenediamine in the presence of
single-walled carbon nanotubes (SWNT) yielded 2 nm-sized
CuNPs. 61 64Cu-labeled CuNPs shielded with bovine serum
albumin (3 nm) were predominantly excreted using the renal
pathway. Conjugation of tumor-specific peptides to the BSA
shell allow for clear visualization of A549 lung tumors. 62 With
regard to in vitro and in vivo applications, copper sulfide
nanomaterials are more suitable. 6 nm-sized CuS nanoclusters
coated with PEG-SH are highly stable over some month in
aqueous solution and show anticancer as well as antibacterial
activity. 63 A comparative in vivo study of 64Cu-labeled CuS
nanodots (ND) covered with PVP (19 and 5.6 nm) revealed that
the 5.6 nm-sized particles are much faster cleared than the larger
ones in mice. About 95% of 5.6 nm-sized particles are excreted
intact through the renal-urinary system within 24 h. The
ultrasmall CuS NDs passively accumulate in 4T1 tumors,
reaching tumor-to-muscle ratios N 10 at 2 h after injection and
near-infrared light irradiation permits efficient tumor ablation
(Figure 3). 64 Oleylamine-capped CuS NDs (b 5 nm) stabilized in
aqueous solution using PEGylated phospholipids are proposed
for photoacoustic imaging-guided photothermal therapy. 65
Cobalt nanoparticles
Cobalt has in the bulk a ferromagnetic behavior, but it is
reported that ultrasmall cobalt nanoparticles (Co NPs) can
display superparamagnetic properties. 66-68 Magnetic metallic
NPs, such as Co NPs, usually possess higher saturation
magnetization than metal oxides such as ferrite or iron oxides
and, therefore, a smaller quantity of nanoparticles could be
sufficient to display the same magnetic properties of oxides. 69
However, toxicity and instability have limited the bioapplications of Co NPs in the past. It has been shown that cobalt
nanoparticles have a high toxicological effect in many cell lines
in vitro. 70 Al Samri et al show that C/Co/SiO2 and C/Co3O4/
SiO2 nanoparticles increase caspase activity and alter the
structure of lungs, but the presence of a silica shell could
improve the biocompatibility of Co NPs. 71 The surface
modification of cobalt nanoparticles with a silica shell is
attracting increasing attention because it renders Co NPs less
toxic and facilitates surface functionalization. 72,73
Ultrasmall Co NPs can be prepared by several bottom-up
methods and, playing with parameters of the reaction, it is
possible to tune particles size, shape and composition. 69,74,75
Often high temperatures and inert atmosphere are necessary
conditions. In Figure 4, four examples of bottom-up synthesis are
reported. Co NPs can be obtained by three main different
typologies of reaction: high temperature liquid phase
synthesis; 69,75,76 reduction at room temperature of cobalt salts
in reverse micelles; 66,77 reduction or thermal decomposition of
cobalt salts using templates. 78,79
The high temperature liquid phase synthesis includes either
the thermal decomposition of Co2(CO)8 in organic solvents, in
the presence of a polymer, a peptide or an aluminium alkyl
compound, 80,81 or the reduction of cobalt salts by means of
superhydrides or polyalcohols in the presence of a
trialkylphosphine. 76,82,83 One of the challenges of the preparation of Co NPs is to avoid the formation of cobalt oxide, to tune
particle size and to stabilize the final particles. In this direction,
the group of Bönnemann et al reported on the synthesis of Co
NPs (size 5 to 10 nm) by thermal decomposition of Co2(CO)8 in
the presence of aluminium alkyl compounds (AlR3). 84-86 This
technique produces long-time air-stable cobalt nanoparticles
thanks to the step of smooth oxidation, which creates a thin
cobalt oxide layer around particles preventing further oxidation.
Particles size can be tuned by changing the length of the alkyl
chain in the AlR3 compound or by varying the molar ratio
between Co2(CO)8 and AlR3.
Chen et al obtained ultrasmall Co NPs with a size of 1.8-4.4
nm by reducing CoCl2 with NaBH4 under inert atmosphere in
toluene inside reverse micelles of the surfactant didodecyldimethyl ammonium bromide (DDAB). 66
Finally, an example of Co NPs fabrication taking advantage of
hard templates was described by Escalera and coworkers. The
authors reported on the production of Co NPs (2-4 nm) by the
reduction of a cobalt salt with NaBH4 inside the pores of mesoporous
silica. The silica material acts as a template and is removed through
dissolution with NaOH after the reaction is completed. 78
Cobalt ferrites, cobalt complexes, cobalt doped iron oxide and
mixed cobalt/metal NPs find several applications in magnetic
resonance imaging (MRI), but for pure Co NPs coated with
carbon or silica few applications are described until now. 87-89
For example, Balla et al conjugated carbon coated Co NPs (≈ 30
nm) with a β-cell-specific single-chain antibody fragment and
investigated the suitability of these ferromagnetic probes for
MRI. In particular, they successfully performed in vivo
visualization of single native pancreatic islets, the sites of insulin
production, in the pancreas of mice. However, these particles
accumulated also in the organs of the MPS most likely due to
their size and surface properties. 90
Oxide nanoparticles
Iron oxide nanoparticles
Depending on their size as well as their intrinsic characteristics, iron oxide NPs can generally be classified into superparamagnetic iron oxide nanoparticles (SPIONs) with a mean
particle diameter of N 50 nm, and ultrasmall superparamagnetic
iron oxide nanoparticles (USPIONs) with smaller hydrodynamic
diameters. 91 The relative large size of SPIONs accompanied by
unfavorable pharmacokinetic behavior impairs their current in
vivo applications, since they rapidly accumulate in the liver and
spleen as a result of opsonization and scavenging by the
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
1667
Figure 3. Pharmacokinetics, biodistribution, and microPET/CT imaging of [ 64Cu]CuS nanodots and [ 64Cu]CuS nanoparticles in mice. Time-activity curves of
blood (A) and biodistribution pattern at 24 h after i.v. injection (B) of the 5.6 nm [ 64Cu]CuS nanodots and the 19 nm [ 64Cu]CuS nanoparticles in blood (n = 5-6)
in female Swiss mice (n = 5). (C,D) Representative co-registration of PET and CT (μPET/CT) maximum intensity projection images after i.v. injection of 5.6
nm [ 64Cu]CuS nanodots (C) and 19 nm [ 64Cu]CuS nanoparticles (D) into tumor-free Swiss mice (n = 3). (E,F) Representative μPET/CT 2D section images
obtained at 10 min after i.v. injection of 5.6 nm [ 64Cu]CuS nanodots, showing significant accumulation of the nanodots in the kidneys (E) and the bladder (F).
Left to right: transverse, coronal, and sagittal views; p values in (B) were calculated by a Student’s t test (**P b 0.001 or *P b 0.01). Reprinted with permission
from ACS Nano, CuS nanodots with ultrahigh efficient renal clearance for positron emission tomography imaging and image-guided photothermal therapy.
Volume 9, Issue 7, 2015, pp 7085-7096, M. Zhou, J. Li, S. Liang, A. K. Sood, D. Liang, and C. Li, Fig. 2.64 Copyright (2015) American Chemical Society.
MPS. 92,93 In contrast, USPIONs are generally less prone to MPS
trapping compared to their larger counterparts due to a reduced
degree of opsonization, and therefore they exhibit longer
half-lives in the circulatory system. 94,95
Iron oxide NPs are composed of an iron oxide crystal core
surrounded by a hydrophilic polymer coating. 95,96 For their
fabrication a number of different chemical methods has been
described including co-precipitation 97-103, laser pyrolysis 104-106,
thermal decomposition 107-119 and polyol reduction process. 120-125
Co-precipitation of ferrous and ferric salts in aqueous
solution represents a straightforward, facile and efficient
synthesis strategy to obtain iron oxide NPs on a large scale. A
wide variety of experimental parameters, such as pH, ionic
strength, reaction temperature, and concentration ratios of Fe II/
Fe III were described to influence size, shape, magnetic
characteristics, and surface properties of the NPs, which have
to be carefully monitored in order to obtain consistent
synthetic outcome. 93,96,126 Since co-precipitation reactions are
1668
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
Figure 4. Four examples of bottom-up synthesis of ultrasmall cobalt nanoparticles (R = CH3, C2H5, C8H17; trialkylphosphine = tributyl- or trioctylphosphine;
DDAB = didodecyldimethyl ammonium bromide). 66,76,78,79,82-86
thermodynamically driven, the control of particle size distribution and crystallinity is limited.
Alternatively, highly crystalline and monodispersed USPIONs
can be synthesized by high-temperature decomposition of organometallic precursors (e.g. iron cupferronate, ferric triacetylacetonate
or iron pentacarbonyl) using high-boiling organic solvents and
surfactants. 127 The size and morphology of the USPIONs can be
precisely controlled by tuning experimental parameters including
temperature of decomposition, the reaction time, as well as the nature
of precursors, solvents and surfactants. In 2011, Hyeon and
coworkers reported an optimized synthesis of uniform and extremely
small-sized iron oxide NPs by thermal decomposition of iron-oleate
complexes in presence of oleyl alcohol at a relatively low
temperature, where the oleyl alcohol acts as a mild reductant and
lowers the reaction temperature, producing a large number of nuclei.
The large number of nuclei coupled with the limited amount of
reduced iron leads to a controlled growth process that results in
uniform 1.5-3 nm USPIONs. 107
However, NPs produced from this non-aqueous method are
soluble only in organic solvents, which necessitate post-preparative ligand-exchange procedures to render them water-soluble and biocompatible. 128 Recently, thermal decomposition
and polyol methods directly resulting in water-soluble USPIONs
have been described. 109,111,115,120,129-131
Perquisites for the successful biomedical use of NPs are their
colloidal stability and biocompatibility in biological environments. The surface of iron oxide NPs has iron atoms on the
surface that can coordinate with molecules or get protonated/
deprotonated. For these reasons, modifying the surface is
essential to provide stability and hydrophilic properties for
extensive biomedical applications. The reactive surface properties of iron oxide also facilitate reactivity with many functional
groups of both inorganic and organic shells.
Organic shells such as monomeric ligands (dopamine,
phosphoric acid), multimeric ligands and zwitterionic ligands
can be introduced by ligand exchange. Furthermore, embedding
the surface of the NPs with polymers has also been widely used.
On the other hand, inorganic shells mainly consist on gold, silica
and tantalum (V) oxide layers. 93,96,132,133
Titanium dioxide nanoparticles
TiO2 NPs are of particular interest for a wide range of
applications including photocatalysis and photoelectric conversion. Water-dispersible and biocompatible ultrasmall TiO2 NPs
for biological applications with a core diameter of 5 nm and
coated with aspartic acid or mercaptosuccinic acid were
described by Cheyne et al. 134 However, the future will show
to what extent TiO2 NPs will be applied in the field of
nanomedicine, e.g. as anticancer drugs, 135 despite an overwhelming number of reports highlighting their toxicity. 136,137
This also applies to nanomaterials composed of nickel oxide that
induce programmed cell death by an increased production of
reactive oxygen species. 138
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
Hafnium oxide nanoparticles
Nanocrystals composed of HfO2 possess appealing physical
attributes for local cancer therapy and are at the same time
described to show chemically inert behavior in cellular and
subcellular systems. 139,140 Due to their high electron density,
crystalline HfO2 NPs offer the possibility to deposit high
amounts of energy within the cancer cells when activated by
ionizing radiation. 141,142 However, there have been published
very few studies on the production sub-10 nm HfO2 NPs 143-147
and, to the best of our knowledge, only a single one describing
their in vitro analysis. 143 This particular report describes a
precipitation method relying on the precipitation of hafnium
tetrachloride in an aqueous solution of sodium hydroxide with
continuous stirring. Interestingly, the size of the particles could
be adjusted by tuning the stirring time of the reaction.
Cytotoxicity studies using mouse fibroblast cells revealed
cytocompatibility at concentrations up to 500 μg/mL and
size-dependent differences in the cell viability upon exposure
to higher concentrations.
Zirconia nanoparticles
The utilization of sub-5 nm fluorescent biocompatible
lanthanide-doped zirconia NPs as sensitive probe for timeresolved (TR) fluorescence resonance energy transfer (FRET)
and optical imaging agent has been highlighted by Liu et al. 148
These monodisperse materials were synthesized by a solvothermal procedure in combination with a subsequent ligand
exchange reaction using 2-aminoethyl dihydrogen phosphate.
Due to the free amine groups on the surface, these agents became
water-dispersible and possessed a positive ζ-potential as well as
a size of ∼ 5 nm.
Manganese oxide nanoparticles
Nanoparticulate contrast agents for MRI on the basis of
ultrasmall manganese oxide NPs have been described recently by
several groups, 149-152 whereby different synthesis strategies
were applied. The thermal decomposition technique in a
nonpolar organic solvent requires the post-synthetic separation
of organo-soluble NPs from the solvent before subsequent
coating procedure via ligand exchange. 149,150 The resulting
MnO NPs dispersed in chloroform were coated with dimercaptosuccinic acid (DMSA) and polyethylene glycol (PEG). In
contrast, the process described by Baek et al combines particle
synthesis and coating with the biocompatible and hydrophilic
ligand D-glucuronic acid in one pot. 151 In vitro and vivo
investigations of these agents possessing size-dependent relaxation properties resulted in high contrast T1-weighted MR
images, illustrating their particular suitability as sensitive T1
MRI contrast agents.
Silica nanoparticles
Silica nanoparticles (SiO2 NPs) can be found in a wide range
of industrial applications such as paints, cosmetics, food,
additives, as well as in numerous studies in the nanomedicine
field, mainly for medical diagnostic and therapeutic
purposes. 153,154 SiO2 NPs can be presented crystalline, amor-
1669
phous and mesoporous forms, and can be prepared in a broad
range of sizes, morphologies and surface chemistry. Features
such as high surface area, easy synthesis and surface functionalization, high stability and biocompatibility, and the capacity
of efficient immobilization/encapsulation of high amount of drug
molecules or biomolecules (e.g. enzymes or peptides) make SiO2
NPs promising candidates as drug delivery systems. 155 Several
examples in the literature have shown the potential application of
smart mesoporous silica delivery carriers (50-200 nm), as
stimuli-responsive systems after incorporation of other types of
nanomaterials in their structure. 156 Moreover, fluorescence
labelled amorphous SiO2 NPs below 50 nm have been described
as good candidates for bioimaging and active targeting, due to
the high capacity of incorporating active molecules on their
surface and efficiently encapsulation of organic dyes. 157
SiO2NPs have shown high biocompatibility, presenting
toxicity at concentrations up to 200 μg/mL in vitro (which is
above the effective particle concentration required for most
therapeutics treatments), and at dosage of 100 mg/kg in
mice. 158,159 The low toxicity of SiO2 NPs is due to the capability
of these NPs to be dissolved, under physiological conditions,
into smaller SiO2 NPs which can be eliminated via renal
excretion. 160-162 However, larger SiO2 NPs can present
instability in biological media; if the NPs need a long time to
be completely dissolved, particle agglomeration may occur,
leading to organ accumulation and therefore to possibility of
long term toxicity. 161 These major drawbacks and the difficulty
to reach the specific target, due to the low circulating time
associated with bigger NPs sizes, are the main reasons to
synthesize particles in the small nanosized regime (b 20 nm). 163
Furthermore, is well known that particles in the nanosized
range can present new physicochemical properties (including
optical, thermal, mechanical and catalytic properties). In a 5 nm
SiO2 NP half of the Si atoms are located on the NPs surface,
leading to an increase of the catalytic properties due to the huge
availability of active silanol groups. The increase in the number
of silanol groups also enables a variety of chemical surface
modifications that permits conjugation of a variety of organic
molecules. 164
Numerous procedures have been described in the literature to
synthesize SiO2 NPs with a specific size, porosity, crystallinity
and morphology. The main synthesis routes of SiO2 NPs are
based on sol–gel processes, reverse microemulsion, and flame
synthesis, with the sol–gel technique being the most common
used. Following the sol–gel process, the Stöber method produces
SiO2 NPs with the desired size distribution ranging from 10 to
2000 nm. 165 The polymerization of silicates from a precursor,
generally an organosilane such as TEOS tetraethyl orthosilicate,
leads to a formation of small colloidal particles after the
hydrolysis and condensation process. Increasing the rate of
TEOS addition and controlling the solvent/TEOS ratio, a
decrease in size distribution till 10 nm in diameter can be
achieved in the synthesis of SiO2 NPs. 166 Many efforts have
been made in recent years to produce nanosilica particles.
Following the Stöber method that allows to obtained monodispersed spherical SiO2 NPs with a specific size by tuning the
reaction parameters, Rahman et al obtained homogenous and
highly dispersed stable SiO2 NPs of 7 nm. 167 Hartlen et al
1670
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
described a simple and robust synthetic route to produce highly
monodisperse small SiO2 NPs, by using peptides such as
L-arginine or lysine, to catalyze nucleation and growth of SiO2
NPs between 10 and 30 nm. 168,169 Moreover, in addition to small
amorphous SiO2 NPs (b 10 nm) have been reported, ultrasmall
mesoporous SiO2 NPs with narrow size distribution between 2
and 10 nm, named Cornell dots or C-dots have been developed
by Wiesner and co-workers. 157 Fluorescent core-shell mesoporous silica have been prepared by one-pot synthesis, in which the
shell corresponds to a polyethylene glycol coating layer and the
core corresponds to a single pore size mesoporous silica that can
incorporate molecules such as dyes (NIR dye such as Cy5.5) or
radioiodine. 170 The polyethylene glycol coating acts as a
protecting layer, increasing the stability in biological fluids,
decreasing the unspecific adsorption of proteins and improving
the in vivo circulating time of the nanosystem by providing
longer half-life in the blood streams. 161,171 This ultrasmall
Cornell-dot system was approved for a first clinical trial for
melanoma cancer targeting, which is described in more detail in
the chapter “Active targeting”. 172
Generally, SiO2 NPs have extremely low toxicity and are
amongst the very few particle platforms approved by the
American Food and Drug Administration (FDA). However
differential cellular toxicity of the amorphous nanosilica particles
has been reported in literature depending on the particle’s size,
shape, solubility, surface charge and functional groups. 173
Several studies had shown particle size-dependent cytotoxicity
induced by small silica particles. 174,175 Also, latent risk in
hemolysis due to the presence of silanol groups has been
revealed. 176 Still no conclusive information on their toxicity is
reported, and therefore biocompatibility, biodegradation and
clearance of the SiO2 NPs need to be further clarified.
Rare earth based nanoparticles
Over recent years considerable effort has been directed
towards the design and synthesis of lanthanide based nanomaterials for biomedical applications. This is due to a large
structural and compositional versatility, providing a manifold of
intriguing properties, such as bright fluorescence, unique redox
and magnetic behavior. The paramagnetic properties of lanthanide oxides have been utilized for the development of new
contrast agents for MRI purposes.
Particularly but not exclusively ultrasmall Gd2O3 NPs were
developed in this direction. 177-180 Materials consisting of
gadolinium, an element with a high atomic number, are also
very attractive for their application as efficient radiosensitizer. 181
Ceria NPs, showing free radical scavenging activity, are
considered as protective material against ischemic stroke. 182
Currently, there is a burgeoning rush to utilize so-called upconverting nanophosphors (UCNPs) for biomedical applications. 183-193
Due to their unique feature to convert longer wavelength radiation
(typically NIR) into higher energetic visible light (“upconverters”),
these lanthanide-doped inorganic NPs are very appealing particularly in bioimaging. On one hand, their excitation with NIR diode
lasers permits a deep tissue penetration. On the other, the induced
bright luminescence provides high-contrast images in the biological
window between 700 and 900 nm.
Park et al developed a synthetic route for fabrication of nearly
monodisperse and highly water-soluble manganese oxide (MnO)
and gadolinium oxide (Gd2O3) NPs with average particle
diameters ranging from 1 to 3 nm in a polyol solvent. Their
one-pot synthesis resulted in hydrophilic and biocompatible
ligand-coated paramagnetic or superparamagnetic metal oxide
NPs, whereas the Gd2O3 NPs turned out to be ideally suited for
T1 MRI contrast agents. 123,194 These water-dispersible rare earth
oxides with high colloidal stability were fabricated by PEGylation, silica coating and stabilization with carboxylic acid and
phosphate groups. The D-glucuronic acid coated ultrasmall
gadolinium oxide NPs (∼ 1 nm) were proven to be non-toxic in
vitro. These particles showed renal excretion and allowed for
high contrast in vivo T1 MR images of rat brain tumors. 194 Two
years later, this group described the one-pot polyol synthesis of
D-glucuronic acid coated ultrasmall Ln2O3 (Ln = Eu, Gd, Dy,
Ho, and Er) NPs with average particle diameters ranging from
2.0 to 3.0 nm, whereas the gadolinium oxide NPs were identified
as potential candidates for a T1 MRI contrast agent and the
dysprosium oxide NPs showed negative contrast enhancement in
T2 MR images, respectively. 195,196 The same coating was used
by this group to generate different water-soluble ultrasmall
Ln2O3 nanoparticles (Ln = Ho and Er). 197,198 Furthermore, this
group also reported on the synthesis of MnO surface doped
Gd2O3 (Gd2O3@MnO) NPs 199 as well as mixed gadolinium-europium oxide NPs. 200 Both ultrasmall, lactobionic acid
coated NP species turned out to be potential T1 and T2 MRI
contrast agents, whereas gadolinium-europium oxide NPs were
also suitable to some extent for in vivo fluorescence imaging.
The synthesis of these MRI contrast enhancing gadolinium oxide
NPs can be modified to generate multimodal imaging
agents 201,202 and - once colloidal stabilized by coating with
PEG - applied for in vivo imaging as well as cell labeling and
subsequent in vivo tracking. 203-207
Very recently, Tegafaw et al reported on the synthesis,
characterization and in vivo application of ultrasmall D-glucuronic
acid coated paramagnetic mixed lanthanide oxide NPs (∼1 nm).
These water-soluble and biocompatible materials composed of
gadolinium-dysprosium oxide enhance the positive as well as
negative contrast in T1 and T2 MR images, respectively and thus can
act as a dual-mode T1 and T2 MRI contrast agents. 208
The team of Perriat and Tillement investigated the synthesis,
stabilization, pharmacokinetics and theranostic potential of
ultrasmall gadolinium-based hybrid NPs. 181,209-216 After producing ∼ 3 nm-sized Gd2O3 cores by alkaline hydrolysis
(NaOH) of GdCl3 in diethylene glycol at elevated temperature,
they were encapsulated in polysiloxane shells containing organic
dyes, such as fluorescein, rhodamine B and Cy5. Upon
PEGylation, the obtained 10 nm-sized NPs circulate in mice
for at least 3 h and were eliminated by renal excretion. 209
Furthermore, this team developed a new kind of ultrasmall rigid
NPs consisting of fragmented multifunctional silica-based rigid
platforms. The 3-4 nm-sized particles contain Cy5.5 fluorophores and the macrocycle DOTA capable of binding metal ions
such us Gd III (MRI) and 111In III (SPECT). Complementary
techniques (MRI, SPECT, CT and fluorescence imaging) prove
without a doubt the renal pathway of these particles with
completely evade uptake by the MPS (Figure 5). 210,211 Recently
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
1671
Figure 5. (A) In vivo SPECT/CT imaging from 15 to 60 min after intravenous injection of silica-based small and rigid platforms (SRPs) on a male c57Bl/6J mouse. Left to
right: maximum intensity projection (MIP), sagittal, coronal, and transversal views centered on the right kidney. (B) 111In-SRP biodistribution at 3 h and 24 h p.i. (for the
bladder, the uptake at 3 h corresponds to the bladder and the urine collected since the beginning of the experience, while at 24 h it corresponds to the bladder only). (C)
Black squares: 111In-SRP accumulation in the bladder from 15 min to 3 h p.i. (average uptake on 8 animals); red circles: 111In-SRP accumulation in the bladder and in the
kidney from 15 min to 3 h p.i.; green triangles: remaining ID in the blood system from 15 min to 3 h p.i. Reprinted with permission from Angewandte Chemie International
Edition, Ultrasmall rigid particles as multimodal probes for medical applications. Volume 50, Issue 51, 2011, pp. 12299-12303, F. Lux, A. Mignot, P. Mowat, C. Louis, S.
Dufort, C. Bernhard, F. Denat, F. Boschetti, C. Brunet, R. Antoine, P. Dugourd, S. Laurent, L. Vander Elst, R. Muller, L. Sancey, V. Josserand, J. L. Coll, V. Stupar, E.
Barbier, C. Rémy, A. Broisat, C. Ghezzi, G. Le Duc, S. Roux, P. Perriat, and O. Tillement, Fig. 4.210.
the team analyzed the radiosensitizing properties of ultrasmall
gadolinium NPs with the commercial gadolinium contrast agents
Magnevist® and DOTAREM® in comparative studies. 217,218
The group of Shi reported recently on the successful
fabrication of ultrasmall NaGdF4 nanodots (∼ 2 nm) by
pyrolysis. Conversion of the hydrophobic nanomaterials into
hydrophilic with PEG and subsequent functionalization with the
chelator DTPA resulted in a hydrodynamic size of 16 nm.
Further investigations showed that these NaGdF4 nanodots are
especially suitable as T1 MRI contrast agents for angiography. 219
The same group described very recently the development of
NaHoF4 NPs with varied particle sizes ranging from ∼ 3
to ∼ 30 nm as dual-modality contrast agents for ultra-high
field MR and CT imaging. PEGylation of these particles led to
hydrodynamic diameters of ∼ 13 to ∼ 56 nm and excellent
biocompatibility. 220
Ultrasmall LaF3:Eu III/Tb III NPs (∼ 3 nm) were obtained by
thermosolvolysis. Stabilization by citric acid and addition of
1,2,4,5-benzenetreacarboxylic acid as sensitizer provide NPs
with enhanced luminescent properties. 221 Highly luminescent
Y2O3:Eu III NPs with a size of about 5 nm were prepared by
hydrothermal treatment of yttrium and europium chloride in the
presence of H3PW12O40. 222 Precipitation of Ln(NO3)3 (Ln =
Gd, Eu, Tb) and [(C4H9)4N)3][Mo(CN)8] dissolved in methanol
in the presence of the biopolymer chitosan yielded 3-4 nm
magneto-luminescent NPs. 223
Monodisperse ultrasmall CeO2 NPs (2-3 nm) can be prepared by
ammonia precipitation of cerium nitrate in aqueous glycol
solution, 224 in ethylenediamine solution 225 and via reverse
micelle-mediated synthesis. 182,226 Ultrasmall ceria NPs show
protective effects against reactive oxygen species (ROS) induced
cell death in vitro (CHO-K1). Importantly, they are able to permeate
ischemic brain tissue in vivo, most likely due to breakage of the
blood–brain-barrier and can thus protect against ischemic stroke. 182
In contrast to rare earth oxides/fluorides discussed vide supra,
the preparation of more complex compounds such as UCNPs
1672
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
with sizes b 3 nm is fairly challenging. 227 For this reason, also
NPs smaller than 10 nm are discussed in this chapter.
In 2010, Chen et al reported the preparation of UCNPs
consisting of NaYF4:Yb III/Er III. The 7-10 nm-sized particles
were obtained by a co-thermolysis method with oleic acid/
oleylamine as capping agents. 228 The luminescent yield can be
significantly enhanced by infrared-laser-induced annealing. 229
Thermal decomposition of precursor salts in the presence of
stabilizing agents such as oleylamine, oleic acid and octadecene
is the most applied method for the preparation of UCNPs. The
size of the particles can be influenced by controlling the
temperature course. Sub-10 nm lanthanide-doped NaLuF4:Gd III/
Yb III/Tm III/Er III UCNPs have been presented as sensitive in vivo
bioimaging agents. 115 To make them water-soluble, the
oleylamine surface groups were replaced by citric acid, yielding
in 11 nm-sized nano-objects. Johnson et al reported potential
bimodal (MRI and fluorescence imaging) probes based on
NaGdF4:Yb III/Tm III to show MRI contrast enhancement. 230 The
size of the hydrophobic oleic acid-stabilized particles is in the
range of 2.5 to 8 nm and increases in aqueous solution to 11 nm
after stabilization with polyvinylpyrrolidone. Further hydrophobic sub-10 nm UCNPs consisting of NaYF4:Yb III/Tm III 231 and
Na(K)GdF4:Yb III/Er III 232,233 have been reported. KGdF4:Yb III/
Er III has been dispersed in water by forming a PEG-phospholipid
shell whereby the fluorescence decreased comparing to the
hydrophobic stabilized UCNPs. The luminescence yield can be
enhanced by varying the dopants 234 and relative proportions as
well as the fabrication of core-shell particles. 230,233
Very recently, Cao et al described the synthesis of oleic
acid-capped KGdF4 NPs by a modified hydrothermal route.
These hydrophobic NPs were converted into hydrophilic by a
ligand exchange procedure using polyacrylic acid resulting in an
increase of the hydrodynamic diameter from ∼ 4.9 nm to ∼ 30
nm. Doping with Yb 3 +/Tm 3 + resulted in the ability to convert
longer wavelength radiation of 980 nm into higher energetic
visible light (“upconversion luminescence”), while doping with
Eu 3 + and exciting at 393 nm leads to “downconversion
luminescence”. 235
Altogether, only a few examples of ultrasmall and hydrophilic
UCNPs have been reported. 230,233,236 In vivo imaging of a black
mouse by subcutaneous injection of citrate-stabilized NaLuF4based UCNPs, excited with 980 nm laser light, was proven and
the particles could be detected even in 2 cm depth (Figure 6).
These particles show low toxicity toward cell proliferation in KB
cells. 236 Adequate information and conclusive results about
biodistribution, pharmacokinetics and formation of protein
corona is still missing for ultrasmall UCNPs.
Semiconductor quantum dots
For the last two decades, QDs composed of semiconductor
elements, e.g. CdSe, CdS, CdTe, PbS, PbSe, PbTe, SnTe, InAs
and InP, have attracted enormous attention in cell and molecular
imaging as well as cancer medicine. 237-239 QDs exhibit optimal
photophysical characteristics for biomedical applications such as
bright fluorescence in the near-infrared region, high quantum
yield and high resistance towards photo-bleaching. 240,241 The
typical size ranges from 1 to 10 nm that can be precisely
Figure 6. In vivo imaging of a black mouse by subcutaneous injection of
cit-Lu6-Tm and cit-Y1-Tm with detection from (A) the chest side and (B)
from the back side (λex = 980 nm, λem = 800 ± 10 nm). Reprinted with
permission from ACS Nano, Sub-10 nm hexagonal lanthanide-doped
NaLuF4 upconversion nanocrystals for sensitive bioimaging in vivo. Volume
133, Issue 43, 2011, pp. 17122-17125, Q. Liu, Y. Sun, T. Yang, W. Feng, C.
Li, and F. Li, Fig. 4.236 Copyright (2011) American Chemical Society.
controlled by the duration, temperature, and use of appropriated
ligand molecules in the synthesis. 242,243 Traditionally, trioctylphosphine oxide (TOPO) and trioctylphosphine (TOP) were
used as solubilizing and stabilizing agents for QDs at elevated
temperatures to produce hydrophobic particles. 244,245 However,
hydrophilic coating of QDs is compulsory for biomedical
purposes. There are different strategies available to fabricate
biocompatible QDs such as capping with hydrophilic thiols,
phosphines, carboxylic acids, dendrons, polymers, phospholipids as well as peptide and antibody coating. 238,239,246
However, until now the inherent toxicity hampers the clinical
application of QDs. 247-251 One way to circumvent the problem of
toxicity is the use of cadmium-free QDs. 252,253 Reduced toxicity
could be demonstrated in vivo for ultrasmall QDs consisting of
CuInS2/ZnS. Whilst CdTeSe/CdZnS QDs caused inflammation
of mice lymph nodes in lower picomolar range, CuInS2/ZnS
QDs did not up to 100 pmol. 253 In parallel, highly stable
hydrophilic coating should prevent or at least reduce the toxicity
of QDs. The evaluation of toxicity aspects is of outstanding
interest and requires reliable methods, including assays testing
the hemocompatibility. 254,255 Many of QDs that are discussed as
probes for fluorescence imaging and diagnostic assays as well
therapeutic applications such as photodynamic therapy have
sizes beyond 10 nm. 256 However, in the last decade a great
amount of effort has been devoted to the fabrication and
characterization of ultrasmall semiconductor QDs. In this
respect, pioneering work has been undertaken by the groups of
Frangioni and Bawendi. In 2007, renal clearable QDs composed
of CdSe (ZnCdS) have been presented, 257,258 which were coated
with dihydrolipoic acid (DHLA), cysteamine, cysteine and
DHLA-connected PEG, respectively. The most promising
properties showed zwitterionic-coated (cysteine) QDs. The
hydrodynamic diameter of these NPs was in the range of 4 and
9 nm. Interestingly, serum protein adsorption was prevented. The
smaller QDs (4.4 nm) were excreted via the renal pathway whilst
high liver uptake was observed for the larger particles (8.7 nm).
However, cystein-coated QDs tend to aggregate over the time
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
due to oxidation of cysteine. Substitution of cysteine by
penicillamine yielded QDs (b 5.5 nm) with high chemical
stability and resistance to oxidation. 259 Penicillamine-coated
QDs were taken up by HeLa cells mainly via clathrin-mediated
endocytosis and to a smaller extent by macropinocytosis. 260
CdS NPs (b 5 nm) stabilized with mercaptoacetic acid and
ammonia have been described to show reasonable high quantum
yields. 261 Cu-doped CdZnS QDs with NIR-fluorescence emission, an ultrasmall size (∼ 3.5 nm) and long-decay (lifetime up
to ∼ 1 μs) were introduced by recently by Chen et al as
lifetime-based pH nanosensors for in vivo imaging. 262 Ultrasmall
ZnS and iron-doped ZnS QDs can be stabilized with mercaptoethanol in aqueous solution. 263 These NPs form strong
complexes with bovine serum albumin. Mercaptopropionic
acid-coated InAs/InP/ZnSe QDs (b 10 nm) showed high tumor
uptake in mice, moderate renal clearance and considerable liver
accumulation. Tumor uptake can be significantly enhanced when
QDs additionally coated with human serum albumin. The
presented data do not allow drawing conclusions about the
chemical and in particular in vivo stability of QDs stabilized with
mercaptopropionic acid. 252 Hydrophilic QDs stabilized with
mercaptopropionic acid can be meanwhile prepared by aqueous
one-pot synthesis. 264,265 In vivo tumor targeting has been
demonstrated with mercaptopropionic acid-coated CdTe/CdS QDs
equipped with folic acid as targeting vector. 265 Gadolinium-doped
CdTe QDs (5 nm) stabilized in aqueous solution by glutathione have
been proven for dual imaging of mice tumors by MRI and
fluorescence imaging. 266 However, compounds with two thiolane
groups like DHLA are more suitable than monodentate ligands. Dual
modal ultrasmall nanoprobes have been reported based on
gadolinium-functionalized CdHgTe/ZnS core-shell QDs coated
with DHLA and DHLA-PEG. 267 QDs stabilized with DHLA-sulfobetaine ligands have been utilized for functional live-cell
imaging. 268,269 Interestingly, the hydrodynamic diameters of
zwitterionic QDs were even smaller than those functionalized with
DHLA alone. 270 The limited long-term stability of QDs coated with
bidentate monozwitterionic ligands observed in vitro can be
considerably improved by tetradentate monozwitterionic as well as
multidentate polyzwitterionic ligands. 271,272 PEG-thiolate protected
CdSe QDs (b 2 nm) possess unique solubility properties and can be
applied for intracellular imaging as demonstrated for fibroblasts. 273
CdS QDs (2-3 nm) have been coated with the biopolymer chitosan
that was covalently conjugated with an anti-CD-20 polyclonal
antibody. 274 These QDs-immunoconjugates showed binding affinity in vitro to CD20 overexpressed in lymphocyte-B cancer cells.
Water-soluble InAs/CdZnS, CdSe/CdS and CdSe/CdZnS QDs
(∼10 nm) have been fabricated by coating with sulfo- and
carboxybetaine-functionalized poly(imidazole) ligands. Detailed in
vitro and in vivo studies demonstrated that zwitterionic-coated QDs
exhibit weak nonspecific binding to serum proteins. In contrast,
PEGylated QDs show virtually no binding to serum proteins.
Interestingly, zwitterionic-coated QDs were significantly faster
cleared through liver and spleen than the PEGylated QDs. 275
Very recently the group of Zhang and Huang introduced
ultrasmall black phosphorus QDs that they synthesized from bulk
crystals by different methods. 276,277 Using a simple liquid
exfoliation technique combining probe as well as bath sonication,
they obtained nanosheets with a lateral size of ∼ 2.6 nm and a
1673
thickness of ∼ 1.5 nm. Their stability in physiological medium and
biocompatibility was enhanced by PEGylation and their high
potential as photothermal agents upon NIR excitation was
impressively demonstrated. 276
Silicon nanoparticles
Ultrasmall silicon nanoparticles (Si NPs) are attracting
increasing interest because of their properties and their
biocompatibility. Si NPs represent a good alternative to classical
semiconductor QDs since they retain the properties of semiconductors, bright tunable luminescence and high resistance against
photobleaching, but, at variance of classical QDs, they are highly
biocompatible. 278 It has been already reported that porous silicon
nanoparticles are biodegradable and the degradation products are
easily cleared through the kidneys in mice. 279-281 Photoluminescence properties of Si NPs are strongly dependent both from
quantum confinement and surface functionalization effects. 282
The first evidence that silicon emits when its size shrinks to
the nanoscale, is reported in the work of Canham et al who
observed red emission in silicon nanowires in 1990. 283 Many
efforts have been done to understand deeply the nature of this
luminescence and the debate on the explanation of emission
properties in silicon nanoparticles is still open and sometimes
controversial.
The deepest reason of the emission properties of silicon
nanoparticles is attributed to the quantum confinement effect, but
fluorescence can be strongly influenced also from defects in the
structure of the particles, 284,285 from surface functionalization
effects and from the synthetic route followed for the preparation
of the NPs. 282,286-289
Silicon nanoparticles are characterized also by an excellent
photophysical and chemical stability and a great advantage relies
on the possibility to exploit the well-known chemistry of silicon
surfaces by functionalizing the particles with different groups
through a very stable Si-C bond.
The preparation of ultrasmall Si NPs is still challenging and
the purification is a critical step. Silicon nanoparticles can be
prepared by several different methods. 290,291 In particular they
can be obtained by several chemical, physicochemical or
physical methods, involving either top-down or bottom-up
approaches. Usually, top-down methods can produce high pure
samples but, with bottom-up techniques the control of the size
and the surface termination of the particles is much higher.
Physical and physicochemical methods include top-down
techniques such as ball milling, 292,293 electrochemical etching,
laser ablation as well as gas phase reactions and pyrolysis
techniques. 291,294,295
Here we will focus mainly on bottom-up techniques which can be
divided in four main different kinds of synthesis: the reduction of a
silicon precursor, 296-306 the oxidation of a silicon precursor, 307-311
microwave-assisted reductions or oxidations 312-314 and high
temperature thermal reduction of silsesquioxanes 282,315-319. An
example for each kind of synthesis is shown in Figure 7. All these
methods are based on the reduction or oxidation, under inert
atmosphere, of a silicon precursor, either in the presence or the
absence of a surfactant, to produce hydrogen or halogen-terminated
Si NPs. In most of the reactions, the obtained NPs are further
1674
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
Figure 7. Four examples of bottom-up synthesis of ultrasmall silicon nanoparticles: reduction of a silicon source (X = OMe, Cl, Br; reducing agent = LiAlH4,
NaBH4, LiBH4 or superhydride; surfactant = tetraoctyl ammonium bromide (TOAB), pentaethylene glycol monododecyl ether (C12E5), tetrabutyl ammonium
bromide (TBAB), cetyltrimethyl ammonium bromide (CTAB), didodecyldimethyl ammonium bromide (DDAB), dodecyltrimethyl ammonium bromide
(DTAB) or tetradodecyl ammonium bromide (TDAB); R = amine, alkyl chain, epoxy group, alkenyl chain) 297-302; oxidation of a silicon source (R = alkyl
chain, alkenyl chain) 307,311; microwave-assisted synthesis 312; thermal decomposition of hydrogen silsesquioxanes (R = amine, alkyl chain, epoxy group,
alkenyl chain). 282,315-319
functionalized through a hydrosilylation step, catalyzed by a Pt
catalyst or by UV irradiation, or through the reaction with
alkyllithium reagents. Both, the kind of surfactant and/or the
reducing agent used influence dramatically the final size obtained.
In conclusion bottom-up techniques give the opportunity to
functionalize the surface of the particles with several different
groups ranging from alkyl or alkenyl chains to amine-, epoxy-,
alkoxy-, and azide-groups. Usually the size of the particles
obtained with these methods is very small, but the emission
properties can change from blue to red according to the synthetic
method used.
Several are the in vitro experiments reported with Si NPs and
here we will report only about few examples. The group of
Ruckenstein 320 and the group of Tilley 298 were the first to test
ultrasmall Si NPs in vitro reporting, respectively, that polyacrylic
acid coated red-emitting Si NPs are interacting with the surface
of Chinese hamster ovary (CHO) cells and that blue-emitting
amine-terminated Si NPs are taken up by HeLa cells and
distributed uniformly inside the cytosol. Si NPs were, later,
tested through MTT (3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl
tetrazolium bromide) assay to show how different surface
functionalization can influence the cytotoxicity of these
nanoparticles. 321-324 In these studies, it has been found that
amine-terminated Si NPs, that are usually positively charged, are
more toxic, if compared with their neutral and carboxylic-terminated analogues. Yamaguchi et al show how internalization in
cells is influenced by surface functionalization and size of Si
NPs. 325 Two kind of functional groups (allylamine and block
copolymer Pluronic F127) and two different sizes (few tens of
nanometers and N 100 nm) of Si NPs were incubated in live and
fixed human umbilical vein endothelial cells (HUVECs). When
using live HUVECs, amine-terminated nanoparticles always
aggregate selectively in lysosomes independently from their size.
Instead, F127-functionalized Si NPs selectively label either the
endoplasmatic reticulum (ER) or the lysosomes, depending on
their size. Si NPs have been also coupled with single-strand
DNA 326-328, folic acid 329 or carbohydrates 330,331. Sugar-terminated Si NPs exhibit very low cytotoxicity in comparison with
amine-terminated Si NPs and are more readily internalized by
cancer cells than by healthy cells. 330 Very recently, ultrasmall
sugar-capped SiNPs were utilized to analyze low-affinity
interactions between cancer-associated glycosphingolipids by
surface plasmon resonance measurements and confocal fluorescence microscopy. 331
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
Kauzlarich et al doped Si NPs with iron or manganese to
obtain a multimodal agent both for magnetic and optical
imaging. 332-334 Manganese doped Si NPs functionalized with
dextran can be used as a dual imaging probe, both for MRI and
near-infrared, excited two-photons imaging. These NPs are
non-toxic for mammalian cells and accumulate, in specific way,
in the macrophages. This is an important result since
atherosclerotic plaques that are vulnerable to rupture are usually
associated with a high density of macrophages. The group of
Kauzlarich was also the first to perform in vivo biodistribution
experiments on ultrasmall Si NPs. 333 Indeed, the authors report on
positron emission tomography (PET) of mice using dextran coated
manganese doped Si NPs that are functionalized with a 64Cu
complex. The particles are rapidly excreted by renal filtration, but
they also accumulate in liver. This is probably due to the distribution
of sizes in the sample: smaller particles are rapidly excreted and
bigger ones accumulate in the liver.
Erogbogbo et al described the preparation of Si NPs, by laser
pyrolysis of silanes, with different sizes (from 2 to 8 nm) and a
range of photoluminescence wavelength from 450 to 900 nm. 335
The Si NPs obtained were subsequently encapsulated in
phospholipidic micelles and conjugated with RGD peptides
which are highly specific for integrins overexpressed in the
tumor vasculature. Micelle-encapsulated RGD-Si NPs and
micelle-encapsulated Si NPs were injected through tail vein in
tumor bearing mice and the in vivo fluorescence imaging at
different post-injection times is shown in Figure 8. The
luminescence intensity in the tumor site increases with time
when RGD-particles are used, but in the case of particles without
RGD functionalization, no uptake was observed. With the same
kind of particles, the authors were able also to perform mapping
of sentinel lymph nodes and multicolor near-infrared imaging in
live mice.
Carbon-based nanoparticles
The peculiar properties of carbon based nanoobjects as
graphene, nanotubes, fullerene and nanodiamond have, especially in the last decade, attracted the attention of many scientists
and most recently the carbon “quantum” dots (CQDs) or carbon
dots (CDs), are conquering the biomedical scene. These
quantum-sized (b 10 nm) luminescent carbon particles, could
represent in the future a valid alternative to the “conventional”
semiconductor QDs, with the advantage that CDs normally do
not present the undesirable toxicity known for classic QDs (e.g.
CdSe, ZnS, etc.…), eliciting great interest for possible biomedical
applications.
As reported for other nanomaterials, two kind of strategies
can be applied to obtain CDs: the “top-down” approach, breaking
down other larger carbon structures (e.g. graphite, nanotubes,
etc.…) or the “bottom-up” approach where the CDs are formed
from smaller precursor, molecular components (e.g. citrate,
carbohydrate, ascorbic acid, etc.). 336-338
Xu and co-workers were investigating an electrophoretic
purification method of single-walled nanotubes obtained by
arc-discharge soot, when they isolated for the first time this new
class of nanomaterial as a side product. This mixture of
luminescent NPs was the first example of CDs. 339 Sun et al in
1675
2006 prepared CDs via laser ablation of a carbon target in the
presence of water vapor with argon as carrier gas, followed by an
acid-treatment with nitric acid. The so-prepared sample was a
mixture of non-emissive NPs with size around 5 nm, however
after surface passivation by using diamine-terminated oligomeric
polyethylene glycol (PEG), the CDs exhibited bright luminescence
emission. 340 Interesting 3 nm CDs were prepared by electrochemical
shocking of multi wall carbon nanotubes by Zhou et al. 341
The “bottom-up” approach has some advantages, such as
giving a more controlled composition and physicochemical
properties. In the last years, several synthesis methods have been
reported to prepare CDs, the majority involving the carbonization of organic or other carbon rich precursors. 336,338,342
Bourlinos and co-workers synthesized CDs via thermal decomposition of different ammonium citrate salts. 342 Peng and
Travas-Sejdic synthesized 5 nm CDs by dehydrating carbohydrates with concentrated sulfuric acid, followed by breaking the
carbonaceous materials into individual particles with nitric acid,
and finally passivating with amine-terminated compounds
(4,7,10-trioxa-1,13-tridecanediamine). 343 Also several “green”
synthesis have been recently reported starting from biocompatible precursors as biomass, 344 candle soot, 345 orange juice, 346
ascorbic acid, 347 etc. mainly using hydrothermal/solvothermal
treatment or microwave irradiation. 336-338
While some “naked” CDs can be luminescent, in general CDs
with efficient surface passivation present stronger and more
stable luminescence properties. Wang et al for example reported
the synthesis of 4 nm CDs with oligomeric PEG diamine
(PEG1500N) exhibiting bright green luminescence with emission
quantum yield close to 60%. 348 N-doped 349-352 in particular, but
also S-doped 353 and P-doped 354 CDs (and doping with other
heteroatoms) can significantly enhance the emission performances. However, at the moment CDs exhibiting high quantum
yield are still rare.
Numerous reports show the potential of CDs in biomedicine as
in vitro/in vivo bioimaging (straightforward cell imaging to specific
tissue targeting), 338,346,349,355,356 biosensing (e.g. for pH variation,
detection of heavy metals or other different kind of ions), 357-361 drug
release 362 and as photodynamic therapy agent 342.
However, some significant problems related to their uncertain
structure composition and to difficulties in obtaining a “clean”,
unique, well defined product have to be solved in order to give
them a concrete future in nanomedicine.
Pharmacokinetics of ultrasmall nanoparticles
Despite the enormous potential of NPs as multimodality agents
with both diagnostic and therapeutic capabilities, challenges for
extended biological and medicinal applications remain. Primarily,
this includes particle toxicity and biocompatibility as well as
unfavorable pharmacokinetics and biodistribution interfering with
diagnostic imaging. Developing agents with ideal pharmacokinetic
behavior will reduce toxicity risks due to minimized exposure times
as a consequence of rapid removal from the body. A combination of
key factors including size, shape, composition, surface chemistry
and charge affects tremendously the pharmacokinetics and biodistribution of NPs in vivo. For detailed information and secondary
references, we highly recommend the excellent review articles by
1676
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
Li et al, Moghimi et al and Lin et al, whereas the latter
clearly summarizes the pharmacokinetics of different inorganic
NPs. 6,363,364
During systemic circulation after intravenous administration,
NPs encounter blood as a highly complex fluid composed of a
wide variety of substances including salts, sugars, proteins as
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
well as amino acids that can destabilize NPs and can cause their
aggregation. Depending on the surface properties of the NPs,
biological macromolecules, such as serum proteins and lipids,
adsorb non-specifically and a dynamic biomolecular corona is
formed. This opsonization consequently leads to NP recognition
as well as uptake by mononuclear phagocytic cells, to removal
from the circulation and - despite their very small size - to
accumulation in the organs of the MPS such as liver and
spleen. 33,257 In addition to this increased scavenging by the
MPS, corona formation alters the effective size of intravascular
NPs and results in an in vivo NP diameter, which may be
significantly larger than the corresponding in vitro diameter.
On one hand, the decoration of the NP surface with
biocompatible polymers preventing undesirable adsorption of
biological macromolecules and phagocyte uptake represents a
successful strategy to minimize the interaction with the MPS. In
particular, the surface modification with charge-neutral, highly
hydrophilic, anti-fouling polymers, such as the attachment of
polyethylene glycol chains (PEGylation), has been extensively
investigated and widely used. Additionally, several zwitterionic
materials have been studied recently as alternative biocompatible
coating materials for different NP platforms. For detailed information on these aspects and secondary references, we direct the
interested reader to several comprehensive review articles. 10,365
On the other hand, the size, shape and charge of intravascular
NPs massively influence the interaction with the MPS as well as
enormously impact the circulatory lifetimes and excretion
pathways in vivo. 92,94,366
Renal clearance
Upon intravenous injection, circulating NPs distribute in the
body and flow along with the blood stream into the
kidneys. 5,367,368 These organs possess a myriad of microscopic
filtration units called renal corpuscles, each of which is
composed of a dense capillary network (glomerulus) and a
Bowman’s capsule (Figure 9). The endothelium of the
glomerular capillaries possesses pores (fenestrae) and is
surrounded by the highly negatively charged glomerular
basement membrane (GBM). Around the capillaries, a squamous
epithelium with characteristic extensions is formed by epithelial
cells (podocytes). During the ultrafiltration process, glomerular
fluid leaves the blood, passes first through the fenestrae, across
the GBM and then through the slit pores formed by spaces
between podocyte extensions. Since fenestrae and slit pores have
a maximal diameter, glomerular filtration is highly dependent on
molecule size. 369 As a consequence, USNPs with an in vivo
hydrodynamic diameter of b 6 nm are filtered charge-independently, while those N 8 nm bypass the filtration process, remain
in the circulation and exit the glomerulus via the efferent
1677
arterioles. NPs within the 6-8 nm range are filtered through the
glomerular capillary wall depending on their charge. Particles
with cationic surfaces are more readily filtered than their equally
sized counterparts possessing anionic surfaces due to electrostatic repulsion by negative charges of the GBM. After
transglomerular passage into the Bowman’s space, NPs may be
reabsorbed within the proximal tubule, transported from the
lumen to the renal interstitium and further into the circulatory
system. Also accumulation of nanomaterials in kidney cells was
observed that may lead to nephrotoxicity. 370,371 NPs remaining
in the non-reabsorbed filtrate (tubular fluid) pass through to the
collecting duct to form urine, which finally exits the kidneys,
enters the bladder through the ureters and is excreted via
the urethra.
While renal elimination minimizes the residence time of NPs
in the body, it is nonetheless considered as the preferred route for
the removal of non-biodegradable materials. In particular, renal
clearance is a highly desirable trait for diagnostic NPs in order to
reduce retention in non-targeted tissue, to achieve reasonable
signal-to-background ratios shortly after injection by efficient
excretion of unbound probe from the body and to minimize
NP toxicity.
Landmark work addressing the issue of renal NP clearance
was carried out by Choi and colleagues. 257,372 Upon intravenous
administration of coated (CdSe)ZnS core-shell QDs with welldefined hydrodynamic diameters ranging from 4.36 to 8.65 nm
into rodents as a model system, they precisely defined an
absolute value for the kidney filtration threshold of ∼ 5.5 nm.
Furthermore, the charge of the coating had a severe effect on the
non-specific binding of serum proteins and on the hydrodynamic
diameter of the QDs. By now, considerable numbers of
publications reporting on renal clearable NPs composed of
different materials 64,373-375 including gadolinium-, 194,199,213
gold- 39-41,376-380 and silica- 210,211,381 based NPs as well as
CDs 382 and QDs 258,383,384 have been published that essentially
confirm the fundamental findings of Choi et al.
While these rules generally apply for spherical NPs, they
appear to be not true for nanomaterials with different shapes and
high aspect ratios such as carbon nanotubes. Several groups
observed immediate and efficient urinary elimination of single
walled carbon nanotubes, although these structures largely
exceed the structural sizes of glomerular pores. 385,386
Very recently, Liang et al systematically investigated the
biodistribution of anionic ultrasmall QDs with a hydrodynamic
diameter of ∼ 3.7 nm after intravenous injection. Also being
smaller than the kidney filtration threshold, these USNPs failed
to be renally excreted most likely due to the repulsion between
the negatively charged particles and the anionic GBM.
Consequently, they gradually accumulate in the kidneys, while
cationic QDs of similar size were excreted into urine. 387
Figure 8. Time-dependent in vivo luminescence imaging of Panc-1 tumor bearing mice (left shoulder, indicated by white arrows) injected with ∼ 5 mg of
micelle-encapsulated RGD-Si NPs (A-E) and of micelle-encapsulated Si NPs (K-O). The autofluorescence and the Si NPs signals are in green and red
respectively. Images (F-J) and images (P-T) correspond to the luminescence images (A-E) and (K-O), respectively. In (U,W) ex vivo images and in (V,X)
luminescence images of tumours at 40 h post-injection in mice treated with micelle-encapsulated RGD-Si NPs (U,V) or with micelle-encapsulated Si NPs
(W,X). Reprinted with permission from ACS Nano, In vivo targeted cancer imaging, sentinel lymph node mapping and multi-channel imaging with
biocompatible silicon nanocrystals. Volume 5, Issue 1, 2011, pp. 413-423, F. Erogbogbo, K. T.Yong, I. Roy, R. Hu, W. C. Law, W. Zhao, H. Ding, F. Wu, R.
Kumar, M. T. Swihart, and P. N. Prasad, Fig. 2.335 Copyright (2011) American Chemical Society.
1678
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
Figure 9. Renal clearance of ultrasmall nanoparticles. Circulating nanoparticles of different size (yellow b6 nm; green 6-8 nm; red N8 nm) enter the Bowman’s capsule via
the afferent arteriole. During ultrafiltration, particles with an in vivo hydrodynamic diameter of b6 nm (yellow) pass the glomerular capillaries through the fenestrations of
their endothelium and across the negatively charged glomerular basement membrane (GBM). Finally, these particles permeate through the slit pores formed by spaces
between podocyte extensions into the Bowman’s space. Nanoparticles N 8 nm (red) bypass the filtration process, remain in the circulation and exit the glomerulus via the
efferent arterioles. Positively charged nanoparticles with intermediate in vivo diameter of 6-8 nm (green) are more readily filtered than their equally sized counterparts
possessing anionic surfaces due to electrostatic repulsion by negative charges of the GBM. After ultrafiltration, nanoparticles reach the proximal tubule, the site of
reabsorption. The non-reabsorbed filtrate passes through to the collecting duct to form urine, which finally exits the kidneys.
The particle size reduction below the kidney filtration threshold
often implicates the alteration or loss of their unique features and
functionalities 388, such as the fluorescence properties of QDs, the
brightness of upconversion materials or the superparamagnetic
properties of iron oxide NPs. A promising approach to retain these
valuable characteristics while ensuring fast clearance kinetics
through renal excretion is the fabrication of biodegradable inorganic
NPs. Upon their controlled in vivo disassembly into smaller
non-toxic fragments, they are rapidly cleared via kidney, bladder
and urine. Sailor and co-workers successfully pursued this strategy
by creating luminescent porous Si NPs with a mean hydrodynamic
diameter of N 100 nm that disintegrate in the liver and spleen into
soluble silicic acid within a few days. 280,389 At least since the
publication of these successful studies, research activities investigating the potential of biodegradable inorganic nanomaterials in the
field of nanomedicine have gained momentum. 390-394 However, it is
beyond the scope of this review to discuss topic of biodegradable
inorganic nanocomposites in detail.
In summary, renal ultrafiltration is a size-, charge- and
shape-dependent process due to the unique architecture and structure
of the glomerular capillaries. Intravascular particles with an in vivo
diameter of around 5-6 nm or less are able to efficiently pass through
the pores of the glomerulus in the kidneys and are thus rapidly
cleared from the circulatory system via bladder and urine. NPs with
intermediate in vivo diameter of up to 8 nm are filtered depending
on their surface charge, whereas positive ones are eliminated
faster than negative or neutral ones. For larger non-biodegradable
particles, the hepatobiliary system represents the only alternative
mode of elimination.
Hepatic clearance
NPs bypassing the renal filtration process will inevitably end
up in the spleen and in the liver. 5,367 The latter organ has a dual
vascular supply, whereas it receives oxygenated, arterial blood
from the hepatic artery as well as blood that have previously
passed through the intestine and spleen via the hepatic portal
vein (Figure 10). Both, venous as well as arterial blood is mixed
in the liver capillaries (sinusoids) and then exits the liver through
the hepatic veins. The hepatic sinusoids are lined mainly by liver
sinusoidal endothelial cells (LSECs) and resident liver macrophages (Kupffer cells). Both cell types, also collectively referred
to as scavenger cells, are responsible for most of the liver uptake
of intravascular NPs. 395-398
The very thin LSECs act as a filter between the lumen of the
hepatic sinusoids and the surrounding hepatocytes, which is
achieved by the presence of numerous transcellular pores in
LSECs (fenestrae). In addition to the number of fenestrae, also
their diameter varies from species to species. For example,
diameters ranging from 50-300 nm have been described for
humans. 399 Soluble substances and NPs smaller than these pores
pass from the sinusoids into a sub-endothelial space (space of
Disse) and come directly in contact with underlying hepatocytes.
These specialized epithelial cells, which represent the most
abundant type of cell in the liver, have many microvilli
projecting into this space for maximized absorption of material
from the blood. Upon internalization by hepatocytes, NPs are
subjected to intracellular enzymatic breakdown potentially
leading to the disruption of the surface coating, dissolution of
ions out of the inorganic crystal core as well as release of toxic
metals. 249,251,400-403 After being slowly degraded by these cells,
NP metabolites are potentially secreted by hepatocytes into the
bile and finally excreted with the faces. 404,405
As mentioned above, Kupffer cells and LSECs represent the
major cell types responsible for liver uptake and metabolism of
NPs. Bargheer and co-workers studied the distribution of
radiolabeled QDs in the liver and demonstrated their colocalization with LSECs as well as with Kupffer cells, but not with
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
Figure 10. Hepatobiliary excretion of nanoparticles. Circulating nanoparticles come in contact with liver sinusoidal endothelial cells (LSECs) and
Kupffer cells, collectively referred to as scavenger cells. Both types of cells
effectively eliminate nanoparticles from the blood circulation, whereas these
materials are endocytosed and lysosomally metabolized if possible.
Nanoparticles smaller than the transcellular pores of LSECs pass into the
space of Disse and are internalized by hepatocytes. After being slowly
enzymatically degraded, nanoparticle metabolites are secreted into the bile
and finally excreted with the faces.
hepatocytes. 398 In accordance with these results, both cell
populations exhibit similar uptake patterns and metabolism rates
of SPIONs, whereas the material was taken up via scavenger
receptor-mediated endocytosis and digested in the
lysosomes. 402,406-409 The uptake and accumulation of non-degradable can stimulate free radical release which may result in
cell damage and inflammation. 410-415 If the NPs are transferred
into the lysosomal compartment but are not biodegradable, they
potentially accumulate there and trigger cell death. 416-419
Targeting of ultrasmall nanoparticles
Passive targeting
Nanoparticulate materials with in vivo hydrodynamic diameters above the glomerular filtration threshold and blood
residence times of at least 6 h substantially accumulate and
retain in tumors through the enhanced permeability and retention
(EPR) effect (Figure 11). 420-423 This passive targeting depends
on the pathophysiological vascular architecture of many tumors,
whereas the tumor microvascular endothelium possesses increased permeability to nanomaterials as well as minimal lymph
drainage. 422,424 Being an accumulative process, this passive
extravasation favors nanomaterials with long blood retention
time. 425,426 Renal clearable USNPs with short blood half-lives
are therefore less prone to passive tumor targeting as they rapidly
diffuse back to the vasculature and re-enter the systemic
circulation, which results in only transient intratumoral presence
without substantial retention. However, Zheng and co-workers
observed considerable passive in vivo tumor targeting of
1679
Figure 11. Size-restricted penetration of a solute through porous membranes.
The ordinate (A/A0) indicates relative effective area for penetration in porous
membranes, where A0 indicates the whole area of pore surfaces. The solid
and broken lines assume the pore radius of 50 nm and 300 nm, respectively.
As the radius of a solute increases, its permeation becomes more restricted
depending on the pore radius. Reprinted from Advanced Drug Delivery
Reviews, Pharmacokinetic considerations for targeted drug delivery. Volume
65, Issue 1, 2013, pp. 139-147. F. Yamashita and M. Hashida, Fig. 2.423
Copyright (2013) with permission from Elsevier.
ultrasmall luminescent gold NPs due to their relatively long
elimination half-life of 8.5 h and slow renal elimination. 41,42,427
To prevent the rapid efflux of passively accumulated USNPs
from the tumor by increasing the interactions between NPs and
tumor cells as well as by improving cellular NP uptake, the
strategy of active or ligand-mediated targeting is pursued.
Active targeting
This approach in general is based on the attachment of
targeting molecules to the NP surface, for which a multitude of
bioconjugation methods are available. 365 These targeting
molecules enable NPs to selectively recognize certain membrane
receptors or antigens on target cells and they can facilitate
cellular internalization through specific interactions such as
receptor-mediated endocytosis. 420
As the molecular targets of actively-targeted NPs are usually
located in the extravascular space of the tumor, ligand-mediated
targeting relies to a large extend on passive extravasation. Only
after leaving the leaky tumor vasculature and upon penetration
into the interstitium, these NPs are able to bind to and interact
with tumor cells. Subsequent efficient internalization may lead to
prolonged retention in the malignant tissues by preventing rapid
efflux from the tumor. 420,428
A variety of targeting molecules including small organic
molecules, peptides, aptamers, carbohydrates as well as proteins,
antibodies and their fragments have been exploited for active
targeting of nanomaterials so far. 429 However, in order to
maintain the hydrodynamic diameter below the kidney filtration
threshold, large targeting molecule such as whole antibody
molecules are not taken into account for renal excretable USNPs
(Figure 12). In this context, it should always be carefully
considered that the biodistribution of the actively-targeted
USNPs might be altered or even dominated by relatively large
targeting moieties.
1680
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
Figure 12. Targeting molecules for ultrasmall nanoparticles include small organic molecules (e.g. folate), peptides (e.g. bombesin), aptamers as well as proteins
of low molecular weight (e.g. nanobodies and affibodies). The hydrodynamic diameter of the targeting molecules add to a greater or lesser extent to the overall
size of the nanoparticulate conjugate, which has been considered when aiming for the creation of renal clearable materials. The structure of the nanobody was
adapted from PDB structure 3DWT. 532
Peptidic targeting units
One of the most popular strategies to actively target USNPs
involves the covalent attachment of small molecules such as
cyclic peptides containing the Arg-Gly-Asp (RGD) amino acid
sequence. 430 These peptides display a strong affinity and
selectivity to cell adhesion integrin αvβ3 that is abundant on
tumoral endothelial cells as well as on various cancer cells. 431-435
The covalent conjugation of RGD peptides to ultrasmall
QDs, 59,436-439 SiO2, 172,440,441 iron oxide, 442-446 silicon, 447 and
gold NPs 448 resulted in their considerable accumulation in
αvβ3-positive tumor cells. A substantial body of work has been
carried out by the team of Wiesner designing ∼ 6 to 7-nm
multimodal core-shell SiO2 NPs termed Cornell dots or
C-dots. 381,449 These FDA-approved particles were PEG-coated,
surface-functionalized with cyclic RGD peptides and radiolabeled with iodine-124. After demonstrating the binding affinity
and specificity to αvβ3-overexpressing cells in vitro, tumor-selective targeting of these particles was shown in vivo using
xenografted αvβ3-overexpressing and αvβ3-nonexpressing
tumors. 172 Two years later, this group described the utilization
of such particles for image-guided intraoperative sentinel lymph
node mapping. 440 In a first-in-human clinical trial these αvβ3targeting probes were administered to patients with metastatic
melanoma. After single-dose injection, particle biodistribution
and tumor uptake were analyzed using positron emission
tomography. Results obtained during this pilot clinical trial
point to largely renal elimination of functionalized particles with
estimated whole-body clearance half-times of 13-21 h and show
some accumulation of the particle tracer at the lesion sites of
several patients. 441
High selective tumor uptake upon injection of ultrasmall silver
sulfide QDs functionalized with cyclic RGD into a αvβ3overexpressing murine tumor model was observed by Tang et al
very recently. Moreover, the authors impressively demonstrated
rapid extravasation of these agents as well as in vitro and in vivo
receptor-specific cellular internalization (Figure 13). 59
Alternative molecular targets addressable by small peptidic
molecules include the somatostatin receptors, gastrin-releasing
peptide receptors, melanocortin receptors, neurotensin receptors,
glucagon-like peptide-1 receptors, and different growth factor
receptors as well as the cholecystokinin receptors. 450-454
Although the somatostatin tetradecapeptide binds to its
receptors with high affinity, it possesses only a limited practical
value due to its short biological half-life of less than three
minutes. For that reason peptide analogs with improved in vivo
stability and thus with prolonged circulation time were developed
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
1681
Figure 13. Representative in vivo fluorescence imaging of luminescent silver sulfide (Ag2S) functionalized with the cyclic peptide, arginine-glycine-aspartic
acid-(D)phenylalanine-lysine (cRGDfk) in 4T1luc tumor-bearing Balb/c mouse at different time points after intravenous administration. Circles indicate bilateral
subcutaneous tumor locations. Red color: quantum dot fluorescence. Reprinted with permission from ACS Nano, Tunable ultrasmall visible-to-extended
near-infrared emitting silver sulfide quantum dots for integrin-targeted cancer imaging. Volume 9, Issue 1, 2015, pp. 220-30, R. Tang, J. Xue, B. Xu, D. Shen, G.
P. Sudlow, and S. Achilefu, Fig. 6.59 Copyright (2015) American Chemical Society.
by circularization and introduction of D-amino acids. As a result,
stabilized eight amino acid analogs termed octreotide and octreotate
containing the bioactive core sequence were successfully created and
intensively studied for tumor targeting. 453,455-457 Consequently, also
the generation of NPs conjugated with different somatostatin
derivatives has been described, 458-463 however, satisfactory in vivo
data of ultrasmall inorganic counterparts is according to the authors'
knowledge still missing.
The tetradecapeptide bombesin of amphibian origin as well as
its human equivalent, the 27-amino-acid gastrin-releasing
peptide, bind strongly and specifically to their molecular target,
which is overexpressed in various human tumor entities
including breast, prostate, small cell lung and pancreatic cancer.
Based on these peptides, various different analogs have been
developed 464-466 and utilized for active NP targeting 467-474,
whereas only a few of these inorganic NP conjugates were
investigated in vivo. 470,471,474 Very recently, Jafari et al
functionalized dextran-coated iron oxide NPs with bombesin
analogs resulting in sub-10 nm bioconjugates that were utilized
for diagnostic in vivo targeting of breast tumors by MRI. 474
Compared to more complex targeting units such as
antibodies, antibody fragments or other proteins, small molecule
targeting units often suffer from in vivo instability. In particular,
peptides are extremely sensitive to peptidases and are rapidly
degraded due to cleavage of peptide bonds by a variety of
proteolytic enzymes present in most tissues. Their utilization as
targeting units thus necessitates the design of metabolically
stable derivatives with prolonged in vivo half-life, e.g. by
cyclization. 453,475 However, such considerable attempts can
significantly influence the biodistribution as well as the binding
to a molecular target and even result in a loss of affinity. 476-478
Other small molecule targeting units
Besides peptidic targeting units, folic acid represents a
well-known and intensively used molecule to achieve active
tumor targeting nanomaterials. 479-481 The expression of the
corresponding receptor is selectively upregulated in many human
malignancies including ovarian carcinomas as well as carcinomas of the kidney, endometrium, lung, breast, bladder, and
pancreas. 482,483 Because of its very small size, folate appears to
be a very attractive targeting unit in particular for
USNPs. 265,484-487 For instance Chen et al took advantage of
this small molecule to design targeting ultrasmall CdTe/CdS
near-infrared-emitting QDs for the detection folate-receptor-positive tumors by in vivo fluorescence imaging. Four hours after
intravenous injection of the optical imaging probe, the tumor was
distinguishable from neighboring tissues due to the accumulation
of the QDs at the target site and the emission of a bright
fluorescence. 265
The team of Babich designed a series of small molecule
inhibitors to target the extracellular domain of prostate-specific
membrane antigen in prostate cancer cells and tissue 488 that they
used after radiolabeling for the in vivo localization of PSMA
expressing tumors by SPECT/CT imaging. 489 These lowmolecular-weight lysine-urea-glutamate analogues (Figure 12)
were shown to bind specifically and with high affinity to
PSMA-positive cells with subsequent cellular internalization.
Moreover, high selectivity for PSMA-expressing tissues was
confirmed by SPECT/CT imaging using PSMA-positive and
PSMA-negative xenografts. 489 Hrkach et al took advantage of a
constituent of these novel PSMA-ligands termed ACUPA
(S,S-2-[3-[5-amino-1-carboxypentyl]-ureido]-pentanedioic acid)
for the preclinical development and clinical translation of
PSMA-targeted polymeric NPs 490 that are currently undergoing
evaluation in a phase 2 clinical trial in patients with non-small
cell lung cancer (designated BIND-014, Accurin). 491
Based on the Glu-NH-CO-NH-Lys pharmacophore, PSMA
inhibitors for PET imaging and endoradiotherapy of prostate
cancer were developed at the German Cancer Research Center
Heidelberg (DKFZ) and successfully applied in patients. 492-498
1682
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
Notwithstanding these successes and the significant progress
already achieved, 499 small PSMA inhibitors have barely been
investigated with regard to active targeting of USNPs. Recently
Felber et al functionalized the surface of gold NPs with a
lysine-urea-glutamate containing PSMA inhibitor, but observed
only minimal tumor uptake and massive accumulation in liver
and spleen, most likely due to the negative surface charge of the
NPs and their hydrodynamic diameter of ∼ 14 nm. 500 Moderate
PSMA-specific tumor accumulation of 68Ga-labeled iron oxide
nanoparticles functionalized with lysine-urea-glutamate moieties
was observed by PET/MR imaging. However, also substantial
MPS trapping of the ∼ 11 nm-sized imaging probes was
detectable already 1 h after tail vein injection into PSMA-positive and PSMA-negative xenografts. 501
Proteinaceous targeting units
Due to their innate high molecular weight well above the
kidney filtration threshold, large proteins such as whole antibody
molecules (≥ 150 kDa), transferrin (∼ 80 kDa) and albumin
(∼ 67 kDa) are obviously unsuitable to achieve targeting, renal
clearable USNPs. In contrast, the compact dimensions of a
variety of antibody fragments and small proteins allow their
utilization as targeting units for this family of nanomaterials.
Affibodies represent a new group of robust target-specific
binding agents derived from staphylococcal protein A. The
amino acid sequence of these low molecular weight (6-7 kDa)
molecules can be randomized in order to create large libraries,
from which binders with high affinity to a desired molecules can
be selected using phage display technology. 502 By implementing
this strategy, Orlova and colleagues obtained several HER2binding affibody molecules with dissociation equilibrium
constants in the picomolar range. 503,504 Although several groups
highlighted the very promising development of nanoparticleaffibody bioconjugates for molecular imaging of EGFR- and
HER2-positive tumors, 505-511 there is according to the author’s
knowledge no report describing the utilization of affibodies as
targeting units for USNPs so far.
Unlike affibodies, nanobodies specifying the unique antigenbinding domains of heavy-chain antibodies, 512 are generated by
immunization of camelids. After cloning the coding sequences of
the produced single-domain antigen-binding fragments into
appropriate phage-display vectors, nanobodies are selected by
consecutive rounds of phage display and panning on solid-phase
coated antigens. 513,514 Their small size, high in vivo stability,
excellent shelf life and solubility as well as their economic high
level production and purification represent the most striking
advantages of nanobodies over conventional antibodies. 513 Due
to their dimensions in the low nanometer range far below the
renal cutoff for glomerular filtration, these molecules can be used
as highly specific diagnostic tools for molecular imaging
applications 515,516 and as novel therapeutic agents. 517-519
For example, the team of Lahoutte revealed the translational
potential of these antibody fragments in their recent phase I study
using anti-HER2-nanobodies labelled with 68Ga. 520
Furthermore, their capability to act as tumor targeting unit for
a variety of inorganic nanomaterials has been impressively
demonstrated several times. 521-532 However, up to now, no in
vivo data on nanobody-functionalized USNPs is available. Of
particular interest in this context are the findings of Sukhanova
et al: the oriented conjugation of QDs possessing a hydrodynamic diameter of 8.8 nm with nanobodies resulted in
bioconjugates with a hydrodynamic diameter of 11.9 nm. 525
This increase in size provoked by attachment of these 14-15 kDa
targeting units of 3.1 nm must be taken into consideration when
aiming for the creation of renal clearable NPs. The conjugation
of 6-7 kDa affibodies likewise resulted in an increase in the
hydrodynamic diameter of 4.2 and 4.6 nm for iron oxide NPs 510
and gold-iron oxide NPs 509, respectively.
Nucleic acid based targeting units
Aptamers are single-stranded oligonucleotides, either of
deoxyribonucleic acid or ribonucleic acid composition, with
unique tertiary conformations due to intramolecular WatsonCrick interactions. These non-toxic and non-immunogenic
nucleic acid probes bind to target antigens with high affinity
and specificity with dissociation equilibrium constants in the
nanomolar to picomolar range, comparable to those of
monoclonal antibodies. Moreover, aptamers can be produced
rapidly and reproducibly by automated synthesis as well as
chemically modified in many different ways. 533,534 These merits
enable aptamers to operate as targeting units of diverse NP
platforms for different medical applications including cell sorting
and sensing as well as targeted imaging and therapy. 535,536
Among the molecular targets of anti-tumor aptamer-functionalized inorganic NPs for cancer diagnosis and therapy are the
prostate-specific membrane antigen, 537-543 cell surface
nucleolin, 544-550 the epidermal growth factor receptor 551-553 as
well as the transmembrane glycoprotein mucin 1. 554-557
Noteworthy, sub-10 nm fluorescent QDs functionalized with
DNA aptamers specific for mucin 1 were designed by Zhang
et al. 556 Their specific interaction with the respective molecular
target as well as their strong binding to mucin 1-positive cells
was confirmed in vitro and in vivo by confocal microscopy and
fluorescence imaging, respectively.
A direct comparison between aptamer- and antibody-conjugated NPs with respect to binding affinity and selective targeting
of the epidermal growth factor receptor was made by Melancon
et al. 553 After radiolabeling with indium-111, pharmacokinetics
and biodistribution of the equally sized particles were investigated in tumor-bearing nude mice. These experiments as well as
micro-SPECT/CT imaging studies indicate that aptamer-coated
NPs possess shorter blood circulation time, faster systemic
clearance and higher tumor uptake than their antibody-conjugated counterparts.
Despite enormous potential, the suitability of aptamers as
targeting unit for nanoparticulate probes is questionable for
several reasons including their in vivo stability and effectiveness,
the considerable costs for their large-scale production, the
negative charge of their sugar-phosphate backbone as well as
their spatial dimensions in the range of proteins adding to the
intrinsic size of the respective core particles. 420,535 Since the
latter aspects can have tremendous effects on the pharmacokinetic profile of prospective nanomaterials, these key issues need
to be addressed in order to step forward from the preclinical
proof-of-principle to clinical development stages.
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
1683
Figure 14. Schematic drawing of the structure of nanoparticle-protein complexes in plasma: the “core” nanoparticle is surrounded by the protein corona
composed of an outer weakly interacting layer of protein (left, full red arrows) rapidly exchanging with a collection of free proteins and a “hard” slowly
exchanging corona of proteins (right). Reprinted with permission from the Journal of the American Chemical Society, What the cell "sees" in bionanoscience.
Volume 132, Issue 16, 2010, pp. 5761-5768, D. Walczyk, F. B. Bombelli, M. P. Monopoli, I. Lynch, and K. A. Dawson, Fig. 1b. 587 Copyright (2010) American
Chemical Society.
(Un)importance of active targeting for nanoparticle delivery
From the large number of studies conducted to create and
investigate actively targeting nanomaterials, no definitive
conclusions have been drawn regarding the relative contributions
of active versus passive targeting in NP delivery. Moreover,
there is an ongoing controversial debate concerning the influence
of ligand-mediated targeting on total NP accumulation in a solid
tumor. 420,428,558 Since the EPR effect for renal clearable USNPs
with a short residence time in the body is less a decisive factor,
their intracellular uptake and tumor retention can be attributable
mainly to active targeting. Therefore, future intensive research
on these designer agents will indicate the extent to which
ligand-mediated targeting contributes to total NP accumulation
in malignant tissues.
Corona formation
The Vroman effect has been observed when NPs are
suspended in biological fluids such as human serum (or
blood). 559,560 The biomolecules such as proteins present in
biofluids, entering into contact with the NPs surface, can be
adsorbed forming the so-called protein corona. The bio-corona
may play a key role in the in vivo biological fate establishing the
bio-identity of the NPs. 9,561,562 Differential protein adsorption
can potentially lead, for example, to different organ distribution
by interacting with different tissue specific receptors or
recognized by different macrophage subpopulations (concept
of “differential adsorption”). 563 The protein corona can normally
be divided in two component called hard corona and soft corona
(Figure 14). The hard corona consists in proteins interacting with
the NPs in a relatively strong way, bonded to the surface; the soft
corona is the dynamic component concerning the proteins that
interact with the hard corona, but are subjected to exchange with
the surrounding proteins present in the biological fluid according
to their abundance and their binding affinities to the NPs surface,
determined by biokinetics rules. 564 It has also been observed that
different materials and of course different surface functionalization can lead to the formation of different protein corona. 565-567
The size differences can be a discriminative parameter concerning the interaction of the NPs with the environmental
proteins. 565-567 The curvature changing of the surface of NPs
can also influence the arrangement of the protein structure
exposing, for example different epitopes that can activate
different receptors. 568,569 So far several studies have been
performed identifying the corona composition of “bigger” NPs
(from 10 to 200 nm), however just a very few reports are present
in literature investigating bio-nano interaction of sub-10 nm NPs.
Considering that most of plasma proteins present a hydrodynamic diameter of about 3-15 nm, the corona of NPs b 3 nm
could be dramatically different respect of the classical model
described for bigger particles.
Kreyling et al reported the investigation of the corona
proteins of 5, 15 and 80 nm gold NPs functionalized with
bis-sulfonatedtriphenylphosphine. 570 After 24 h of incubation in
mouse serum, the corona proteins were isolated and treated with
sodium dodecyl sulfate (SDS) and separated using SDS-polyacrylamide gel electrophoresis (SDS-PAGE). Interestingly, after
staining the gel showed decreasing amount of protein per NP
with the increasing of the NPs size. At the same total of surface
areas (30 cm 2), 80 nm AuNPs bound the smallest fraction of total
protein which is less than 10% in respect of the 15 nm AuNPs
and less than 30% in respect of 5 nm AuNPs. In this example, the
higher is the surface curvature, the higher the protein binding
capacity per surface area. 571 On the other hand, Benetti and
co-worker, investigating the corona formed in human blood for
different sizes of AuNPs (10, 60 and 200 nm), found a highest
total amount of bound proteins for the bigger NPs (200 nm). 572
The study reported by Mahmoudi and collaborators concern
SPIONs incubate in fetal bovine serum (FBS), including
ultrasmall sizes with a core between 3.5 and 15 nm. 573 In this
1684
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
case, proteins with low molecular weights were preferentially
adsorbed onto the surface of smaller NPs and vice-versa larger
proteins with larger NPs.
At the moment the results reported on the bio-corona of
ultrasmall NPs are still rare and sometimes controversial. To
precisely define the bio-corona of a NP is highly complex,
especially in the ultrasmall range; however it represents a crucial
step in order to obtain engineered nanomedicine for concrete
future applications.
Nanoparticle interaction with cells
NPs possess an appropriate size to engage with the
endogenous cellular machinery, thus permitting uptake through
active energy processes. 574,575 Depending on their surface
chemistry, NPs have the potential to trigger cellular pathways,
however this is also dependent on the exposure conditions and
the dose accumulated in cells. 576-578 The role of adsorbed
biomolecules derived from the environment significantly
modifies the NP surface in such a manner that the bionanointeractions are radically different from those suggested by the bare
material itself (Figure 15, A). 579,580 Furthermore, the presence of
physiologically relevant protein concentrations reduces the NP
dose and thus modulates NP induced cytoxicity. 561,581,582
It is now recognized that most non-targeting NPs and the
adsorbed corona proteins enter the cells and accumulate in the
lysosomes (Figure 15, B). 583 A cytometry-based method has
been developed to distinguish between NP degradation, export
and effects of cell division. In many instances, the NPs are not
exported and continue to accumulate in the lysosomes without
acute toxic response, with the internalized load diluting over time
as the cell divides. 584,585 However, some NPs have been shown
to induce cell death. Amino-modified polystyrene particles have
been studied for their toxic impacts. Lysosomal degradation of
the corona proteins can lead to lysosomal damages, cytosolic
release of the lysosomal content and ultimately apoptosis. 351 At
lower doses, cell death levels remain low while cell cycle
progression is arrested. 586
In an effort to determine biological outcomes, current
targeting strategies involve the conjugation of bio-functional
moieties to NPs. However, NP grafting of targeting molecules
(even where the protein remains functional) does not simply
imply recognition by the corresponding receptors. Requisite
surface characterization is still considered to be one of the main
limiting factors in the practical understanding of how functionalized nanomaterials interact with biological assemblies. It has
been established that in the increased complexity of a biological
environment NPs are exposed to fluid characteristics which can
greatly lower targeting efficiency, such as adsorptive events
(protein corona), competition for molecular recognition at target
receptors, as well as possible agglomerating conditions. 9,565,587
Functionalization to specifically interact with selected
receptor targets, while avoiding non-specific interactions, has
proven to be complex issue when moving beyond serum free in
vitro conditions to more realistic protein rich biological
environments. Different targeting vectors may be affected in
different ways by the biological environment, ranging from
Figure 15. The protein corona screens the positive charges of amino modified
polystyrene nanoparticles (PS-NH2) and delays their impact on cells. (A)
Propidium iodide (PI) permeability of 1321N1 cells treated with 50 μg/mL
PS-NH2-S in the absence and presence of proteins (sfDMEM and cDMEM,
respectively). PI permeability was used as indicator of plasma membrane
integrity, and showed that in serum free conditions strong effects could be
detected on membrane permeabilization, already after 1 h. However, the
early membrane permeabilization was not observed when the nanoparticles
were suspended in cDMEM and cell death was observed only at later times.
(B) Schematic representation of the impact of PS-NH2 nanoparticles exposed
to cells in different conditions: as shown by the results in panel A, in the
absence of serum (left), the PS-NH2 nanoparticles damage the cell membrane
leading to quick cell membrane permeabilization; in the presence of serum
(right) PS-NH2 nanoparticles are covered by a protein corona which screens
their positive charges, and is retained during nanoparticle uptake and until
trafficked to the lysosomes. In the lysosomes the corona is degraded and this
is followed by lysosomal membrane permeabilization and ultimately cell
death.Reprinted with from Nanomedicine: Nanotechnology, Biology and
Medicine, The biomolecular corona is retained during nanoparticle uptake
and protects the cells from the damage induced by cationic nanoparticles until
degraded in the lysosomes. Volume 9, Issue 8, 2013, pp. 1159-1168, F.
Wang, L. Yu, M. P. Monopoli, P. Sandin, E. Mahon, A. Salvati, K. A.
Dawson, Fig. 5.583 Copyright (2013) with permission from Elsevier.
complete loss of specificity to partial loss. 530,562 Thus there is a
need to understand more effectively why and, if possible, to
provide design prompts for future conjugation strategies,
including more advanced characterization approaches and
subsequent in vitro testing performed in media containing
relevant molecules to ensure that the exposure is meaningful.
Furthermore, the interaction between proteins within the
corona and cell receptors may give rise to “non-specific” or
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
non-targeted uptake and clearance of the NPs from the
circulation by the liver. Although it is clear that NP size and
shape are key factors in determining uptake, it is suggested that
biological recognition is driven those biomolecules taken from
the biological milieu, and that this is expected to dominate
cellular uptake and ultimately such issues as biodistribution.
However, for new materials these ideas will have to be
significantly evolved.
Application of ultrasmall nanomaterials in nanomedicine
The exceptional nature of all sorts of nanomaterials has
without any doubt opened up a multitude of imaginable
applications in the field of nanomedicine and nanobiology
ranging from drug and gene delivery, biomarker mapping,
molecular sensing and separation to isolation, tracking and
manipulation of biological molecules and cells as well as
diagnostic imaging and treatment of diseases. 588,589
Due to their specific pharmacokinetic properties and good
tissue penetration, renal excretable USNPs qualify for special
purposes for which NPs with long retention time in the body are
not suitable. These included first and foremost their diagnostic
application as molecular imaging agents since this requires fast
and specific accumulation at target sites within few hours.
Combined with rapid excretion from non-targeted tissues, this
allows faster imaging after injection and results in high
signal-to-background ratios. 7,590 Owing to these obvious
advantages, various USNPs have been proposed as exogenous
contrast agents for different imaging modalities. A considerable
body of literature has been accumulated particularly on T1 and
T2 contrast agents for MRI including ultrasmall superparamagnetic Co NPs, 68 USPIONs, 96,100,102,108,109,116,118,121,123,
124,127,132
MnO NPs, 1 5 0 - 1 5 3 and lanthanide-based
195-203,209,210,213,219
. Near-infrared absorbing NPs have
NPs
been considered for photoacoustic imaging, 34,65 while near-infrared emitting ultrasmall Au 41-43 and Ag NPs 58,59 as well as
UCNPs, 234 semiconductor QDs 250, 263-265,439 and fluorescent
dye labeled USNPs 170,381,440,441,484,591 have been developed as
optical imaging probes. Additionally, some of these ultrasmall
nanoparticulate probes have been utilized as intraoperative
visualization tools during image-guided surgical and interventional procedures. 439,440,591
Depending on the attached or incorporated radiolabel, USNPs
can be either applied for SPECT 40,211 or PET 45,62,64,172,235,441
imaging. For example, Zhou et al synthesized radioactive
[ 198Au]AuNPs with a core size and hydrodynamic diameter
of ∼ 2.6 nm and ∼ 3.0 nm, respectively, by one-step thermal
reduction of 197Au and 198Au ions in the presence of glutathione.
Since these renal clearable particles emit in addition to gamma
rays also near-infrared light upon excitation at 470 nm, they are
proposed as dual-modality imaging probes for optical and
SPECT imaging. 40 Although direct integration of radionuclides
into the structure of the nanomaterials allows chelator-free
radiolabeling, 592 it requires complete chemical resynthesis
whenever the respective NPs are needed due to the nuclear
decay of the radioisotopes. 40,45,62,64,235 Depending on the
complexity of the synthesis, this might necessitate special
1685
technical equipment as well as professional chemical competence
and could hinder their clinical translation. In contrast, chelator
functionalized NPs can be synthesized in reasonable amounts prior
to their application, distributed and stored depending on their shelf
life and radiolabeled on demand by a clinical technician in a standard
nuclear medicine laboratory. 102,530,593
In addition to diagnostic molecular imaging, ultrasmall paramagnetic gadolinium oxide NPs and USPIONs have been applied
for direct cell labeling and tracking experiments. 98,99,204-206 This
technique in principle involves the incubation of cells such as
endothelial, stem or tumor cells ex vivo with appropriate NPs and
subsequent implantation by local or systemic injection. As cell
tracking allows the noninvasive monitoring of cells at anatomical
resolution as well as the assessment of their distribution and
migration in vivo over a short period of time, it has become a
valuable tool in preclinical research on various diseases. 594,595
In a recent study, Di Corato et al used ultrasmall iron oxide
and gadolinium oxide NPs to simultaneously image and track
endothelial cells and stem cells, respectively, at cellular level in
vitro and in vivo. 204 The former kind of USNPs is known as
negative contrast agents reducing the T2 relaxation time, which
eventually leads to quenching or even loss of the MRI signal.
Vice versa, paramagnetic gadolinium oxide NPs belong to the
group of positive contrast agents reducing the T1 relaxation time,
thereby enhancing the MRI signal. Consequently, cells labeled
with USPIONs appear as dark spots in T2-weighted images,
whereas those containing gadolinium oxide NPs appear white on
T1-weighted images. This dual labeling approach allows
noninvasive tracking of different cell types at high resolution
and the manipulation of their localization by application of an
external magnetic field.
Besides their applications as nanodiagnostics, USNPs
have been discussed as nanotherapeutics for the treatment of
diseases, primarily cancer, through nanomaterial-enabled
radiosensitization, 3 7 , 3 8 , 1 8 1 , 2 1 2 , 2 1 5 - 2 1 8 , 5 9 6 photothermal
therapy, 64,65,276,597,598 photodynamic therapy, 599 magnetic
hyperthermia 89 and drug delivery 600,601.
USNPs containing chemical elements with a high atomic
number (high Z elements) such as Au, Gd, Hf, Ag, Pt or Bi can
act as radiosensitizers that scatter and/or absorb incident
radiation (gamma or X-rays) and reemit radiation energy in the
form of photons or electrons. Auger electrons, for example,
induce the formation of ROS by radiolysis of water molecules
and thereby cause oxidative damage to surrounding cells and
tissues. 602 Sancey et al summarized recently experimental data
regarding the radiosensitizing effect of ultrasmall gadolinium-containing NPs. Since these non-toxic nanoparticulate materials have
been identified not only as adequate MRI agents for tumor diagnosis
but also as efficient radiosensitizers for cancer therapy, they possess
without a doubt significant potential as theranostic agents. 603
Summary and conclusions
A vast number of nanoparticulate materials have been
intensively investigated and proposed for a variety of medicinal
applications within the last decade, in particular for diagnosis
and therapy of cancer, due to the unique properties of these
1686
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
7
materials. Recently, boosting research has been devoted to USNPs
as these materials display properties, such as size as well as
physicochemical and pharmacokinetic characteristics, which are at
the interface between molecules and larger particles. 4 This review
has provided a comprehensive overview of the current scenario of
preparation, surface modification, characterization and biomedical
applications of the most thoroughly investigated and emerging
inorganic USNP platforms. Of particular importance is their
potential systemic clearance via the renal pathway once they possess
appropriate surface characteristics and their size is below the kidney
filtration threshold. As not all USNPs can per se be cleared renally,
we recommend using the pharmacological term “renal excretable
nanoparticles” to differentiate them in the future from standard NPs
as too large for renal elimination.
Although a tremendous amount of outstanding research has
been published on this particular subset of nanomaterials, a wide
variety of issues remain unexplored, unclear or unexplained.
This concerns in particular the interactions of USNPs with
individual cells including intracellular trafficking and precise
targeting of certain cellular organelles e.g. mitochondria. As
mentioned before, future research should furthermore shed light
on the extent to which ligand-mediated targeting contributes to
total NP accumulation at the pathological site.
With regard to the application of renal excretable NPs in the
field of nanomedicine, it has to be stated that extremely exciting
and sophisticated ideas have been conceived. However, their
clinical translation often fails due to unresolved regulatory
challenges. Here primarily a scalable, controlled and reproducible synthesis procedure resulting in defined, highly monodisperse and uniform products under GMP conditions is an essential
prerequisite. This problem commonly faced also for bigger NPs
get exacerbated in the ultrasmall range where even small
differences in size and shape have a tremendous impact on
blood circulation time, biodistribution and elimination of NPs.
Another major issue is related to the characterization: the
available techniques to characterize NPs are often not suitable for
USNPs, due to instrumental limit of detection. Moreover, a lack of a
precise surface characterization, once again lead to deeper
consequences for USNPs resulting in inconsistent outcomes in in
vivo and in vitro tests. Perfectly reproducible USNPs samples are
therefore a challenging goal and, in order to achieve this objective, it
will be necessary to radically improve the synthesis methods as well
as find alternative characterization protocols and methods. This issue
is of fundamental importance for a meaningful study of biological
interactions and pharmacokinetics of renal excretable NPs.
Finally, clear benefits of renal excretable nanoparticulate
materials over conventional probes and drugs already in clinical
practice are only rarely demonstrated yet. Thus, many critical
studies addressing the pros and cons of these materials have to be
conducted in the future to deploy their full medical potential and
to increase the clinical impact of renal excretable nanodiagnostics and nanotherapeutics.
References
1. Kharissova OV, Kharisov BI, Jimenez-Perez VM, Munoz Flores B,
Ortiz Mendez U. Ultrasmall particles and nanocomposites: State of the
art. RSC Adv 2013;3:22648-82.
2. Nützenadel C, Züttel A, Chartouni D, Schmid G, Schlapbach L. Critical
size and surface effect of the hydrogen interaction of palladium clusters.
Eur Phys J D 2000;8:245-50.
3. McBride JR, Dukes III AD, Schreuder MA, Rosenthal SJ. On
ultrasmall nanocrystals. Chem Phys Lett 2010;498:1-9.
4. Kim BH, Hackett MJ, Park J, Hyeon T. Synthesis, characterization, and
application of ultrasmall nanoparticles. Chem Mater 2014;26:59-71.
5. Longmire M, Choyke PL, Kobayashi H. Clearance properties of nanosized particles and molecules as imaging agents: Considerations and
caveats. Nanomedicine (Lond) 2008;3:703-17.
6. Lin Z, Monteiro-Riviere NA, Riviere JE. Pharmacokinetics of metallic
nanoparticles. Wiley Interdiscip Rev Nanomed Nanobiotechnol
2015;7:189-217.
7. Baetke SC, Lammers T, Kiessling F. Applications of nanoparticles for
diagnosis and therapy of cancer. Br J Radiol 2015:20150207.
8. Albanese A, Tang PS, Chan WC. The effect of nanoparticle size, shape,
and surface chemistry on biological systems. Annu Rev Biomed Eng
2012;14:1-16.
9. Monopoli MP, Åberg C, Salvati A, Dawson KA. Biomolecular coronas
provide the biological identity of nanosized materials. Nat Nanotechnol
2012;7:779-86.
10. Pombo Garcia K, Zarschler K, Barbaro L, Barreto JA, O'Malley W,
Spiccia L, et al. Zwitterionic-coated "stealth" nanoparticles for
biomedical applications: Recent advances in countering biomolecular
corona formation and uptake by the mononuclear phagocyte system.
Small 2014;10:2516-29.
11. Giljohann DA, Seferos DS, Daniel WL, Massich MD, Patel PC, Mirkin
CA. Gold nanoparticles for biology and medicine. Angew Chem Int Ed
Engl 2010;49:3280-94.
12. Duncan B, Kim C, Rotello VM. Gold nanoparticle platforms as drug
and biomacromolecule delivery systems. J Control Release
2010;148:122-7.
13. Dreaden EC, Alkilany AM, Huang X, Murphy CJ, El-Sayed MA. The
golden age: Gold nanoparticles for biomedicine. Chem Soc Rev
2012;41:2740-79.
14. Leifert A, Pan-Bartnek Y, Simon U, Jahnen-Dechent W. Molecularly
stabilised ultrasmall gold nanoparticles: Synthesis, characterization and
bioactivity. Nanoscale 2013;5:6224-42.
15. Shang L, Dong SJ, Nienhaus GU. Ultra-small fluorescent metal
nanoclusters: Synthesis and biological applications. Nano Today
2011;6:401-18.
16. Leifert A, Pan Y, Kinkeldey A, Schiefer F, Setzler J, Scheel O, et al.
Differential hERG ion channel activity of ultrasmall gold nanoparticles.
Proc Natl Acad Sci U S A 2013;110:8004-9.
17. Jin R. Quantum sized, thiolate-protected gold nanoclusters. Nanoscale
2010;2:343-62.
18. Dreaden EC, Mackey MA, Huang X, Kang B, El-Sayed MA. Beating
cancer in multiple ways using nanogold. Chem Soc Rev
2011;40:3391-404.
19. Patra CR, Bhattacharya R, Mukhopadhyay D, Mukherjee P. Fabrication of gold nanoparticles for targeted therapy in pancreatic cancer. Adv
Drug Deliv Rev 2010;62:346-61.
20. He Z, Zhong A, Zhang H, Xiong L, Xu Y, Wang T, et al. In situ
formation of dual-phase thermosensitive ultrasmall gold nanoparticles.
Chemistry 2015;21:10220-5.
21. Schmid G. Metal-Clusters and Cluster Metals. Polyhedron
1988;7:2321-9.
22. Turkevich J, Stevenson PC, Hillier J. A study of the nucleation and
growth processes in the synthesis of colloidal gold. Discuss Faraday
Soc 1951:55 [&].
23. Kimling J, Maier M, Okenve B, Kotaidis V, Ballot H, Plech A.
Turkevich method for gold nanoparticle synthesis revisited. J Phys
Chem B 2006;110:15700-7.
24. Brust M, Fink J, Bethell D, Schiffrin DJ, Kiely C. Synthesis and
reactions of functionalised gold nanoparticles. J Chem Soc Chem
Commun 1995:1655.
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
25. Link S, Beeby A, FitzGerald S, El-Sayed MA, Schaaff TG, Whetten
RL. Visible to infrared luminescence from a 28-atom gold cluster. J
Phys Chem B 2002;106:3410-5.
26. Martin MN, Basham JI, Chando P, Eah SK. Charged gold nanoparticles
in non-polar solvents: 10-min synthesis and 2D self-assembly. Langmuir 2010;26:7410-7.
27. Zhao WA, Gonzaga F, Li YF, Brook MA. Highly stabilized nucleotidecapped small gold nanoparticles with tunable size. Adv Mater
2007;19:1766 [+].
28. Tsunoyama H, Tsukuda T. Magic numbers of gold clusters stabilized
by PVP. J Am Chem Soc 2009;131:18216-7.
29. Wang ZJ, Zhang QX, Kuehner D, Ivaska A, Niu L. Green synthesis of
1-2 nm gold nanoparticles stabilized by amine-terminated ionic liquid
and their electrocatalytic activity in oxygen reduction. Green Chem
2008;10:907-9.
30. Kim YG, Oh SK, Crooks RM. Preparation and characterization of 1-2
nm dendrimer-encapsulated gold nanoparticles having very narrow size
distributions. Chem Mater 2004;16:167-72.
31. Khlebtsov N, Dykman L. Biodistribution and toxicity of engineered
gold nanoparticles: A review of in vitro and in vivo studies. Chem Soc
Rev 2011;40:1647-71.
32. De Jong WH, Hagens WI, Krystek P, Burger MC, Sips AJ, Geertsma
RE. Particle size-dependent organ distribution of gold nanoparticles
after intravenous administration. Biomaterials 2008;29:1912-9.
33. Semmler-Behnke M, Kreyling WG, Lipka J, Fertsch S, Wenk A,
Takenaka S, et al. Biodistribution of 1.4- and 18-nm gold particles in
rats. Small 2008;4:2108-11.
34. Poon W, Heinmiller A, Zhang X, Nadeau JL. Determination of
biodistribution of ultrasmall, near-infrared emitting gold nanoparticles
by photoacoustic and fluorescence imaging. J Biomed Opt
2015;20:066007.
35. Hainfeld JF, Slatkin DN, Focella TM, Smilowitz HM. Gold nanoparticles: A
new X-ray contrast agent. Br J Radiol 2006;79:248-53.
36. Luo Z, Yuan X, Yu Y, Zhang Q, Leong DT, Lee JY, et al. From
aggregation-induced emission of Au(I)-thiolate complexes to ultrabright Au(0)@Au(I)-thiolate core-shell nanoclusters. J Am Chem Soc
2012;134:16662-70.
37. Zhang XD, Chen J, Luo Z, Wu D, Shen X, Song SS, et al. Enhanced
tumor accumulation of sub-2 nm gold nanoclusters for cancer radiation
therapy. Adv Healthc Mater 2014;3:133-41.
38. Zhang XD, Luo Z, Chen J, Song S, Yuan X, Shen X, et al. Ultrasmall
glutathione-protected gold nanoclusters as next generation radiotherapy
sensitizers with high tumor uptake and high renal clearance. Sci Rep
2015;5:8669.
39. Zhou C, Long M, Qin Y, Sun X, Zheng J. Luminescent gold
nanoparticles with efficient renal clearance. Angew Chem Int Ed Engl
2011;50:3168-72.
40. Zhou C, Hao G, Thomas P, Liu J, Yu M, Sun S, et al. Near-infrared
emitting radioactive gold nanoparticles with molecular pharmacokinetics. Angew Chem Int Ed Engl 2012;51:10118-22.
41. Liu J, Yu M, Zhou C, Yang S, Ning X, Zheng J. Passive tumor targeting
of renal-clearable luminescent gold nanoparticles: Long tumor retention
and fast normal tissue clearance. J Am Chem Soc 2013;135:4978-81.
42. Liu J, Yu M, Ning X, Zhou C, Yang S, Zheng J. PEGylation and
zwitterionization: Pros and cons in the renal clearance and tumor
targeting of near-IR-emitting gold nanoparticles. Angew Chem Int Ed
Engl 2013;52:12572-6.
43. Wu X, He X, Wang K, Xie C, Zhou B, Qing Z. Ultrasmall near-infrared
gold nanoclusters for tumor fluorescence imaging in vivo. Nanoscale
2010;2:2244-9.
44. Huang K, Ma H, Liu J, Huo S, Kumar A, Wei T, et al. Size-dependent
localization and penetration of ultrasmall gold nanoparticles in cancer
cells, multicellular spheroids, and tumors in vivo. ACS Nano
2012;6:4483-93.
45. Zhao Y, Sultan D, Detering L, Luehmann H, Liu Y. Facile synthesis,
pharmacokinetic and systemic clearance evaluation, and positron
1687
64
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
emission tomography cancer imaging of Cu-Au alloy nanoclusters.
Nanoscale 2014;6:13501-9.
Pan Y, Neuss S, Leifert A, Fischler M, Wen F, Simon U, et al. Sizedependent cytotoxicity of gold nanoparticles. Small 2007;3:1941-9.
Pan Y, Leifert A, Graf M, Schiefer F, Thoroe-Boveleth S, Broda J, et al.
High-sensitivity real-time analysis of nanoparticle toxicity in green
fluorescent protein-expressing zebrafish. Small 2013;9:863-9.
Rizzo LY, Golombek SK, Mertens ME, Pan Y, Laaf D, Broda J, et al.
In vivo nanotoxicity testing using the zebrafish embryo assay. J Mater
Chem B Mater Biol Med 2013;1:3918-25.
Kim CK, Ghosh P, Pagliuca C, Zhu ZJ, Menichetti S, Rotello VM.
Entrapment of hydrophobic drugs in nanoparticle monolayers with
efficient release into cancer cells. J Am Chem Soc 2009;131:1360-1.
Moyano DF, Saha K, Prakash G, Yan B, Kong H, Yazdani M, et al.
Fabrication of corona-free nanoparticles with tunable hydrophobicity.
ACS Nano 2014;8:6748-55.
Murthy AK, Stover RJ, Hardin WG, Schramm R, Nie GD, Gourisankar
S, et al. Charged gold nanoparticles with essentially zero serum protein
adsorption in undiluted fetal bovine serum. J Am Chem Soc
2013;135:7799-802.
Mizuhara T, Saha K, Moyano DF, Kim CS, Yan B, Kim YK, et al.
Acylsulfonamide-functionalized zwitterionic gold nanoparticles for
enhanced cellular uptake at tumor pH. Angew Chem Int Ed Engl
2015;54:6567-70.
Lee HJ, Do MA, Kim EJ, Yeum JH, Ghim HD, Choi JH. Novel
synthesis of ultra-small silver nanoparticles with high antimicrobial
activity. Multi-Functional Materials and Structures, Pts 1 and 2, 47–
50; 2008. p. 1080-3.
Zheng KY, Yuan X, Goswami N, Zhang QB, Xie JP. Recent advances
in the synthesis, characterization, and biomedical applications of
ultrasmall thiolated silver nanoclusters. RSC Adv 2014;4:60581-96.
Raino G, Stoferle T, Park C, Kim HC, Topuria T, Rice PM, et al.
Plasmonic nanohybrid with ultrasmall Ag nanoparticles and fluorescent
dyes. ACS Nano 2011;5:3536-41.
Luo Z, Zheng K, Xie J. Engineering ultrasmall water-soluble gold and
silver nanoclusters for biomedical applications. Chem Commun
(Camb) 2014;50:5143-55.
Shang L, Dorlich RM, Trouillet V, Bruns M, Nienhaus GU. Ultrasmall
fluorescent silver nanoclusters: Protein adsorption and its effects on
cellular responses. Nano Res 2012;5:531-42.
Le Guevel X, Spies C, Daum N, Jung G, Schneider M. Highly
fluorescent silver nanoclusters stabilized by glutathione: A promising
fluorescent label for bioimaging. Nano Res 2012;5:379-87.
Tang R, Xue J, Xu B, Shen D, Sudlow GP, Achilefu S. Tunable
ultrasmall visible-to-extended near-infrared emitting silver sulfide
quantum dots for integrin-targeted cancer imaging. ACS Nano
2015;9:220-30.
Cheng ZP, Zhong H, Xu JM, Chu XZ, Song YZ, Xu M, et al. Facile
fabrication of ultrasmall and uniform copper nanoparticles. Mater Lett
2011;65:3005-8.
Brege JJ, Hamilton CE, Crouse CA, Barron AR. Ultrasmall copper
nanoparticles from a hydrophobically immobilized surfactant template.
Nano Lett 2009;9:2239-42.
Gao F, Cai P, Yang W, Xue J, Gao L, Liu R, et al. Ultrasmall [ 64Cu]Cu
nanoclusters for targeting orthotopic lung tumors using accurate
positron emission tomography imaging. ACS Nano 2015;9:4976-86.
Wang HY, Hua XW, Wu FG, Li B, Liu P, Gu N, et al. Synthesis of
ultrastable copper sulfide nanoclusters via trapping the reaction
intermediate: Potential anticancer and antibacterial applications. ACS
Appl Mater Interfaces 2015;7:7082-92.
Zhou M, Li J, Liang S, Sood AK, Liang D, Li C. CuS nanodots with ultrahigh
efficient renal clearance for positron emission tomography imaging and
image-guided photothermal therapy. ACS Nano 2015;9:7085-96.
Mou J, Li P, Liu C, Xu H, Song L, Wang J, et al. Ultrasmall Cu2-x S
nanodots for highly efficient photoacoustic imaging-guided photothermal therapy. Small 2015;11:2275-83.
1688
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
66. Chen JP, Sorensen CM, Klabunde KJ, Hadjipanayis GC. Magnetic
properties of nanophase cobalt particles synthesized in inversed
micelles. J Appl Phys 1994;76:6316-8.
67. Khanna SN, Linderoth S. Magnetic behavior of clusters of ferromagnetic transition metals. Phys Rev Lett 1991;67:742-5.
68. Parkes LM, Hodgson R, Lu le T, Tung le D, Robinson I, Fernig DG, et
al. Cobalt nanoparticles as a novel magnetic resonance contrast agent –
relaxivities at 1.5 and 3 Tesla. Contrast Media Mol Imaging
2008;3:150-6.
69. Lu LY, Yu LN, Xu XG, Jiang Y. Monodisperse magnetic metallic
nanoparticles: Synthesis, performance enhancement, and advanced
applications. Rare Metals 2013;32:323-31.
70. Sengupta J, Ghosh S, Datta P, Gomes A, Gomes A. Physiologically
important metal nanoparticles and their toxicity. J Nanosci Nanotechnol 2014;14:990-1006.
71. Al Samri MT, Silva R, Almarzooqi S, Albawardi A, Othman AR, Al
Hanjeri RS, et al. Lung toxicities of core-shell nanoparticles composed
of carbon, cobalt, and silica. Int J Nanomedicine 2013;8:1223-44.
72. Kobayashi Y, Horie M, Konno M, Rodriguez-Gonzalez B, Liz-Marzan
LM. Preparation and properties of silica-coated cobalt nanoparticles. J
Phys Chem B 2003;107:7420-5.
73. Batail N, Clémençon I, Legens C, Chaumonnot A, Uzio D. Controlled
synthesis and high oxidation stability of cobalt nanoparticles encapsulated in
mesoporous silica using a modified Stöber approach and a pseudomorphic
transformation. Eur J Inorg Chem 2013;2013:1258-64.
74. Margeat O, Amiens C, Chaudret B, Lecante P, Benfield RE. Chemical
control of structural and magnetic properties of cobalt nanoparticles.
Chem Mater 2005;17:107-11.
75. Zhang S, Lee J, Sun S. Controlled synthesis of monodisperse magnetic
nanoparticles in solution phase. Open Surf Sci J 2012;4:26-34.
76. Sun SH, Murray CB. Synthesis of monodisperse cobalt nanocrystals
and their assembly into magnetic superlattices. J Appl Phys
1999;85:4325-30.
77. Yang HT, Shen CM, Su YK, Yang TZ, Gao HJ, Wang YG. Selfassembly and magnetic properties of cobalt nanoparticles. Appl Phys
Lett 2003;82:4729-31.
78. Escalera E, Ballem MA, Cordoba JM, Antti ML, Oden M. Synthesis of
homogeneously dispersed cobalt nanoparticles in the pores of
functionalized SBA-15 silica. Powder Technol 2012;221:359-64.
79. Baaziz W, Florea I, Moldovan S, Papaefthimiou V, Zafeiratos S, BeginColin S, et al. Microscopy investigations of the microstructural change
and thermal response of cobalt-based nanoparticles confined inside a
carbon nanotube medium. J Mater Chem A 2015;3:11203-14.
80. Thanh NTK, Puntes VF, Tung LD, Fernig DG. Peptides as capping
ligands for in situ synthesis of water soluble Co nanoparticles for
bioapplications. In: Pankhurst Q, editor. Fifth International Conference
on Fine Particle Magnetism. London, England: IOP Publishing LTD,
Dirac House, Temple Back, Bristol BS1 6BE, England, Univ Coll
London; 2005. p. 70-6.
81. Thomas JR. Preparation and magnetic properties of colloidal cobalt
particles. J Appl Phys 1966;37:2914 [&].
82. Osorio-Cantillo C, Santiago-Miranda AN, Perales-Perez O, Xin Y.
Size- and phase-controlled synthesis of cobalt nanoparticles for
potential biomedical applications. J Appl Phys 2012;111:07B324.
83. Murray CB, Sun S, Doyle H, Betley T. Monodisperse 3d transitionmetal (Co, Ni, Fe) nanoparticles and their assembly into nanoparticle
superlattices. MRS Bull 2012;26:985-91.
84. Bönnemann H, Brijoux W, Brinkmann R, Matoussevitch N, Waldöfner
N, Palina N, et al. A size-selective synthesis of air stable colloidal
magnetic cobalt nanoparticles. Inorg Chim Acta 2003;350:617-24.
85. Bönnemann H, Brijoux W, Brinkmann R, Matoussevitch N, N. W..
Monodispersable magnetic nanocolloids having an adjustable size
and method for the production thereof; 2003 [Germany].
86. Behrens S, Bönnemann H, Matoussevitch N, Dinjus E, Modrow H,
Palina N, et al. Air-stable Co-, Fe-, and Fe/Co-nanoparticles and
ferrofluids. Z Phys Chem 2006;220:3-40.
87. Klostergaard J, Seeney CE. Magnetic nanovectors for drug delivery.
Nanomedicine 2012;8(Suppl 1):S37-50.
88. Scarberry KE, Dickerson EB, McDonald JF, Zhang ZJ. Magnetic
nanoparticle-peptide conjugates for in vitro and in vivo targeting and
extraction of cancer cells. J Am Chem Soc 2008;130:10258-62.
89. Fantechi E, Innocenti C, Zanardelli M, Fittipaldi M, Falvo E, Carbo M,
et al. A smart platform for hyperthermia application in cancer treatment:
Cobalt-doped ferrite nanoparticles mineralized in human ferritin cages.
ACS Nano 2014;8:4705-19.
90. Balla DZ, Gottschalk S, Shajan G, Ueberberg S, Schneider S, HardtkeWolenski M, et al. In vivo visualization of single native pancreatic islets
in the mouse. Contrast Media Mol Imaging 2013;8:495-504.
91. Benderbous S, Corot C, Jacobs P, Bonnemain B. Superparamagnetic
agents: Physicochemical characteristics and preclinical imaging
evaluation. Acad Radiol 1996;3(Suppl 2):S292-4.
92. Almeida JP, Chen AL, Foster A, Drezek R. In vivo biodistribution of
nanoparticles. Nanomedicine (Lond) 2011;6:815-35.
93. Gupta AK, Gupta M. Synthesis and surface engineering of iron oxide
nanoparticles for biomedical applications. Biomaterials
2005;26:3995-4021.
94. Ernsting MJ, Murakami M, Roy A, Li SD. Factors controlling the
pharmacokinetics, biodistribution and intratumoral penetration of
nanoparticles. J Control Release 2013;172:782-94.
95. Zhao X, Zhao H, Chen Z, Lan M. Ultrasmall superparamagnetic iron
oxide nanoparticles for magnetic resonance imaging contrast agent. J
Nanosci Nanotechnol 2014;14:210-20.
96. Laurent S, Forge D, Port M, Roch A, Robic C, Vander Elst L, et al.
Magnetic iron oxide nanoparticles: Synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications.
Chem Rev 2008;108:2064-110.
97. Zhang C, Wängler B, Morgenstern B, Zentgraf H, Eisenhut M,
Untenecker H, et al. Silica- and alkoxysilane-coated ultrasmall
superparamagnetic iron oxide particles: A promising tool to label
cells for magnetic resonance imaging. Langmuir 2007;23:1427-34.
98. Wang YXJ, Quercy-Jouvet T, Wang HH, Li AW, Chak CP, Xuan SH,
et al. Efficacy and durability in direct labeling of mesenchymal stem
cells using ultrasmall superparamagnetic iron oxide nanoparticles with
organosilica, dextran, and PEG coatings. Materials 2011;4:703-15.
99. Li Z, Yi PW, Sun Q, Lei H, Zhao HL, Zhu ZH, et al. Ultrasmall watersoluble and biocompatible magnetic iron oxide nanoparticles as
positive and negative dual contrast agents. Adv Funct Mater
2012;22:2387-93.
100. Sun S, Zeng H, Robinson DB, Raoux S, Rice PM, Wang SX, et al.
Monodisperse MFe2O4 (M = Fe, Co, Mn) nanoparticles. J Am Chem
Soc 2004;126:273-9.
101. Park JY, Daksha P, Lee GH, Woo S, Chang Y. Highly waterdispersible PEG surface modified ultra small superparamagnetic iron
oxide nanoparticles useful for target-specific biomedical applications.
Nanotechnology 2008;19:365603.
102. Pombo Garcia K, Zarschler K, Barreto JA, Hesse J, Spiccia L, Graham
B, et al. Design, synthesis, characterisation and in vitro studies of
hydrophilic, colloidally stable, 64Cu(II)-labelled, ultra-small iron oxide
nanoparticles in a range of human cell lines. RSC Adv
2013;3:22443-54.
103. Bumb A, Brechbiel MW, Choyke PL, Fugger L, Eggeman A,
Prabhakaran D, et al. Synthesis and characterization of ultra-small
superparamagnetic iron oxide nanoparticles thinly coated with silica.
Nanotechnology 2008;19:335601.
104. Martinez G, Malumbres A, Mallada R, Hueso JL, Irusta S, BomatiMiguel O, et al. Use of a polyol liquid collection medium to obtain
ultrasmall magnetic nanoparticles by laser pyrolysis. Nanotechnology
2012;23:425605.
105. Costo R, Bello V, Robic C, Port M, Marco JF, Puerto Morales M, et al.
Ultrasmall iron oxide nanoparticles for biomedical applications:
Improving the colloidal and magnetic properties. Langmuir
2012;28:178-85.
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
106. Malumbres A, Martinez G, Mallada R, Hueso JL, Bomati-Miguel O,
Santamaria J. Continuous production of iron-based nanocrystals by
laser pyrolysis. Effect of operating variables on size, composition and
magnetic response. Nanotechnology 2013;24:325603.
107. Kim BH, Lee N, Kim H, An K, Park YI, Choi Y, et al. Large-scale
synthesis of uniform and extremely small-sized iron oxide nanoparticles for high-resolution T1 magnetic resonance imaging contrast agents.
J Am Chem Soc 2011;133:12624-31.
108. Hu F, Jia Q, Li Y, Gao M. Facile synthesis of ultrasmall PEGylated iron
oxide nanoparticles for dual-contrast T1- and T2-weighted magnetic
resonance imaging. Nanotechnology 2011;22:245604.
109. Li Z, Wei L, Gao MY, Lei H. One-pot reaction to synthesize
biocompatible magnetite nanoparticles. Adv Mater 2005;17:1001-5.
110. Redl FX, Black CT, Papaefthymiou GC, Sandstrom RL, Yin M, Zeng
H, et al. Magnetic, electronic, and structural characterization of
nonstoichiometric iron oxides at the nanoscale. J Am Chem Soc
2004;126:14583-99.
111. Li Z, Chen H, Bao H, Gao M. One-pot reaction to synthesize watersoluble magnetite nanocrystals. Chem Mater 2004;16:1391-3.
112. Farrell D, Majetich SA, Wilcoxon JP. Preparation and characterization
of monodisperse Fe nanoparticles. J Phys Chem B 2003;107:11022-30.
113. Jana NR, Chen Y, Peng X. Size- and shape-controlled magnetic (Cr,
Mn, Fe, Co, Ni) oxide nanocrystals via a simple and general approach.
Chem Mater 2004;16:3931-5.
114. Li Y, Afzaal M, O'Brien P. The synthesis of amine-capped magnetic
(Fe, Mn, Co, Ni) oxide nanocrystals and their surface modification for
aqueous dispersibility. J Mater Chem 2006;16:2175-80.
115. Xiao L, Li J, Brougham DF, Fox EK, Feliu N, Bushmelev A, et al.
Water-soluble superparamagnetic magnetite nanoparticles with biocompatible coating for enhanced magnetic resonance imaging. ACS
Nano 2011;5:6315-24.
116. Hyeon T, Lee SS, Park J, Chung Y, Na HB. Synthesis of highly
crystalline and monodisperse maghemite nanocrystallites without a
size-selection process. J Am Chem Soc 2001;123:12798-801.
117. Taboada E, Rodriguez E, Roig A, Oro J, Roch A, Muller RN.
Relaxometric and magnetic characterization of ultrasmall iron oxide
nanoparticles with high magnetization. Evaluation as potential T1
magnetic resonance imaging contrast agents for molecular imaging.
Langmuir 2007;23:4583-8.
118. Park J, An K, Hwang Y, Park JG, Noh HJ, Kim JY, et al. Ultra-largescale syntheses of monodisperse nanocrystals. Nat Mater
2004;3:891-5.
119. Guardia P, Perez N, Labarta A, Batlle X. Controlled synthesis of iron
oxide nanoparticles over a wide size range. Langmuir 2010;26:5843-7.
120. Hu F, MacRenaris KW, Waters EA, Liang T, Schultz-Sikma EA,
Eckermann AL, et al. Ultrasmall, water-soluble magnetite nanoparticles
with high relaxivity for magnetic resonance imaging. J Phys Chem C
2009;113:20855-60.
121. Jia X, Chen D, Jiao X, Zhai S. Environmentally-friendly preparation of
water-dispersible magnetite nanoparticles. Chem Commun (Camb)
2009:968-70.
122. Wan J, Cai W, Meng X, Liu E. Monodisperse water-soluble magnetite
nanoparticles prepared by polyol process for high-performance
magnetic resonance imaging. Chem Commun (Camb) 2007:5004-6.
123. Park JY, Choi ES, Baek MJ, Lee GH, Woo S, Chang Y. Water-soluble
ultra small paramagnetic or superparamagnetic metal oxide
nanoparticles for molecular MR imaging. Eur J Inorg Chem
2009;2009:2477-81.
124. Cai W, Wan J. Facile synthesis of superparamagnetic magnetite
nanoparticles in liquid polyols. J Colloid Interface Sci 2007;305:366-70.
125. Gonçalves RH, Cardoso CA, Leite ER. Synthesis of colloidal magnetite
nanocrystals using high molecular weight solvent. J Mater Chem
2010;20:1167-72.
126. Babes L, Denizot B, Tanguy G, Le Jeune JJ, Jallet P. Synthesis of iron
oxide nanoparticles used as MRI contrast agents: A parametric study. J
Colloid Interface Sci 1999;212:474-82.
1689
127. Tartaj P, Morales MP, Veintemillas-Verdaguer S, Gonzalez-Carreño T,
Serna CJ. Synthesis, properties and biomedical applications of
magnetic nanoparticles. In: Buschow KHJ, editor. Handbook of
magnetic materials. Amsterdam, The Netherlands: Elsevier; 2006. p.
403-82.
128. Quarta A, Curcio A, Kakwere H, Pellegrino T. Polymer coated
inorganic nanoparticles: Tailoring the nanocrystal surface for designing
nanoprobes with biological implications. Nanoscale 2012;4:3319-34.
129. Li Z, Sun Q, Gao M. Preparation of water-soluble magnetite
nanocrystals from hydrated ferric salts in 2-pyrrolidone: Mechanism
leading to Fe3O4. Angew Chem Int Ed Engl 2004;44:123-6.
130. Hu F, Li Z, Tu C, Gao M. Preparation of magnetite nanocrystals with
surface reactive moieties by one-pot reaction. J Colloid Interface Sci
2007;311:469-74.
131. Shen LH, Bao JF, Wang D, Wang YX, Chen ZW, Ren L, et al. Onestep synthesis of monodisperse, water-soluble ultra-small Fe3O4
nanoparticles for potential bio-application. Nanoscale 2013;5:2133-41.
132. Ling D, Hyeon T. Chemical design of biocompatible iron oxide
nanoparticles for medical applications. Small 2013;9:1450-66.
133. Colombo M, Carregal-Romero S, Casula MF, Gutierrez L, Morales
MP, Böhm IB, et al. Biological applications of magnetic nanoparticles.
Chem Soc Rev 2012;41:4306-34.
134. Cheyne RW, Smith TA, Trembleau L, McLaughlin AC. Synthesis and
characterisation of biologically compatible TiO2 nanoparticles. Nanoscale Res Lett 2011;6:423.
135. Seo JW, Chung H, Kim MY, Lee J, Choi IH, Cheon J. Development of
water-soluble single-crystalline TiO2 nanoparticles for photocatalytic
cancer-cell treatment. Small 2007;3:850-3.
136. Czajka M, Sawicki K, Sikorska K, Popek S, Kruszewski M, KapkaSkrzypczak L. Toxicity of titanium dioxide nanoparticles in central
nervous system. Toxicol In Vitro 2015;29:1042-52.
137. Shi H, Magaye R, Castranova V, Zhao J. Titanium dioxide
nanoparticles: A review of current toxicological data. Part Fibre
Toxicol 2013;10:15.
138. Ahamed M, Ali D, Alhadlaq HA, Akhtar MJ. Nickel oxide
nanoparticles exert cytotoxicity via oxidative stress and induce
apoptotic response in human liver cells (HepG2). Chemosphere
2013;93:2514-22.
139. Garcia-Saucedo C, Field JA, Otero-Gonzalez L, Sierra-Alvarez R. Low
toxicity of HfO2, SiO2, Al2O3 and CeO2 nanoparticles to the yeast,
Saccharomyces cerevisiae. J Hazard Mater 2011;192:1572-9.
140. Field JA, Luna-Velasco A, Boitano SA, Shadman F, Ratner BD, Barnes
C, et al. Cytotoxicity and physicochemical properties of hafnium oxide
nanoparticles. Chemosphere 2011;84:1401-7.
141. Marill J, Anesary NM, Zhang P, Vivet S, Borghi E, Levy L, et al.
Hafnium oxide nanoparticles: Toward an in vitro predictive biological
effect? Radiat Oncol 2014;9:150.
142. Maggiorella L, Barouch G, Devaux C, Pottier A, Deutsch E, Bourhis J,
et al. Nanoscale radiotherapy with hafnium oxide nanoparticles. Future
Oncol 2012;8:1167-81.
143. Jayaraman V, Bhavesh G, Chinnathambi S, Ganesan S, Aruna P.
Synthesis and characterization of hafnium oxide nanoparticles for biosafety. Mater Expr 2014;4:375-83.
144. De Roo J, De Keukeleere K, Feys J, Lommens P, Hens Z, Van
Driessche I. Fast, microwave-assisted synthesis of monodisperse HfO2
nanoparticles. J Nanopart Res 2013;15:1-11.
145. Dahal N, Chikan V. Synthesis of hafnium oxide-gold core-shell
nanoparticles. Inorg Chem 2012;51:518-22.
146. Tang J, Fabbri J, Robinson RD, Zhu Y, Herman IP, Steigerwald ML, et
al. Solid-solution nanoparticles: Use of a nonhydrolytic sol–gel
synthesis to prepare HfO2 and HfxZr1-xO2 nanocrystals. Chem
Mater 2004;16:1336-42.
147. Rauwel P, Rauwel E, Persson C, Sunding MF, Galeckas A. One step
synthesis of pure cubic and monoclinic HfO2 nanoparticles: Correlating
the structure to the electronic properties of the two polymorphs. J Appl
Phys 2012;112:104107-1 to 104107-8.
1690
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
148. Liu Y, Zhou S, Tu D, Chen Z, Huang M, Zhu H, et al. Aminefunctionalized lanthanide-doped zirconia nanoparticles: Optical spectroscopy, time-resolved fluorescence resonance energy transfer biodetection, and targeted imaging. J Am Chem Soc 2012;134:15083-90.
149. Na HB, Lee JH, An K, Park YI, Park M, Lee IS, et al. Development of a
T1 contrast agent for magnetic resonance imaging using MnO
nanoparticles. Angew Chem Int Ed Engl 2007;46:5397-401.
150. Letourneau M, Tremblay M, Faucher L, Rojas D, Chevallier P, Gossuin
Y, et al. MnO-labeled cells: Positive contrast enhancement in MRI. J
Phys Chem B 2012;116:13228-38.
151. Baek MJ, Park JY, Xu W, Kattel K, Kim HG, Lee EJ, et al. Watersoluble MnO nanocolloid for a molecular T1 MR imaging: A facile onepot synthesis, in vivo T1 MR images, and account for relaxivities. ACS
Appl Mater Interfaces 2010;2:2949-55.
152. Seo WS, Jo HH, Lee K, Kim B, Oh SJ, Park JT. Size-dependent
magnetic properties of colloidal Mn3O4 and MnO nanoparticles. Angew Chem Int Ed Engl 2004;43:1115-7.
153. Martinez HP, Kono Y, Blair SL, Sandoval S, Wang-Rodriguez J,
Mattrey RF, et al. Hard shell gas-filled contrast enhancement particles
for colour Doppler ultrasound imaging of tumors. MedChemComm
2010;1:266-70.
154. Slowing II, Trewyn BG, Giri S, Lin VSY. Mesoporous silica
nanoparticles for drug delivery and biosensing applications. Adv
Funct Mater 2007;17:1225-36.
155. Barbé C, Bartlett J, Kong L, Finnie K, Lin HQ, Larkin M, et al. Silica
particles: A novel drug-delivery system. Adv Mater 2004;16:1959-66.
156. Baek S, Singh RK, Khanal D, Patel KD, Lee EJ, Leong KW, et al. Smart
multifunctional drug delivery towards anticancer therapy harmonized in
mesoporous nanoparticles. Nanoscale 2015;7:14191-216.
157. Ow H, Larson DR, Srivastava M, Baird BA, Webb WW, Wiesner U.
Bright and stable core–shell fluorescent silica nanoparticles. Nano Lett
2005;5:113-7.
158. Lu J, Liong M, Li Z, Zink JI, Tamanoi F. Biocompatibility,
biodistribution, and drug-delivery efficiency of mesoporous silica
nanoparticles for cancer therapy in animals. Small 2010;6:1794-805.
159. Tao Z, Morrow MP, Asefa T, Sharma KK, Duncan C, Anan A, et al.
Mesoporous silica nanoparticles inhibit cellular respiration. Nano Lett
2008;8:1517-26.
160. Chen K, Zhang J, Gu H. Dissolution from inside: A unique degradation
behaviour of core-shell magnetic mesoporous silica nanoparticles and
the effect of polyethyleneimine coating. J Mater Chem
2012;22:22005-12.
161. He Q, Zhang Z, Gao F, Li Y, Shi J. In vivo biodistribution and urinary
excretion of mesoporous silica nanoparticles: Effects of particle size
and PEGylation. Small 2011;7:271-80.
162. Kumar R, Roy I, Ohulchanskky TY, Vathy LA, Bergey EJ, Sajjad M, et
al. In vivo biodistribution and clearance studies using multimodal
organically modified silica nanoparticles. ACS Nano 2010;4:699-708.
163. Alexis F, Pridgen E, Molnar LK, Farokhzad OC. Factors affecting the
clearance and biodistribution of polymeric nanoparticles. Mol Pharm
2008;5:505-15.
164. Rahman IA, Vejayakumaran P, Sipaut CS, Ismail J, Chee CK. Sizedependent physicochemical and optical properties of silica nanoparticles. Mater Chem Phys 2009;114:328-32.
165. Stöber W, Fink A, Bohn E. Controlled growth of monodisperse silica
spheres in the micron size range. J Colloid Interface Sci 1968;26:62-9.
166. Park SK, Kim KD, Kim HT. Preparation of silica nanoparticles:
Determination of the optimal synthesis conditions for small and uniform
particles. Colloids Surf A Physicochem Eng Asp 2002;197:7-17.
167. Rahman IA, Vejayakumaran P, Sipaut CS, Ismail J, Bakar MA, Adnan R, et
al. An optimized sol–gel synthesis of stable primary equivalent silica
particles. Colloids Surf A Physicochem Eng Asp 2007;294:102-10.
168. Hartlen KD, Athanasopoulos APT, Kitaev V. Facile preparation of
highly monodisperse small silica spheres (15 to N 200 nm) suitable for
colloidal templating and formation of ordered arrays. Langmuir
2008;24:1714-20.
169. Yokoi T, Sakamoto Y, Terasaki O, Kubota Y, Okubo T, Tatsumi T.
Periodic arrangement of silica nanospheres assisted by amino acids. J
Am Chem Soc 2006;128:13664-5.
170. Ma K, Sai H, Wiesner U. Ultrasmall sub-10 nm near-infrared
fluorescent mesoporous silica nanoparticles. J Am Chem Soc
2012;134:13180-3.
171. Lin Y-S, Abadeer N, Haynes CL. Stability of small mesoporous silica
nanoparticles in biological media. Chem Commun (Camb)
2011;47:532-4.
172. Benezra M, Penate-Medina O, Zanzonico PB, Schaer D, Ow H, Burns
A, et al. Multimodal silica nanoparticles are effective cancer-targeted
probes in a model of human melanoma. J Clin Invest
2011;121:2768-80.
173. Napierska D, Thomassen LC, Lison D, Martens JA, Hoet PH. The
nanosilica hazard: Another variable entity. Part Fibre Toxicol
2010;7:39.
174. McCarthy J, Inkielewicz-Stępniak I, Corbalan JJ, Radomski MW.
Mechanisms of toxicity of amorphous silica nanoparticles on human
lung submucosal cells in vitro: Protective effects of fisetin. Chem Res
Toxicol 2012;25:2227-35.
175. Napierska D, Thomassen LCJ, Rabolli V, Lison D, Gonzalez L, KirschVolders M, et al. Size-dependent cytotoxicity of monodisperse silica
nanoparticles in human endothelial cells. Small 2009;5:846-53.
176. Yu T, Malugin A, Ghandehari H. Impact of silica nanoparticle design
on cellular toxicity and hemolytic activity. ACS Nano 2011;5:5717-28.
177. Zhu D, Liu F, Ma L, Liu D, Wang Z. Nanoparticle-based systems for
T1-weighted magnetic resonance imaging contrast agents. Int J Mol Sci
2013;14:10591-607.
178. Kim TJ, Chae KS, Chang Y, Lee GH. Gadolinium oxide nanoparticles
as potential multimodal imaging and therapeutic agents. Curr Top Med
Chem 2013;13:422-33.
179. Comby S, Surender EM, Kotova O, Truman LK, Molloy JK,
Gunnlaugsson T. Lanthanide-functionalized nanoparticles as MRI
and luminescent probes for sensing and/or imaging applications. Inorg
Chem 2014;53:1867-79.
180. Park JY, Chang Y, Lee GH. Multi-modal imaging and cancer therapy
using lanthanide oxide nanoparticles: Current status and perspectives.
Curr Med Chem 2015;22:569-81.
181. Mowat P, Mignot A, Rima W, Lux F, Tillement O, Roulin C, et al. In
vitro radiosensitizing effects of ultrasmall gadolinium based particles
on tumour cells. J Nanosci Nanotechnol 2011;11:7833-9.
182. Kim CK, Kim T, Choi IY, Soh M, Kim D, Kim YJ, et al. Ceria
nanoparticles that can protect against ischemic stroke. Angew Chem Int
Ed Engl 2012;51:11039-43.
183. Chen NT, Cheng SH, Liu CP, Souris JS, Chen CT, Mou CY, et al.
Recent advances in nanoparticle-based Förster resonance energy
transfer for biosensing, molecular imaging and drug release profiling.
Int J Mol Sci 2012;13:16598-623.
184. Liu Y, Tu D, Zhu H, Chen X. Lanthanide-doped luminescent
nanoprobes: Controlled synthesis, optical spectroscopy, and bioapplications. Chem Soc Rev 2013;42:6924-58.
185. Min YZ, Li JM, Liu F, Padmanabhan P, Yeow EKL, Xing BG. Recent
advance of biological molecular imaging based on lanthanide-doped
upconversion-luminescent nanomaterials. Nanomaterials 2014;4:129-54.
186. Sun LD, Wang YF, Yan CH. Paradigms and challenges for
bioapplication of rare earth upconversion luminescent nanoparticles:
Small size and tunable emission/excitation spectra. Acc Chem Res
2014;47:1001-9.
187. Gorris HH, Wolfbeis OS. Photon-upconverting nanoparticles for
optical encoding and multiplexing of cells, biomolecules, and
microspheres. Angew Chem Int Ed Engl 2013;52:3584-600.
188. Zhou J, Liu Z, Li F. Upconversion nanophosphors for small-animal
imaging. Chem Soc Rev 2012;41:1323-49.
189. Chen G, Qiu H, Prasad PN, Chen X. Upconversion nanoparticles:
Design, nanochemistry, and applications in theranostics. Chem Rev
2014;114:5161-214.
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
190. Cheng L, Wang C, Liu Z. Upconversion nanoparticles and their
composite nanostructures for biomedical imaging and cancer therapy.
Nanoscale 2013;5:23-37.
191. Haase M, Schäfer H. Upconverting nanoparticles. Angew Chem Int Ed
Engl 2011;50:5808-29.
192. Wang F, Banerjee D, Liu YS, Chen XY, Liu XG. Upconversion
nanoparticles in biological labeling, imaging, and therapy. Analyst
2010;135:1839-54.
193. Lee DE, Koo H, Sun IC, Ryu JH, Kim K, Kwon IC. Multifunctional
nanoparticles for multimodal imaging and theragnosis. Chem Soc Rev
2012;41:2656-72.
194. Park JY, Baek MJ, Choi ES, Woo S, Kim JH, Kim TJ, et al.
Paramagnetic ultrasmall gadolinium oxide nanoparticles as advanced
T1 MRI contrast agent: Account for large longitudinal relaxivity,
optimal particle diameter, and in vivo T1 MR images. ACS Nano
2009;3:3663-9.
195. Kattel K, Park JY, Xu W, Kim HG, Lee EJ, Bony BA, et al. A facile
synthesis, in vitro and in vivo MR studies of D-glucuronic acid-coated
ultrasmall Ln2O3 (Ln = Eu, Gd, Dy, Ho, and Er) nanoparticles as a new
potential MRI contrast agent. ACS Appl Mater Interfaces
2011;3:3325-34.
196. Kattel K, Park JY, Xu W, Kim HG, Lee EJ, Bony BA, et al. Paramagnetic
dysprosium oxide nanoparticles and dysprosium hydroxide nanorods as T2
MRI contrast agents. Biomaterials 2012;33:3254-61.
197. Kattel K, Park JY, Xu WL, Kim HG, Lee EJ, Bony BA, et al. Watersoluble ultrasmall Eu2O3 nanoparticles as a fluorescent imaging agent:
In vitro and in vivo studies. Colloids Surf A Physicochem Eng Asp
2012;394:85-91.
198. Kattel K, Kim CR, Xu W, Kim TJ, Park JW, Chang Y, et al. Synthesis,
magnetic properties, map images, and water proton relaxivities of Dglucuronic acid coated Ln2O3 nanoparticles (Ln = Ho and Er). J
Nanosci Nanotechnol 2015;15:7311-6.
199. Choi ES, Park JY, Baek MJ, Xu W, Kattel K, Kim JH, et al. Watersoluble ultra-small manganese oxide surface doped gadolinium oxide
(Gd2O3@MnO) nanoparticles for MRI contrast agent. Eur J Inorg
Chem 2010;2010:4555-60.
200. Xu W, Park JY, Kattel K, Bony BA, Heo WC, Jin S, et al. A T1, T2
magnetic resonance imaging (MRI)-fluorescent imaging (FI) by using
ultrasmall mixed gadolinium-europium oxide nanoparticles. New J
Chem 2012;36:2361-7.
201. Ahrén M, Selegård L, Klasson A, Soderlind F, Abrikossova N,
Skoglund C, et al. Synthesis and characterization of PEGylated Gd2O3
nanoparticles for MRI contrast enhancement. Langmuir
2010;26:5753-62.
202. Petoral RM, Söderlind F, Klasson A, Suska A, Fortin MA, Abrikossova
N, et al. Synthesis and characterization of Tb 3 +-doped Gd2O3
nanocrystals: A bifunctional material with combined fluorescent
labeling and MRI contrast agent properties. J Phys Chem C
2009;113:6913-20.
203. Faucher L, Tremblay M, Lagueux J, Gossuin Y, Fortin MA. Rapid
synthesis of PEGylated ultrasmall gadolinium oxide nanoparticles for
cell labeling and tracking with MRI. ACS Appl Mater Interfaces
2012;4:4506-15.
204. Di Corato R, Gazeau F, Le Visage C, Fayol D, Levitz P, Lux F, et al.
High-resolution cellular MRI: Gadolinium and iron oxide nanoparticles
for in-depth dual-cell imaging of engineered tissue constructs. ACS
Nano 2013;7:7500-12.
205. Faucher L, Guay-Begin AA, Lagueux J, Cote MF, Petitclerc E, Fortin
MA. Ultra-small gadolinium oxide nanoparticles to image brain cancer
cells in vivo with MRI. Contrast Media Mol Imaging 2011;6:209-18.
206. Söderlind F, Fortin MA, Petoral RM, Klasson A, Veres T, Engström M,
et al. Colloidal synthesis and characterization of ultrasmall perovskite
GdFeO3 nanocrystals. Nanotechnology 2008;19.
207. Guay-Begin AA, Chevallier P, Faucher L, Turgeon S, Fortin MA.
Surface modification of gadolinium oxide thin films and nanoparticles
using poly(ethylene glycol)-phosphate. Langmuir 2012;28:774-82.
1691
208. Tegafaw T, Xu W, Ahmad MW, Baeck JS, Chang Y, Bae JE, et al.
Dual-mode T1 and T2 magnetic resonance imaging contrast agent based
on ultrasmall mixed gadolinium-dysprosium oxide nanoparticles:
Synthesis, characterization, and in vivo application. Nanotechnology
2015;26:365102.
209. Bridot JL, Faure AC, Laurent S, Riviere C, Billotey C, Hiba B, et al.
Hybrid gadolinium oxide nanoparticles: Multimodal contrast agents for
in vivo imaging. J Am Chem Soc 2007;129:5076-84.
210. Lux F, Mignot A, Mowat P, Louis C, Dufort S, Bernhard C, et al.
Ultrasmall rigid particles as multimodal probes for medical applications. Angew Chem Int Ed Engl 2011;50:12299-303.
211. Mignot A, Truillet C, Lux F, Sancey L, Louis C, Denat F, et al. A topdown synthesis route to ultrasmall multifunctional Gd-based silica
nanoparticles for theranostic applications. Chemistry 2013;19:6122-36.
212. Miladi I, Duc GL, Kryza D, Berniard A, Mowat P, Roux S, et al.
Biodistribution of ultra small gadolinium-based nanoparticles as
theranostic agent: Application to brain tumors. J Biomater Appl
2013;28:385-94.
213. Sancey L, Kotb S, Truillet C, Appaix F, Marais A, Thomas E, et al.
Long-term in vivo clearance of gadolinium-based AGuIX nanoparticles
and their biocompatibility after systemic injection. ACS Nano
2015;9:2477-88.
214. Roux S, Tillement O, Billotey C, Coll JL, Le Duc G, Marquette CA, et
al. Multifunctional nanoparticles: From the detection of biomolecules
to the therapy. Int J Nanotechnol 2010;7:781-801.
215. Miladi I, Aloy MT, Armandy E, Mowat P, Kryza D, Magne N, et al.
Combining ultrasmall gadolinium-based nanoparticles with photon
irradiation overcomes radioresistance of head and neck squamous cell
carcinoma. Nanomedicine 2015;11:247-57.
216. Le Duc G, Miladi I, Alric C, Mowat P, Brauer-Krisch E, Bouchet A, et
al. Toward an image-guided microbeam radiation therapy using
gadolinium-based nanoparticles. ACS Nano 2011;5:9566-74.
217. Le Duc G, Roux S, Paruta-Tuarez A, Dufort S, Brauer E, Marais A, et
al. Advantages of gadolinium based ultrasmall nanoparticles vs
molecular gadolinium chelates for radiotherapy guided by MRI for
glioma treatment. Cancer Nanotechnol 2014;5:4.
218. Taupin F, Flaender M, Delorme R, Brochard T, Mayol JF, Arnaud J, et
al. Gadolinium nanoparticles and contrast agent as radiation sensitizers.
Phys Med Biol 2015;60:4449-64.
219. Xing H, Zhang S, Bu W, Zheng X, Wang L, Xiao Q, et al. Ultrasmall
NaGdF4 nanodots for efficient MR angiography and atherosclerotic
plaque imaging. Adv Mater 2014;26:3867-72.
220. Ni D, Zhang J, Bu W, Zhang C, Yao Z, Xing H, et al. PEGylated
NaHoF4 nanoparticles as contrast agents for both X-ray computed
tomography and ultra-high field magnetic resonance imaging. Biomaterials 2016;76:218-25.
221. Li S, Zhang X, Hou Z, Cheng Z, Ma P, Lin J. Enhanced emission of ultrasmall-sized LaF3:RE3+ (RE = Eu, Tb) nanoparticles through 1,2,4,5benzenetetracarboxylic acid sensitization. Nanoscale 2012;4:5619-26.
222. Huang H, Zhang HC, Zhang WS, Lian SY, Kang ZH, Liu Y. Ultrasmall sized Y2O3:Eu 3 + nanocrystals: One-step polyoxometalateassisted synthesis and their photoluminescence properties. J Lumin
2012;132:2155-60.
223. Chelebaeva E, Larionova J, Guari Y, Ferreira RAS, Carlos LD, Trifonov
AA, et al. Nanoscale coordination polymers exhibiting luminescence
properties and NMR relaxivity. Nanoscale 2011;3:1200-10.
224. Sreeremya TS, Thulasi KM, Krishnan A, Ghosh S. A novel aqueous
route to fabricate ultrasmall monodisperse lipophilic cerium oxide
nanoparticles. Ind Eng Chem Res 2012;51:318-26.
225. Kar S, Patel C, Santra S. Direct room temperature synthesis of valence
state engineered ultra-small ceria nanoparticles: Investigation on the
role of ethylenediamine as a capping agent. J Phys Chem C
2009;113:4862-7.
226. Yu T, Moon J, Park J, Park YI, Na HB, Kim BH, et al. Various-shaped
uniform Mn3O4 nanocrystals synthesized at low temperature in air
atmosphere. Chem Mater 2009;21:2272-9.
1692
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
227. Gong LJ, Yang JC, Li YY, Ma M, Xu CF, Ren GZ, et al. Solvothermal
synthesis and upconversion emission of monodisperse ultrasmall
SrYbF5 nanocrystals. J Mater Sci 2013;48:3672-8.
228. Chen G, Ohulchanskyy TY, Kumar R, Agren H, Prasad PN. Ultrasmall
monodisperse NaYF4:Yb3+/Tm3+ nanocrystals with enhanced near-infrared
to near-infrared upconversion photoluminescence. ACS Nano 2010;4:3163-8.
229. Bednarkiewicz A, Wawrzynczyk D, Gagor A, Kepinski L, Kurnatowska M, Krajczyk L, et al. Giant enhancement of upconversion in
ultra-small Er 3+/Yb 3+:NaYF4 nanoparticles via laser annealing. Nanotechnology 2012;23:145705.
230. Johnson NJJ, Oakden W, Stanisz GJ, Prosser RS, van Veggel FCJM.
Size-tunable, ultrasmall NaGdF4 nanoparticles: Insights into their T1
MRI contrast enhancement. Chem Mater 2011;23:3714-22.
231. Chen GY, Qiu HL, Fan RW, Hao SW, Tan S, Yang CH, et al.
Lanthanide-doped ultrasmall yttrium fluoride nanoparticles with
enhanced multicolor upconversion photoluminescence. J Mater Chem
2012;22:20190-6.
232. Ryu J, Park HY, Kim K, Kim H, Yoo JH, Kang M, et al. Facile
synthesis of ultrasmall and hexagonal NaGdF4: Yb 3+, Er 3+ nanoparticles with magnetic and upconversion imaging properties. J Phys
Chem C 2010;114:21077-82.
233. Wong HT, Vetrone F, Naccache R, Chan HLW, Hao JH, Capobianco
JA. Water dispersible ultra-small multifunctional KGdF4:Tm 3+, Yb 3+
nanoparticles with near-infrared to near-infrared upconversion. J Mater
Chem 2011;21:16589-96.
234. Chen D, Yu Y, Huang F, Wang Y. Phase transition from hexagonal
LnF3 (Ln = La, Ce, Pr) to cubic Ln0.8M0.2F2.8 (M = Ca, Sr, Ba)
nanocrystals with enhanced upconversion induced by alkaline-earth
doping. Chem Commun (Camb) 2011;47:2601-3.
235. Cao X, Cao F, Xiong L, Yang Y, Cao T, Cai X, et al. Cytotoxicity,
tumor targeting and PET imaging of sub-5 nm KGdF4 multifunctional
rare earth nanoparticles. Nanoscale 2015;7:13404-9.
236. Liu Q, Sun Y, Yang T, Feng W, Li C, Li F. Sub-10 nm hexagonal
lanthanide-doped NaLuF4 upconversion nanocrystals for sensitive
bioimaging in vivo. J Am Chem Soc 2011;133:17122-5.
237. Bentolila LA, Michalet X, Pinaud FF, Tsay JM, Doose S, Li JJ, et al.
Quantum dots for molecular imaging and cancer medicine. Discov Med
2005;5:213-8.
238. Michalet X, Pinaud FF, Bentolila LA, Tsay JM, Doose S, Li JJ, et al.
Quantum dots for live cells, in vivo imaging, and diagnostics. Science
2005;307:538-44.
239. Medintz IL, Uyeda HT, Goldman ER, Mattoussi H. Quantum dot
bioconjugates for imaging, labelling and sensing. Nat Mater 2005;4:435-46.
240. Hild WA, Breunig M, Goepferich A. Quantum dots - nano-sized probes
for the exploration of cellular and intracellular targeting. Eur J Pharm
Biopharm 2008;68:153-68.
241. True LD, Gao X. Quantum dots for molecular pathology: Their time
has arrived. J Mol Diagn 2007;9:7-11.
242. Alivisatos AP. Semiconductor clusters, nanocrystals, and quantum
dots. Science 1996;271:933-7.
243. Sharma P, Brown S, Walter G, Santra S, Moudgil B. Nanoparticles for
bioimaging. Adv Colloid Interface Sci 2006;123–126:471-85.
244. Walling MA, Novak JA, Shepard JR. Quantum dots for live cell and in
vivo imaging. Int J Mol Sci 2009;10:441-91.
245. Harrell SM, McBride JR, Rosenthal SJ. Synthesis of ultrasmall and
magic-sized CdSe nanocrystals. Chem Mater 2013;25:1199-210.
246. Zhelev Z, Bakalova R, Ohba H, Jose R, Imai Y, Baba Y. Uncoated,
broad fluorescent, and size-homogeneous CdSe quantum dots for
bioanalyses. Anal Chem 2006;78:321-30.
247. Tsay JM, Michalet X. New light on quantum dot cytotoxicity. Chem
Biol 2005;12:1159-61.
248. Shiohara A, Hoshino A, Hanaki K, Suzuki K, Yamamoto K. On the cytotoxicity caused by quantum dots. Microbiol Immunol 2004;48:669-75.
249. Kirchner C, Liedl T, Kudera S, Pellegrino T, Muñoz Javier A, Gaub
HE, et al. Cytotoxicity of colloidal CdSe and CdSe/ZnS nanoparticles.
Nano Lett 2005;5:331-8.
250. Tan X, Jin R. Ultrasmall metal nanoclusters for bio-related applications.
Wiley Interdiscip Rev Nanomed Nanobiotechnol 2013;5:569-81.
251. Derfus AM, Chan WCW, Bhatia SN. Probing the cytotoxicity of
semiconductor quantum dots. Nano Lett 2004;4:11-8.
252. Gao J, Chen K, Xie R, Xie J, Lee S, Cheng Z, et al. Ultrasmall nearinfrared non-cadmium quantum dots for in vivo tumor imaging. Small
2010;6:256-61.
253. Pons T, Pic E, Lequeux N, Cassette E, Bezdetnaya L, Guillemin F, et al.
Cadmium-free CuInS2/ZnS quantum dots for sentinel lymph node
imaging with reduced toxicity. ACS Nano 2010;4:2531-8.
254. Tarantola M, Schneider D, Sunnick E, Adam H, Pierrat S, Rosman C, et
al. Cytotoxicity of metal and semiconductor nanoparticles indicated by
cellular micromotility. ACS Nano 2009;3:213-22.
255. Samuel SP, Santos-Martinez MJ, Medina C, Jain N, Radomski MW,
Prina-Mello A, et al. CdTe quantum dots induce activation of human
platelets: Implications for nanoparticle hemocompatibility. Int J
Nanomedicine 2015;10:2723-34.
256. Barreto JA, O'Malley W, Kubeil M, Graham B, Stephan H, Spiccia L.
Nanomaterials: Applications in cancer imaging and therapy. Adv Mater
2011;23:H18-40.
257. Choi HS, Liu W, Misra P, Tanaka E, Zimmer JP, Itty Ipe B, et al. Renal
clearance of quantum dots. Nat Biotechnol 2007;25:1165-70.
258. Liu W, Choi HS, Zimmer JP, Tanaka E, Frangioni JV, Bawendi M.
Compact cysteine-coated CdSe(ZnCdS) quantum dots for in vivo
applications. J Am Chem Soc 2007;129:14530-1.
259. Breus VV, Heyes CD, Tron K, Nienhaus GU. Zwitterionic biocompatible quantum dots for wide pH stability and weak nonspecific
binding to cells. ACS Nano 2009;3:2573-80.
260. Jiang X, Rocker C, Hafner M, Brandholt S, Dorlich RM, Nienhaus GU.
Endo- and exocytosis of zwitterionic quantum dot nanoparticles by live
HeLa cells. ACS Nano 2010;4:6787-97.
261. Raevskaya AE, Stroyuk OL, Solonenko DI, Dzhagan VM, Lehmann D,
Kuchmiy SY, et al. Synthesis and luminescent properties of ultrasmall
colloidal CdS nanoparticles stabilized by Cd(II) complexes with
ammonia and mercaptoacetate. J Nanopart Res 2014;16.
262. Chen C, Zhang P, Zhang L, Gao D, Gao G, Yang Y, et al. Long-decay
near-infrared-emitting doped quantum dots for lifetime-based in vivo
pH imaging. Chem Commun (Camb) 2015;51:11162-5.
263. Khani O, Rajabi HR, Yousefi MH, Khosravi AA, Jannesari M,
Shamsipur M. Synthesis and characterizations of ultra-small ZnS and
Zn(1-x)Fe(x)S quantum dots in aqueous media and spectroscopic study
of their interactions with bovine serum albumin. Spectrochim Acta A
Mol Biomol Spectrosc 2011;79:361-9.
264. Xuan T, Wang S, Wang X, Liu J, Chen J, Li H, et al. Single-step
noninjection synthesis of highly luminescent water soluble Cu + doped
CdS quantum dots: Application as bio-imaging agents. Chem Commun
(Camb) 2013;49:9045-7.
265. Chen LN, Wang J, Li WT, Han HY. Aqueous one-pot synthesis of
bright and ultrasmall CdTe/CdS near-infrared-emitting quantum dots
and their application for tumor targeting in vivo. Chem Commun
(Camb) 2012;48:4971-3.
266. Zhang F, Sun TT, Zhang Y, Li Q, Chai C, Lu L, et al. Facile synthesis
of functional gadolinium-doped CdTe quantum dots for tumor-targeted
fluorescence and magnetic resonance dual-modality imaging. J Mater
Chem B 2014;2:7201-9.
267. Gao D, Zhang P, Jia J, Li M, Sheng Z, Hu D, et al. Ultrasmall
paramagnetic near infrared quantum dots as dual modal nanoprobes.
RSC Adv 2013;3:21247-50.
268. Muro E, Pons T, Lequeux N, Fragola A, Sanson N, Lenkei Z, et al.
Small and stable sulfobetaine zwitterionic quantum dots for functional
live-cell imaging. J Am Chem Soc 2010;132:4556-7.
269. Muro E, Fragola A, Pons T, Lequeux N, Ioannou A, Skourides P, et al.
Comparing intracellular stability and targeting of sulfobetaine quantum
dots with other surface chemistries in live cells. Small 2012;8:1029-37.
270. Susumu K, Oh E, Delehanty JB, Blanco-Canosa JB, Johnson BJ, Jain
V, et al. Multifunctional compact zwitterionic ligands for preparing
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
271.
272.
273.
274.
275.
276.
277.
278.
279.
280.
281.
282.
283.
284.
285.
286.
287.
288.
289.
290.
robust biocompatible semiconductor quantum dots and gold nanoparticles. J Am Chem Soc 2011;133:9480-96.
Zhan N, Palui G, Safi M, Ji X, Mattoussi H. Multidentate zwitterionic
ligands provide compact and highly biocompatible quantum dots. J Am
Chem Soc 2013;135:13786-95.
Giovanelli E, Muro E, Sitbon G, Hanafi M, Pons T, Dubertret B, et al.
Highly enhanced affinity of multidentate versus bidentate zwitterionic
ligands for long-term quantum dot bioimaging. Langmuir
2012;28:15177-84.
Lawrence KN, Dolai S, Lin Y-H, Dass A, Sardar R. Enhancing the
physicochemical and photophysical properties of small (b2.0 nm)
CdSe nanoclusters for intracellular imaging applications. RSC Adv
2014;4:30742-53.
Mansur AA, Mansur HS, Soriano-Araujo A, Lobato ZI. Fluorescent
nanohybrids based on quantum dot-chitosan-antibody as potential
cancer biomarkers. ACS Appl Mater Interfaces 2014;6:11403-12.
Han HS, Martin JD, Lee J, Harris DK, Fukumura D, Jain RK, et al.
Spatial charge configuration regulates nanoparticle transport and
binding behavior in vivo. Angew Chem Int Ed Engl 2013;52:1414-9.
Sun Z, Xie H, Tang S, Yu XF, Guo Z, Shao J, et al. Ultrasmall black
phosphorus quantum dots: Synthesis and use as photothermal agents.
Angew Chem Int Ed Engl 2015;54:11526-30.
Zhang X, Xie H, Liu Z, Tan C, Luo Z, Li H, et al. Black phosphorus
quantum dots. Angew Chem Int Ed Engl 2015;54:3653-7.
Cheng X, Lowe SB, Reece PJ, Gooding JJ. Colloidal silicon quantum dots:
From preparation to the modification of self-assembled monolayers (SAMs)
for bio-applications. Chem Soc Rev 2014;43:2680-700.
Peng F, Su Y, Zhong Y, Fan C, Lee ST, He Y. Silicon nanomaterials
platform for bioimaging, biosensing, and cancer therapy. Acc Chem
Res 2014;47:612-23.
Park JH, Gu L, von Maltzahn G, Ruoslahti E, Bhatia SN, Sailor MJ.
Biodegradable luminescent porous silicon nanoparticles for in vivo
applications. Nat Mater 2009;8:331-6.
Tasciotti E, Liu X, Bhavane R, Plant K, Leonard AD, Price BK, et al.
Mesoporous silicon particles as a multistage delivery system for
imaging and therapeutic applications. Nat Nanotechnol 2008;3:151-7.
Dasog M, Yang Z, Regli S, Atkins TM, Faramus A, Singh MP, et al.
Chemical insight into the origin of red and blue photoluminescence
arising from freestanding silicon nanocrystals. ACS Nano
2013;7:2676-85.
Canham LT. Silicon quantum wire array fabrication by electrochemical
and chemical dissolution of wafers. Appl Phys Lett 1990;57:1046-8.
Sugimoto H, Fujii M, Imakita K, Hayashi S, Akamatsu K. Allinorganic near-infrared luminescent colloidal silicon nanocrystals:
High dispersibility in polar liquid by phosphorus and boron codoping.
J Phys Chem C 2012;116:17969-74.
Sugimoto H, Fujii M, Imakita K, Hayashi S, Akamatsu K. Codoping nand p-type impurities in colloidal silicon nanocrystals: Controlling
luminescence energy from below bulk band gap to visible range. J Phys
Chem C 2013;117:11850-7.
Dohnalova K, Poddubny AN, Prokofiev AA, de Boer WDAM, Umesh
CP, Paulusse JMJ, et al. Surface brightens up Si quantum dots: Direct
bandgap-like size-tunable emission. Light Sci Appl 2013;2:e47.
Siekierzycka JR, Rosso-Vasic M, Zuilhof H, Brouwer AM. Photophysics of n-butyl-capped silicon nanoparticles. J Phys Chem C
2011;115:20888-95.
Llansola Portolés MJ, Pis Diez R, Dell’Arciprete ML, Caregnato P,
Romero JJ, Mártire DO, et al. Understanding the parameters affecting
the photoluminescence of silicon nanoparticles. J Phys Chem C
2012;116:11315-25.
Romero JJ, Llansola-Portolés MJ, Dell’Arciprete ML, Rodríguez HB,
Moore AL, Gonzalez MC. Photoluminescent 1-2 nm sized
silicon nanoparticles: A surface-dependent system. Chem Mater
2013;25:3488-98.
Kang Z, Liu Y, Lee ST. Small-sized silicon nanoparticles: New
nanolights and nanocatalysts. Nanoscale 2011;3:777-91.
1693
291. Veinot JG. Synthesis, surface functionalization, and properties of
freestanding silicon nanocrystals. Chem Commun (Camb)
2006:4160-8.
292. Sun H, Miyazaki S, Tamamitsu H, Saitow K. One-pot facile synthesis
of a concentrated Si nanoparticle solution. Chem Commun (Camb)
2013;49:10302-4.
293. Heintz AS, Fink MJ, Mitchell BS. Silicon nanoparticles with
chemically tailored surfaces. Appl Organomet Chem 2010;24:236-40.
294. Chinnathambi S, Chen S, Ganesan S, Hanagata N. Silicon quantum
dots for biological applications. Adv Healthc Mater 2014;3:10-29.
295. Gonçalves HMR, Esteves da Silva JCG. A new insight on silicon dots.
Curr Anal Chem 2012;8:67-77.
296. Heath JR. A liquid-solution-phase synthesis of crystalline silicon.
Science 1992;258:1131-3.
297. Wilcoxon JP, Samara GA, Provencio PN. Optical and electronic
properties of Si nanoclusters synthesized in inverse micelles. Phys Rev
B 1999;60:2704-14.
298. Warner JH, Hoshino A, Yamamoto K, Tilley RD. Water-soluble
photoluminescent silicon quantum dots. Angew Chem Int Ed Engl
2005;44:4550-4.
299. Shiohara A, Prabakar S, Faramus A, Hsu CY, Lai PS, Northcote PT, et
al. Sized controlled synthesis, purification, and cell studies with silicon
quantum dots. Nanoscale 2011;3:3364-70.
300. Rosso-Vasic M, Spruijt E, van Lagen B, De Cola L, Zuilhof H. Alkylfunctionalized oxide-free silicon nanoparticles: Synthesis and optical
properties. Small 2008;4:1835-41.
301. Rosso-Vasic M, Spruijt E, Popovic Z, Overgaag K, van Lagen B,
Grandidier B, et al. Amine-terminated silicon nanoparticles: Synthesis,
optical properties and their use in bioimaging. J Mater Chem
2009;19:5926-33.
302. Linehan K, Doyle H. Size controlled synthesis of silicon nanocrystals
using cationic surfactant templates. Small 2014;10:584-90.
303. Baldwin RK, Pettigrew KA, Ratai E, Augustine MP, Kauzlarich SM.
Solution reduction synthesis of surface stabilized silicon nanoparticles.
Chem Commun (Camb) 2002:1822-3.
304. Bley RA, Kauzlarich SM. A low-temperature solution phase route for
the synthesis of silicon nanoclusters. J Am Chem Soc
1996;118:12461-2.
305. Yang CS, Bley RA, Kauzlarich SM, Lee HWH, Delgado GR. Synthesis
of alkyl-terminated silicon nanoclusters by a solution route. J Am Chem
Soc 1999;121:5191-5.
306. Baldwin RK, Pettigrew KA, Garno JC, Power PP, Liu GY, Kauzlarich
SM. Room temperature solution synthesis of alkyl-capped tetrahedral
shaped silicon nanocrystals. J Am Chem Soc 2002;124:1150-1.
307. Pettigrew KA, Liu Q, Power PP, Kauzlarich SM. Solution synthesis of
alkyl- and alkyl/alkoxy-capped silicon nanoparticles via oxidation of
Mg2Si. Chem Mater 2003;15:4005-11.
308. Cho B, Baek S, Woo HG, Sohn H. Synthesis of silicon quantum dots
showing high quantum efficiency. J Nanosci Nanotechnol
2014;14:5868-72.
309. Nolan BM, Henneberger T, Waibel M, Fassler TF, Kauzlarich SM.
Silicon nanoparticles by the oxidation of [Si4] 4 −- and [Si9] 4 −containing Zintl phases and their corresponding yield. Inorg Chem
2015;54:396-401.
310. Neiner D, Chiu HW, Kauzlarich SM. Low-temperature solution route
to macroscopic amounts of hydrogen terminated silicon nanoparticles.
J Am Chem Soc 2006;128:11016-7.
311. Liu Q, Kauzlarich SM. A new synthetic route for the synthesis of
hydrogen terminated silicon nanoparticles. Mater Sci Eng B-Solid State
Mater Adv Technol 2002;96:72-5.
312. Zhong Y, Peng F, Bao F, Wang S, Ji X, Yang L, et al. Large-scale
aqueous synthesis of fluorescent and biocompatible silicon nanoparticles and their use as highly photostable biological probes. J Am Chem
Soc 2013;135:8350-6.
313. Atkins TM, Thibert A, Larsen DS, Dey S, Browning ND, Kauzlarich
SM. Femtosecond ligand/core dynamics of microwave-assisted
1694
314.
315.
316.
317.
318.
319.
320.
321.
322.
323.
324.
325.
326.
327.
328.
329.
330.
331.
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
synthesized silicon quantum dots in aqueous solution. J Am Chem Soc
2011;133:20664-7.
Atkins TM, Louie AY, Kauzlarich SM. An efficient microwaveassisted synthesis method for the production of water soluble amineterminated Si nanoparticles. Nanotechnology 2012;23:294006.
Hessel CM, Henderson EJ, Veinot JGC. Hydrogen silsesquioxane: A
molecular precursor for nanocrystalline Si-SiO2 composites and
freestanding hydride-surface-terminated silicon nanoparticles. Chem
Mater 2006;18:6139-46.
Henderson EJ, Kelly JA, Veinot JGC. Influence of HSiO1.5 sol–gel
polymer structure and composition on the size and luminescent
properties of silicon nanocrystals. Chem Mater 2009;21:5426-34.
Mastronardi ML, Hennrich F, Henderson EJ, Maier-Flaig F, Blum C,
Reichenbach J, et al. Preparation of monodisperse silicon nanocrystals
using density gradient ultracentrifugation. J Am Chem Soc
2011;133:11928-31.
Mastronardi ML, Maier-Flaig F, Faulkner D, Henderson EJ, Kubel C,
Lemmer U, et al. Size-dependent absolute quantum yields for sizeseparated colloidally-stable silicon nanocrystals. Nano Lett
2012;12:337-42.
Mastronardi ML, Henderson EJ, Puzzo DP, Ozin GA. Small silicon, big
opportunities: The development and future of colloidally-stable
monodisperse silicon nanocrystals. Adv Mater 2012;24:5890-8.
Li ZF, Ruckenstein E. Water-soluble poly(acrylic acid) grafted
luminescent silicon nanoparticles and their use as fluorescent biological
staining labels. Nano Lett 2004;4:1463-7.
Ruizendaal L, Bhattacharjee S, Pournazari K, Rosso-Vasic M, de Haan
LHJ, Alink GM, et al. Synthesis and cytotoxicity of silicon
nanoparticles with covalently attached organic monolayers. Nanotoxicology 2009;3:339-47.
Bhattacharjee S, de Haan LH, Evers NM, Jiang X, Marcelis AT,
Zuilhof H, et al. Role of surface charge and oxidative stress in
cytotoxicity of organic monolayer-coated silicon nanoparticles towards
macrophage NR8383 cells. Part Fibre Toxicol 2010;7:25.
Bhattacharjee S, Rietjens IM, Singh MP, Atkins TM, Purkait TK, Xu Z,
et al. Cytotoxicity of surface-functionalized silicon and germanium
nanoparticles: The dominant role of surface charges. Nanoscale
2013;5:4870-83.
Cheng X, Lowe SB, Ciampi S, Magenau A, Gaus K, Reece PJ, et al.
Versatile "click chemistry" approach to functionalizing silicon quantum
dots: Applications toward fluorescent cellular imaging. Langmuir
2014;30:5209-16.
Ohta S, Shen P, Inasawa S, Yamaguchi Y. Size- and surface chemistrydependent intracellular localization of luminescent silicon quantum dot
aggregates. J Mater Chem 2012;22:10631-8.
Ruizendaal L, Pujari SP, Gevaerts V, Paulusse JM, Zuilhof H.
Biofunctional silicon nanoparticles by means of thiol-ene click
chemistry. Chem Asian J 2011;6:2776-86.
Wang L, Reipa V, Blasic J. Silicon nanoparticles as a luminescent label
to DNA. Bioconjug Chem 2004;15:409-12.
Intartaglia R, Barchanski A, Bagga K, Genovese A, Das G, Wagener P,
et al. Bioconjugated silicon quantum dots from one-step green
synthesis. Nanoscale 2012;4:1271-4.
Erogbogbo F, Swihart MT. Imaging pancreatic cancer with folic acid
terminated luminescent silicon nanocrystals. In: Borsella E, editor.
Bonsai project symposium: Breakthroughs in nanoparticles for bioimaging. Amer Inst Physics, 2 Huntington Quadrangle, Ste 1no1,
Melville, Ny 11747–4501 USARome, ITALY: ENEA Res Ctr Frascati;
2010. p. 35-9.
Ahire JH, Behray M, Webster CA, Wang Q, Sherwood V, Saengkrit N,
et al. Synthesis of carbohydrate capped silicon nanoparticles and their
reduced cytotoxicity, in vivo toxicity, and cellular uptake. Adv Healthc
Mater 2015;4:1877-86.
Lai CH, Hutter J, Hsu CW, Tanaka H, Varela-Aramburu S, De Cola L, et al.
Analysis of carbohydrate-carbohydrate interactions using sugar-functionalized
silicon nanoparticles for cell imaging. Nano Lett 2016;16:807-11.
332. Singh MP, Atkins TM, Muthuswamy E, Kamali S, Tu C, Louie AY, et
al. Development of iron-doped silicon nanoparticles as bimodal
imaging agents. ACS Nano 2012;6:5596-604.
333. Tu C, Ma X, House A, Kauzlarich SM, Louie AY. PET Imaging and
biodistribution of silicon quantum dots in mice. ACS Med Chem Lett
2011;2:285-8.
334. Tu C, Ma X, Pantazis P, Kauzlarich SM, Louie AY. Paramagnetic,
silicon quantum dots for magnetic resonance and two-photon imaging
of macrophages. J Am Chem Soc 2010;132:2016-23.
335. Erogbogbo F, Yong KT, Roy I, Hu R, Law WC, Zhao W, et al. In vivo
targeted cancer imaging, sentinel lymph node mapping and multichannel imaging with biocompatible silicon nanocrystals. ACS Nano
2011;5:413-23.
336. Lim SY, Shen W, Gao Z. Carbon quantum dots and their applications.
Chem Soc Rev 2015;44:362-81.
337. Wang Y, Hu A. Carbon quantum dots: Synthesis, properties and
applications. J Mater Chem C 2014;2:6921-39.
338. Luo PG, Sahu S, Yang S-T, Sonkar SK, Wang J, Wang H, et al. Carbon
“quantum” dots for optical bioimaging. J Mater Chem B 2013;1:2116-27.
339. Xu X, Ray R, Gu Y, Ploehn HJ, Gearheart L, Raker K, et al.
Electrophoretic analysis and purification of fluorescent single-walled
carbon nanotube fragments. J Am Chem Soc 2004;126:12736-7.
340. Sun Y-P, Zhou B, Lin Y, Wang W, Fernando KS, Pathak P, et al.
Quantum-sized carbon dots for bright and colorful photoluminescence.
J Am Chem Soc 2006;128:7756-7.
341. Zhou J, Booker C, Li R, Zhou X, Sham T-K, Sun X, et al. An
electrochemical avenue to blue luminescent nanocrystals from multiwalled carbon nanotubes (MWCNTs). J Am Chem Soc
2007;129:744-5.
342. Li H, He X, Kang Z, Huang H, Liu Y, Liu J, et al. Water-soluble
fluorescent carbon quantum dots and photocatalyst design. Angew
Chem Int Ed Engl 2010;49:4430-4.
343. Peng H, Travas-Sejdic J. Simple aqueous solution route to luminescent
carbogenic dots from carbohydrates. Chem Mater 2009;21:5563-5.
344. Krysmann MJ, Kelarakis A, Giannelis EP. Photoluminescent carbogenic nanoparticles directly derived from crude biomass. Green Chem
2012;14:3141-5.
345. Liu H, Ye T, Mao C. Fluorescent carbon nanoparticles derived from
candle soot. Angew Chem Int Ed Engl 2007;46:6473-5.
346. Sahu S, Behera B, Maiti TK, Mohapatra S. Simple one-step synthesis of
highly luminescent carbon dots from orange juice: Application as
excellent bio-imaging agents. Chem Commun (Camb) 2012;48:8835-7.
347. Zhang B, Cy Liu, Liu Y. A novel one-step approach to synthesize
f l uo r e sc e n t c a r b on n a n o p a r t i c l e s . E u r J I n o r g C h e m
2010;2010:4411-4.
348. Wang X, Cao L, Yang ST, Lu F, Meziani MJ, Tian L, et al. Bandgaplike strong fluorescence in functionalized carbon nanoparticles. Angew
Chem Int Ed Engl 2010;122:5438-42.
349. Zhu S, Meng Q, Wang L, Zhang J, Song Y, Jin H, et al. Highly
photoluminescent carbon dots for multicolor patterning, sensors, and
bioimaging. Angew Chem Int Ed Engl 2013;125:4045-9.
350. Yang Y, Cui J, Zheng M, Hu C, Tan S, Xiao Y, et al. One-step synthesis
of amino-functionalized fluorescent carbon nanoparticles by
hydrothermal carbonization of chitosan. Chem Commun (Camb)
2012;48:380-2.
351. Wang F, Bexiga MG, Anguissola S, Boya P, Simpson JC, Salvati A, et
al. Time resolved study of cell death mechanisms induced by aminemodified polystyrene nanoparticles. Nanoscale 2013;5:10868-76.
352. Zhou J, Yang Y, C-y Zhang. A low-temperature solid-phase method to
synthesize highly fluorescent carbon nitride dots with tunable emission.
Chem Commun (Camb) 2013;49:8605-7.
353. Sun D, Ban R, Zhang P-H, Wu G-H, Zhang J-R, Zhu J-J. Hair fiber as a
precursor for synthesizing of sulfur-and nitrogen-co-doped carbon dots
with tunable luminescence properties. Carbon 2013;64:424-34.
354. Prasad KS, Pallela R, Kim DM, Shim YB. Microwave-assisted one-pot
synthesis of metal-free nitrogen and phosphorus dual-doped
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
355.
356.
357.
358.
359.
360.
361.
362.
363.
364.
365.
366.
367.
368.
369.
370.
371.
372.
373.
374.
375.
376.
nanocarbon for electrocatalysis and cell imaging. Part Part Syst
Charact 2013;30:557-64.
Yang S-T, Cao L, Luo PG, Lu F, Wang X, Wang H, et al. Carbon dots
for optical imaging in vivo. J Am Chem Soc 2009;131:11308-9.
Li W, Zhang Z, Kong B, Feng S, Wang J, Wang L, et al. Simple and green
synthesis of nitrogen-doped photoluminescent carbonaceous nanospheres
for bioimaging. Angew Chem Int Ed Engl 2013;52:8151-5.
Yan F, Zou Y, Wang M, Mu X, Yang N, Chen L. Highly
photoluminescent carbon dots-based fluorescent chemosensors for
sensitive and selective detection of mercury ions and application of
imaging in living cells. Sens Actuat B Chem 2014;192:488-95.
Zhang S, Wang Q, Tian G, Ge H. A fluorescent turn-off/on method for
detection of Cu 2+ and oxalate using carbon dots as fluorescent probes in
aqueous solution. Mater Lett 2014;115:233-6.
Dong Y, Shao J, Chen C, Li H, Wang R, Chi Y, et al. Blue luminescent
graphene quantum dots and graphene oxide prepared by tuning the
carbonization degree of citric acid. Carbon 2012;50:4738-43.
Kong B, Zhu A, Ding C, Zhao X, Li B, Tian Y. Carbon dot-based
inorganic–organic nanosystem for two-photon imaging and biosensing
of pH variation in living cells and tissues. Adv Mater 2012;24:5844-8.
Wee SS, Ng YH, Ng SM. Synthesis of fluorescent carbon dots via
simple acid hydrolysis of bovine serum albumin and its potential as
sensitive sensing probe for lead (II) ions. Talanta 2013;116:71-6.
Wang Q, Huang X, Long Y, Wang X, Zhang H, Zhu R, et al. Hollow
luminescent carbon dots for drug delivery. Carbon 2013;59:192-9.
Li SD, Huang L. Pharmacokinetics and biodistribution of nanoparticles.
Mol Pharm 2008;5:496-504.
Moghimi SM, Hunter AC, Andresen TL. Factors controlling
nanoparticle pharmacokinetics: An integrated analysis and perspective.
Annu Rev Pharmacol Toxicol 2012;52:481-503.
Nam J, Won N, Bang J, Jin H, Park J, Jung S, et al. Surface engineering
of inorganic nanoparticles for imaging and therapy. Adv Drug Deliv
Rev 2013;65:622-48.
Toy R, Peiris PM, Ghaghada KB, Karathanasis E. Shaping cancer
nanomedicine: The effect of particle shape on the in vivo journey of
nanoparticles. Nanomedicine (Lond) 2014;9:121-34.
Wang B, He X, Zhang Z, Zhao Y, Feng W. Metabolism of
nanomaterials in vivo: Blood circulation and organ clearance. Acc
Chem Res 2013;46:761-9.
Liu J, Yu M, Zhou C, Zheng J. Renal clearable inorganic nanoparticles:
A new frontier of bionanotechnology. Mater Today 2013;16:477-86.
Deen WM, Lazzara MJ, Myers BD. Structural determinants of glomerular
permeability. Am J Physiol Renal Physiol 2001;281:F579-96.
Yamagishi Y, Watari A, Hayata Y, Li X, Kondoh M, Yoshioka Y, et al.
Acute and chronic nephrotoxicity of platinum nanoparticles in mice.
Nanoscale Res Lett 2013;8:395.
Sebekova K, Dusinska M, Simon Klenovics K, Kollarova R, Boor P,
Kebis A, et al. Comprehensive assessment of nephrotoxicity of
intravenously administered sodium-oleate-coated ultra-small superparamagnetic iron oxide (USPIO) and titanium dioxide (TiO2)
nanoparticles in rats. Nanotoxicology 2014;8:142-57.
Choi HS, Ipe BI, Misra P, Lee JH, Bawendi MG, Frangioni JV. Tissueand organ-selective biodistribution of NIR fluorescent quantum dots.
Nano Lett 2009;9:2354-9.
Liu F, He X, Zhang J, Zhang H, Wang Z. Employing tryptone as a
general phase transfer agent to produce renal clearable nanodots for
bioimaging. Small 2015;11:3676-85.
Zhou Z, Wang L, Chi X, Bao J, Yang L, Zhao W, et al. Engineered
iron-oxide-based nanoparticles as enhanced T1 contrast agents for
efficient tumor imaging. ACS Nano 2013;7:3287-96.
Bonitatibus Jr PJ, Torres AS, Goddard GD, FitzGerald PF, Kulkarni AM.
Synthesis, characterization, and computed tomography imaging of a tantalum
oxide nanoparticle imaging agent. Chem Commun (Camb) 2010;46:8956-8.
Alric C, Miladi I, Kryza D, Taleb J, Lux F, Bazzi R, et al. The
biodistribution of gold nanoparticles designed for renal clearance.
Nanoscale 2013;5:5930-9.
1695
377. Zhang XD, Wu D, Shen X, Liu PX, Fan FY, Fan SJ. In vivo renal
clearance, biodistribution, toxicity of gold nanoclusters. Biomaterials
2012;33:4628-38.
378. Balogh L, Nigavekar SS, Nair BM, Lesniak W, Zhang C, Sung LY, et
al. Significant effect of size on the in vivo biodistribution of gold
composite nanodevices in mouse tumor models. Nanomedicine
2007;3:281-96.
379. Simpson CA, Salleng KJ, Cliffel DE, Feldheim DL. In vivo toxicity,
biodistribution, and clearance of glutathione-coated gold nanoparticles.
Nanomedicine 2013;9:257-63.
380. Hirn S, Semmler-Behnke M, Schleh C, Wenk A, Lipka J, Schäffler M,
et al. Particle size-dependent and surface charge-dependent biodistribution of gold nanoparticles after intravenous administration. Eur J
Pharm Biopharm 2011;77:407-16.
381. Burns AA, Vider J, Ow H, Herz E, Penate-Medina O, Baumgart M, et
al. Fluorescent silica nanoparticles with efficient urinary excretion for
nanomedicine. Nano Lett 2009;9:442-8.
382. Huang X, Zhang F, Zhu L, Choi KY, Guo N, Guo J, et al. Effect of
injection routes on the biodistribution, clearance, and tumor uptake of
carbon dots. ACS Nano 2013;7:5684-93.
383. Fischer HC, Liu L, Pang KS, Chan WCW. Pharmacokinetics of
nanoscale quantum dots: In vivo distribution, sequestration, and
clearance in the rat. Adv Funct Mater 2006;16:1299-305.
384. Ma N, Marshall AF, Gambhir SS, Rao J. Facile synthesis, silanization,
and biodistribution of biocompatible quantum dots. Small
2010;6:1520-8.
385. Ruggiero A, Villa CH, Bander E, Rey DA, Bergkvist M, Batt CA, et al.
Paradoxical glomerular filtration of carbon nanotubes. Proc Natl Acad
Sci U S A 2010;107:12369-74.
386. Mulvey JJ, Feinberg EN, Alidori S, McDevitt MR, Heller DA,
Scheinberg DA. Synthesis, pharmacokinetics, and biological use of
lysine-modified single-walled carbon nanotubes. Int J Nanomedicine
2014;9:4245-55.
387. Liang X, Wang H, Zhu Y, Zhang R, Cogger VC, Liu X, et al. Short- and
long-term tracking of anionic ultrasmall nanoparticles in kidney. ACS
Nano 2016;10:387-95.
388. Zhang XD, Yang J, Song SS, Long W, Chen J, Shen X, et al. Passing
through the renal clearance barrier: Toward ultrasmall sizes with stable
ligands for potential clinical applications. Int J Nanomedicine
2014;9:2069-72.
389. Gu L, Hall DJ, Qin Z, Anglin E, Joo J, Mooney DJ, et al. In vivo timegated fluorescence imaging with biodegradable luminescent porous
silicon nanoparticles. Nat Commun 2013;4:2326.
390. Chou LY, Zagorovsky K, Chan WC. DNA assembly of nanoparticle
superstructures for controlled biological delivery and elimination. Nat
Nanotechnol 2014;9:148-55.
391. Yang S, Sun S, Zhou C, Hao G, Liu J, Ramezani S, et al. Renal
clearance and degradation of glutathione-coated copper nanoparticles.
Bioconjug Chem 2015;26:511-9.
392. Cassano D, Rota Martir D, Signore G, Piazza V, Voliani V.
Biodegradable hollow silica nanospheres containing gold nanoparticle
arrays. Chem Commun (Camb) 2015;51:9939-41.
393. Tam JM, Tam JO, Murthy A, Ingram DR, Ma LL, Travis K, et al.
Controlled assembly of biodegradable plasmonic nanoclusters for nearinfrared imaging and therapeutic applications. ACS Nano
2010;4:2178-84.
394. Hon NK, Shaposhnik Z, Diebold ED, Tamanoi F, Jalali B. Tailoring the
biodegradability of porous silicon nanoparticles. J Biomed Mater Res A
2012;100:3416-21.
395. Sadauskas E, Wallin H, Stoltenberg M, Vogel U, Doering P, Larsen A,
et al. Kupffer cells are central in the removal of nanoparticles from the
organism. Part Fibre Toxicol 2007;4:10.
396. Sørensen KK, McCourt P, Berg T, Crossley C, Le Couteur D, Wake K,
et al. The scavenger endothelial cell: A new player in homeostasis
and immunity. Am J Physiol Regul Integr Comp Physiol
2012;303:R1217-30.
1696
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
397. Smedsrød B. Clearance function of scavenger endothelial cells. Comp
Hepatol 2004;3(Suppl 1):S22.
398. Bargheer D, Giemsa A, Freund B, Heine M, Waurisch C, Stachowski
GM, et al. The distribution and degradation of radiolabeled superparamagnetic iron oxide nanoparticles and quantum dots in mice.
Beilstein J Nanotechnol 2015;6:111-23.
399. Braet F, Wisse E. Structural and functional aspects of liver sinusoidal
endothelial cell fenestrae: A review. Comp Hepatol 2002;1:1.
400. Caballero-Díaz E, Pfeiffer C, Kastl L, Rivera-Gil P, Simonet B,
Valcárcel M, et al. The toxicity of silver nanoparticles depends on their
uptake by cells and thus on their surface chemistry. Part Part Syst
Charact 2013;30:1079-85.
401. Kreyling WG, Abdelmonem AM, Ali Z, Alves F, Geiser M, Haberl N,
et al. In vivo integrity of polymer-coated gold nanoparticles. Nat
Nanotechnol 2015;10:619-23.
402. Lartigue L, Alloyeau D, Kolosnjaj-Tabi J, Javed Y, Guardia P,
Riedinger A, et al. Biodegradation of iron oxide nanocubes: Highresolution in situ monitoring. ACS Nano 2013;7:3939-52.
403. Levy M, Luciani N, Alloyeau D, Elgrabli D, Deveaux V, Pechoux C, et
al. Long term in vivo biotransformation of iron oxide nanoparticles.
Biomaterials 2011;32:3988-99.
404. Kolosnjaj-Tabi J, Javed Y, Lartigue L, Volatron J, Elgrabli D,
Marangon I, et al. The one year fate of iron oxide coated gold
nanoparticles in mice. ACS Nano 2015;9:7925-39.
405. Estevanato LL, Lacava LM, Carvalho LC, Azevedo RB, Silva O,
Pelegrini F, et al. Long-term biodistribution and biocompatibility
investigation of dextran-coated magnetite nanoparticle using mice as
the animal model. J Biomed Nanotechnol 2012;8:301-8.
406. Briley-Saebo K, Bjørnerud A, Grant D, Ahlstrom H, Berg T, Kindberg GM.
Hepatic cellular distribution and degradation of iron oxide nanoparticles
following single intravenous injection in rats: Implications for magnetic
resonance imaging. Cell Tissue Res 2004;316:315-23.
407. Pouliquen D, Le Jeune JJ, Perdrisot R, Ermias A, Jallet P. Iron oxide
nanoparticles for use as an MRI contrast agent: Pharmacokinetics and
metabolism. Magn Reson Imaging 1991;9:275-83.
408. Gu L, Fang RH, Sailor MJ, Park JH. In vivo clearance and toxicity of
monodisperse iron oxide nanocrystals. ACS Nano 2012;6:4947-54.
409. Weissleder R, Stark DD, Engelstad BL, Bacon BR, Compton CC,
White DL, et al. Superparamagnetic iron oxide: Pharmacokinetics and
toxicity. AJR Am J Roentgenol 1989;152:167-73.
410. Pan Y, Leifert A, Ruau D, Neuss S, Bornemann J, Schmid G, et al. Gold
nanoparticles of diameter 1.4 nm trigger necrosis by oxidative stress
and mitochondrial damage. Small 2009;5:2067-76.
411. AshaRani PV, Low Kah Mun G, Hande MP, Valiyaveettil S.
Cytotoxicity and genotoxicity of silver nanoparticles in human cells.
ACS Nano 2009;3:279-90.
412. Soenen SJ, Manshian B, Montenegro JM, Amin F, Meermann B,
Thiron T, et al. Cytotoxic effects of gold nanoparticles: A multiparametric study. ACS Nano 2012;6:5767-83.
413. Lee HM, Shin DM, Song HM, Yuk JM, Lee ZW, Lee SH, et al.
Nanoparticles up-regulate tumor necrosis factor-alpha and CXCL8 via
reactive oxygen species and mitogen-activated protein kinase activation. Toxicol Appl Pharmacol 2009;238:160-9.
414. Panas A, Marquardt C, Nalcaci O, Bockhorn H, Baumann W, Paur HR,
et al. Screening of different metal oxide nanoparticles reveals selective
toxicity and inflammatory potential of silica nanoparticles in lung
epithelial cells and macrophages. Nanotoxicology 2013;7:259-73.
415. Park EJ, Park K. Oxidative stress and pro-inflammatory responses
induced by silica nanoparticles in vivo and in vitro. Toxicol Lett
2009;184:18-25.
416. Lunov O, Syrovets T, Röcker C, Tron K, Nienhaus GU, Rasche V, et al.
Lysosomal degradation of the carboxydextran shell of coated superparamagnetic iron oxide nanoparticles and the fate of professional
phagocytes. Biomaterials 2010;31:9015-22.
417. Lunov O, Syrovets T, Buchele B, Jiang X, Rocker C, Tron K, et al. The
effect of carboxydextran-coated superparamagnetic iron oxide nano-
418.
419.
420.
421.
422.
423.
424.
425.
426.
427.
428.
429.
430.
431.
432.
433.
434.
435.
436.
437.
438.
439.
particles on c-Jun N-terminal kinase-mediated apoptosis in human
macrophages. Biomaterials 2010;31:5063-71.
Chattopadhyay S, Dash SK, Kar Mahapatra S, Tripathy S, Ghosh T,
Das B, et al. Chitosan-modified cobalt oxide nanoparticles stimulate
TNF-alpha-mediated apoptosis in human leukemic cells. J Biol Inorg
Chem 2014;19:399-414.
Lovric J, Cho SJ, Winnik FM, Maysinger D. Unmodified cadmium
telluride quantum dots induce reactive oxygen species formation
leading to multiple organelle damage and cell death. Chem Biol
2005;12:1227-34.
Bertrand N, Wu J, Xu X, Kamaly N, Farokhzad OC. Cancer
nanotechnology: The impact of passive and active targeting in the era
of modern cancer biology. Adv Drug Deliv Rev 2014;66:2-25.
Maeda H. The enhanced permeability and retention (EPR) effect in
tumor vasculature: The key role of tumor-selective macromolecular
drug targeting. Adv Enzyme Regul 2001;41:189-207.
Iyer AK, Khaled G, Fang J, Maeda H. Exploiting the enhanced
permeability and retention effect for tumor targeting. Drug Discov
Today 2006;11:812-8.
Yamashita F, Hashida M. Pharmacokinetic considerations for targeted
drug delivery. Adv Drug Deliv Rev 2013;65:139-47.
Nakamura H, Jun F, Maeda H. Development of next-generation
macromolecular drugs based on the EPR effect: Challenges and pitfalls.
Expert Opin Drug Deliv 2015;12:53-64.
Matsumura Y, Maeda H. A new concept for macromolecular
therapeutics in cancer chemotherapy: Mechanism of tumoritropic
accumulation of proteins and the antitumor agent smancs. Cancer Res
1986;46:6387-92.
Kiessling F, Mertens ME, Grimm J, Lammers T. Nanoparticles for
imaging: Top or flop? Radiology 2014;273:10-28.
Yu M, Zheng J. Clearance pathways and tumor targeting of imaging
nanoparticles. ACS Nano 2015;9:6655-74.
Lammers T, Kiessling F, Hennink WE, Storm G. Drug targeting to
tumors: Principles, pitfalls and (pre-) clinical progress. J Control
Release 2012;161:175-87.
Bazak R, Houri M, El Achy S, Kamel S, Refaat T. Cancer active
targeting by nanoparticles: A comprehensive review of literature. J
Cancer Res Clin Oncol 2015;141:769-84.
Ruoslahti E. Peptides as targeting elements and tissue penetration
devices for nanoparticles. Adv Mater 2012;24:3747-56.
Danhier F, Le Breton A, Preat V. RGD-based strategies to target αVβ3
integrin in cancer therapy and diagnosis. Mol Pharm 2012;9:2961-73.
Haubner R, Maschauer S, Prante O. PET radiopharmaceuticals for
imaging integrin expression: Tracers in clinical studies and recent
developments. Biomed Res Int 2014;2014:871609.
Cai H, Conti PS. RGD-based PET tracers for imaging receptor integrin
αVβ3 expression. J Labelled Comp Radiopharm 2013;56:264-79.
Liu Z, Wang F. Development of RGD-based radiotracers for tumor
imaging and therapy: Translating from bench to bedside. Curr Mol
Med 2013;13:1487-505.
Gaertner FC, Kessler H, Wester HJ, Schwaiger M, Beer AJ.
Radiolabelled RGD peptides for imaging and therapy. Eur J Nucl
Med Mol Imaging 2012;39(Suppl 1):S126-38.
Choi HS, Liu W, Liu F, Nasr K, Misra P, Bawendi MG, et al. Design
considerations for tumour-targeted nanoparticles. Nat Nanotechnol
2010;5:42-7.
Lu Y, Zhong Y, Wang J, Su Y, Peng F, Zhou Y, et al. Aqueous
synthesized near-infrared-emitting quantum dots for RGD-based in
vivo active tumour targeting. Nanotechnology 2013;24:135101.
He H, Feng M, Hu J, Chen C, Wang J, Wang X, et al. Designed short
RGD peptides for one-pot aqueous synthesis of integrin-binding
CdTe and CdZnTe quantum dots. ACS Appl Mater Interfaces
2012;4:6362-70.
Li Y, Li Z, Wang X, Liu F, Cheng Y, Zhang B, et al. In vivo cancer
targeting and imaging-guided surgery with near infrared-emitting
quantum dot bioconjugates. Theranostics 2012;2:769-76.
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
440. Bradbury MS, Phillips E, Montero PH, Cheal SM, Stambuk H, Durack
JC, et al. Clinically-translated silica nanoparticles as dual-modality
cancer-targeted probes for image-guided surgery and interventions.
Integr Biol (Camb) 2013;5:74-86.
441. Phillips E, Penate-Medina O, Zanzonico PB, Carvajal RD, Mohan P,
Ye Y, et al. Clinical translation of an ultrasmall inorganic optical-PET
imaging nanoparticle probe. Sci Transl Med 2014;6:260ra149.
442. Kiessling F, Huppert J, Zhang C, Jayapaul J, Zwick S, Woenne EC, et
al. RGD-labeled USPIO inhibits adhesion and endocytotic activity of
αVβ3-integrin-expressing glioma cells and only accumulates in the
vascular tumor compartment. Radiology 2009;253:462-9.
443. Lin RY, Dayananda K, Chen TJ, Chen CY, Liu GC, Lin KL, et al.
Targeted RGD nanoparticles for highly sensitive in vivo integrin
receptor imaging. Contrast Media Mol Imaging 2012;7:7-18.
444. Xie J, Chen K, Lee HY, Xu C, Hsu AR, Peng S, et al. Ultrasmall
c(RGDyK)-coated Fe3O4 nanoparticles and their specific targeting to
integrin αVβ3-rich tumor cells. J Am Chem Soc 2008;130:7542-3.
445. Liu C, Liu DB, Long GX, Wang JF, Mei Q, Hu GY, et al. Specific
targeting of angiogenesis in lung cancer with RGD-conjugated
ultrasmall superparamagnetic iron oxide particles using a 4.7T
magnetic resonance scanner. Chin Med J (Engl) 2013;126:2242-7.
446. Luo Y, Yang J, Yan Y, Li J, Shen M, Zhang G, et al. RGDfunctionalized ultrasmall iron oxide nanoparticles for targeted T1weighted MR imaging of gliomas. Nanoscale 2015;7:14538-46.
447. Song C, Zhong Y, Jiang X, Peng F, Lu Y, Ji X, et al. Peptide-conjugated
fluorescent silicon nanoparticles enabling simultaneous tracking and specific
destruction of cancer cells. Anal Chem 2015;87:6718-23.
448. Poon W, Zhang X, Bekah D, Teodoro JG, Nadeau JL. Targeting B16
tumors in vivo with peptide-conjugated gold nanoparticles. Nanotechnology 2015;26:285101.
449. Choi J, Burns AA, Williams RM, Zhou Z, Flesken-Nikitin A, Zipfel
WR, et al. Core-shell silica nanoparticles as fluorescent labels for
nanomedicine. J Biomed Opt 2007;12:064007.
450. Accardo A, Aloj L, Aurilio M, Morelli G, Tesauro D. Receptor binding
peptides for target-selective delivery of nanoparticles encapsulated
drugs. Int J Nanomedicine 2014;9:1537-57.
451. Ferro-Flores G, Ramirez Fde M, Melendez-Alafort L, Santos-Cuevas
CL. Peptides for in vivo target-specific cancer imaging. Mini Rev Med
Chem 2010;10:87-97.
452. Miao Y, Quinn TP. Peptide-targeted radionuclide therapy for
melanoma. Crit Rev Oncol Hematol 2008;67:213-28.
453. Fani M, Maecke HR. Radiopharmaceutical development of radiolabelled peptides. Eur J Nucl Med Mol Imaging 2012;39(Suppl
1):S11-30.
454. Dash A, Chakraborty S, Pillai MR, Knapp Jr FF. Peptide receptor
radionuclide therapy: An overview. Cancer Biother Radiopharm
2015;30:47-71.
455. Hofland LJ, van der Hoek J, Feelders R, van der Lely AJ, de Herder W,
Lamberts SW. Pre-clinical and clinical experiences with novel
somatostatin ligands: Advantages, disadvantages and new prospects.
J Endocrinol Invest 2005;28:36-42.
456. Maecke HR, Hofmann M, Haberkorn U. 68Ga-labeled peptides in
tumor imaging. J Nucl Med 2005;46(Suppl 1):172S-8S.
457. Laznicek M, Laznickova A, Macke HR, Eisenwiener K, Reubi JC, Wenger
S. Octreotide and octreotate derivatives radiolabeled with yttrium:
Pharmacokinetics in rats. Cancer Biother Radiopharm 2002;17:527-33.
458. Surujpaul PP, Gutierrez-Wing C, Ocampo-Garcia B, Ramirez Fde M,
Arteaga de Murphy C, Pedraza-Lopez M, et al. Gold nanoparticles
conjugated to [Tyr3]octreotide peptide. Biophys Chem 2008;138:83-90.
459. Mendoza-Nava H, Ferro-Flores G, Ocampo-Garcia B, SermentGuerrero J, Santos-Cuevas C, Jimenez-Mancilla N, et al. Laser heating
of gold nanospheres functionalized with octreotide: In vitro effect on
HeLa cell viability. Photomed Laser Surg 2013;31:17-22.
460. Sreenivasan VK, Kim EJ, Goodchild AK, Connor M, Zvyagin AV.
Targeting somatostatin receptors using in situ-bioconjugated fluorescent nanoparticles. Nanomedicine (Lond) 2012;7:1551-60.
1697
461. Feng Q, Yu MZ, Wang JC, Hou WJ, Gao LY, Ma XF, et al. Synergistic
inhibition of breast cancer by co-delivery of VEGF siRNA and
paclitaxel via vapreotide-modified core-shell nanoparticles. Biomaterials 2014;35:5028-38.
462. Zhu J, Chin J, Wangler C, Wangler B, Lennox RB, Schirrmacher R.
Rapid 18F-labeling and loading of PEGylated gold nanoparticles for in
vivo applications. Bioconjug Chem 2014;25:1143-50.
463. Li X, Du X, Huo T, Liu X, Zhang S, Yuan F. Specific targeting of
breast tumor by octreotide-conjugated ultrasmall superparamagnetic
iron oxide particles using a clinical 3.0-Tesla magnetic resonance
scanner. Acta Radiol 2009;50:583-94.
464. Smith CJ, Volkert WA, Hoffman TJ. Radiolabeled peptide conjugates
for targeting of the bombesin receptor superfamily subtypes. Nucl Med
Biol 2005;32:733-40.
465. Schottelius M, Wester HJ. Molecular imaging targeting peptide
receptors. Methods 2009;48:161-77.
466. Schroeder RP, van Weerden WM, Bangma C, Krenning EP, de Jong M.
Peptide receptor imaging of prostate cancer with radiolabelled
bombesin analogues. Methods 2009;48:200-4.
467. Montet X, Weissleder R, Josephson L. Imaging pancreatic cancer with
a peptide-nanoparticle conjugate targeted to normal pancreas. Bioconjug Chem 2006;17:905-11.
468. Martin AL, Hickey JL, Ablack AL, Lewis JD, Luyt LG, Gillies ER.
Synthesis of bombesin-functionalized iron oxide nanoparticles and
their specific uptake in prostate cancer cells. J Nanopart Res
2009;12:1599-608.
469. Hosta-Rigau L, Olmedo I, Arbiol J, Cruz LJ, Kogan MJ, Albericio F.
Multifunctionalized gold nanoparticles with peptides targeted to
gastrin-releasing peptide receptor of a tumor cell line. Bioconjug
Chem 2010;21:1070-8.
470. Mendoza-Sánchez AN, Ferro-Flores G, Ocampo-García BE, MoralesAvila E, de M Ramírez F, De León-Rodríguez LM, et al. Lys3bombesin conjugated to 99mTc-labelled gold nanoparticles for in vivo
gastrin releasing peptide-receptor imaging. J Biomed Nanotechnol
2010;6:375-84.
471. Chanda N, Kattumuri V, Shukla R, Zambre A, Katti K, Upendran A, et
al. Bombesin functionalized gold nanoparticles show in vitro and in
vivo cancer receptor specificity. Proc Natl Acad Sci U S A
2010;107:8760-5.
472. Jimenez-Mancilla N, Ferro-Flores G, Santos-Cuevas C, OcampoGarcia B, Luna-Gutierrez M, Azorin-Vega E, et al. Multifunctional
targeted therapy system based on 99mTc/ 177Lu-labeled gold nanoparticles-Tat(49–57)-Lys 3 -bombesin internalized in nuclei of prostate
cancer cells. J Labelled Comp Radiopharm 2013;56:663-71.
473. Suresh D, Zambre A, Chanda N, Hoffman TJ, Smith CJ, Robertson JD,
et al. Bombesin peptide conjugated gold nanocages internalize via
clathrin mediated endocytosis. Bioconjug Chem 2014;25:1565-79.
474. Jafari A, Salouti M, Shayesteh SF, Heidari Z, Rajabi AB, Boustani K, et
al. Synthesis and characterization of Bombesin-superparamagnetic iron
oxide nanoparticles as a targeted contrast agent for imaging of breast
cancer using MRI. Nanotechnology 2015;26:075101.
475. Reubi JC. Peptide receptors as molecular targets for cancer diagnosis
and therapy. Endocr Rev 2003;24:389-427.
476. Raposinho PD, Xavier C, Correia JDG, Falcão S, Gomes P, Santos I.
Melanoma targeting with α-melanocyte stimulating hormone analogs
labeled with fac-[ 99mTc(CO)3] +: Effect of cyclization on tumor-seeking
properties. J Biol Inorg Chem 2008;13:449-59.
477. von Guggenberg E, Sallegger W, Helbok A, Ocak M, King R, Mather SJ, et
al. Cyclic minigastrin analogues for gastrin receptor scintigraphy with
Technetium-99m: Preclinical evaluation. J Med Chem 2009;52:4786-93.
478. Quinn T, Zhang X, Miao Y. Targeted melanoma imaging and therapy
with radiolabeled alpha-melanocyte stimulating hormone peptide
analogues. G Ital Dermatol Venereol 2010;145:245-58.
479. Kolhatkar R, Lote A, Khambati H. Active tumor targeting of
nanomaterials using folic acid, transferrin and integrin receptors.
Curr Drug Discov Technol 2011;8:197-206.
1698
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
480. Franzen S. A comparison of peptide and folate receptor targeting of
cancer cells: From single agent to nanoparticle. Expert Opin Drug
Deliv 2011;8:281-98.
481. Tu Q, Zhang Y, Liu R, Wang JC, Li L, Nie N, et al. Active drug
targeting of disease by nanoparticles functionalized with ligand to
folate receptor. Curr Med Chem 2012;19:3152-62.
482. Weitman SD, Lark RH, Coney LR, Fort DW, Frasca V, Zurawski Jr
VR, et al. Distribution of the folate receptor GP38 in normal and
malignant cell lines and tissues. Cancer Res 1992;52:3396-401.
483. Parker N, Turk MJ, Westrick E, Lewis JD, Low PS, Leamon CP. Folate
receptor expression in carcinomas and normal tissues determined by a
quantitative radioligand binding assay. Anal Biochem 2005;338:284-93.
484. Das M, Mishra D, Dhak P, Gupta S, Maiti TK, Basak A, et al.
Biofunctionalized, phosphonate-grafted, ultrasmall iron oxide nanoparticles for combined targeted cancer therapy and multimodal
imaging. Small 2009;5:2883-93.
485. Jalilian AR, Hosseini-Salekdeh SL, Mahmoudi M, Yousefnia H,
Majdabadi A, Pouladian M. Preparation and biological evaluation of
radiolabeled-folate embedded superparamagnetic nanoparticles in wildtype rats. J Radioanal Nucl Chem 2011;287:119-27.
486. Qiao J, Mu X, Qi L, Deng J, Mao L. Folic acid-functionalized
fluorescent gold nanoclusters with polymers as linkers for cancer cell
imaging. Chem Commun (Camb) 2013;49:8030-2.
487. Yin Q, Jin XY, Yang GC, Jiang CH, Song ZK, Sun GY. Biocompatible
folate-modified Gd 3+/Yb 3+-doped ZnO nanoparticles for dualmodal
MRI/CT imaging. RSC Adv 2014;4:53561-9.
488. Maresca KP, Hillier SM, Femia FJ, Keith D, Barone C, Joyal JL, et al.
A series of halogenated heterodimeric inhibitors of prostate specific
membrane antigen (PSMA) as radiolabeled probes for targeting
prostate cancer. J Med Chem 2009;52:347-57.
489. Hillier SM, Maresca KP, Femia FJ, Marquis JC, Foss CA, Nguyen N, et
al. Preclinical evaluation of novel glutamate-urea-lysine analogues that
target prostate-specific membrane antigen as molecular imaging
pharmaceuticals for prostate cancer. Cancer Res 2009;69:6932-40.
490. Hrkach J, Von Hoff D, Mukkaram Ali M, Andrianova E, Auer J,
Campbell T, et al. Preclinical development and clinical translation of a
PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci Transl Med 2012;4:128ra39.
491. Nie G, Bai Z, Yu W, Chen J. Electrochemiluminescence biosensor
based on conducting poly(5-formylindole) for sensitive detection of
Ramos cells. Biomacromolecules 2013;14:834-40.
492. Eder M, Schäfer M, Bauder-Wüst U, Hull WE, Wängler C, Mier W, et
al. 68Ga-complex lipophilicity and the targeting property of a ureabased PSMA inhibitor for PET imaging. Bioconjug Chem
2012;23:688-97.
493. Eder M, Neels O, Müller M, Bauder-Wüst U, Remde Y, Schäfer M, et
al. Novel preclinical and radiopharmaceutical aspects of [ 68Ga]GaPSMA-HBED-CC: A new PET tracer for imaging of prostate cancer.
Pharmaceuticals (Basel) 2014;7:779-96.
494. Kratochwil C, Giesel FL, Eder M, Afshar-Oromieh A, Benešová M,
Mier W, et al. [ 177Lu]Lutetium-labelled PSMA ligand-induced
remission in a patient with metastatic prostate cancer. Eur J Nucl
Med Mol Imaging 2015;42:987-8.
495. Benešová M, Schäfer M, Bauder-Wüst U, Afshar-Oromieh A,
Kratochwil C, Mier W, et al. Preclinical evaluation of a tailor-made
DOTA-conjugated PSMA inhibitor with optimized linker moiety for
imaging and endoradiotherapy of prostate cancer. J Nucl Med
2015;56:914-20.
496. Haberkorn U, Kopka K, Hadaschik B. Positron emission tomographycomputed tomography with prostate-specific membrane antigen ligands as a
promising tool for imaging of prostate cancer. Eur Urol 2016;69:397-9.
497. Afshar-Oromieh A, Hetzheim H, Kratochwil C, Benešová M, Eder M,
Neels OC, et al. The theranostic PSMA ligand PSMA-617 in the
diagnosis of prostate cancer by PET/CT: Biodistribution in humans,
radiation dosimetry, and first evaluation of tumor lesions. J Nucl Med
2015;56:1697-705.
498. Liolios CC, Schäfer M, Haberkorn U, Eder M, Kopka K. Novel
bispecific PSMA/GRPr targeting radioligands with optimized pharmacokinetics for improved PET imaging of prostate cancer. Bioconjug
Chem 2016;27:737-51.
499. Haberkorn U, Eder M, Kopka K, Babich JW, Eisenhut M. New
strategies in prostate cancer: Prostate-specific membrane antigen
(PSMA) ligands for diagnosis and therapy. Clin Cancer Res
2016;22:9-15.
500. Felber M, Bauwens M, Mateos JM, Imstepf S, Mottaghy FM, Alberto
R. 99mTc radiolabeling and biological evaluation of nanoparticles
functionalized with a versatile coating ligand. Chemistry
2015;21:6090-9.
501. Moon SH, Yang BY, Kim YJ, Hong MK, Lee YS, Lee DS, et al.
Development of a complementary PET/MR dual-modal imaging probe
for targeting prostate-specific membrane antigen (PSMA). Nanomedicine 2015;12:871-9.
502. Nord K, Gunneriusson E, Ringdahl J, Stahl S, Uhlen M, Nygren PA.
Binding proteins selected from combinatorial libraries of an alphahelical bacterial receptor domain. Nat Biotechnol 1997;15:772-7.
503. Orlova A, Magnusson M, Eriksson TL, Nilsson M, Larsson B, HöidenGuthenberg I, et al. Tumor imaging using a picomolar affinity HER2
binding affibody molecule. Cancer Res 2006;66:4339-48.
504. Tolmachev V, Tran TA, Rosik D, Sjöberg A, Abrahmsen L, Orlova A.
Tumor targeting using affibody molecules: Interplay of affinity, target
expression level, and binding site composition. J Nucl Med
2012;53:953-60.
505. Alexis F, Basto P, Levy-Nissenbaum E, Radovic-Moreno AF, Zhang L,
Pridgen E, et al. HER-2-targeted nanoparticle-affibody bioconjugates
for cancer therapy. ChemMedChem 2008;3:1839-43.
506. Kinoshita M, Yoshioka Y, Okita Y, Hashimoto N, Yoshimine T. MR
molecular imaging of HER-2 in a murine tumor xenograft by SPIO
labeling of anti-HER-2 affibody. Contrast Media Mol Imaging
2010;5:18-22.
507. Gao J, Chen K, Miao Z, Ren G, Chen X, Gambhir SS, et al. Affibodybased nanoprobes for HER2-expressing cell and tumor imaging. Biomaterials 2011;32:2141-8.
508. Jokerst JV, Miao Z, Zavaleta C, Cheng Z, Gambhir SS. Affibodyfunctionalized gold-silica nanoparticles for Raman molecular imaging
of the epidermal growth factor receptor. Small 2011;7:625-33.
509. Yang M, Cheng K, Qi S, Liu H, Jiang Y, Jiang H, et al. Affibody
modified and radiolabeled gold-iron oxide hetero-nanostructures for
tumor PET, optical and MR imaging. Biomaterials 2013;34:2796-806.
510. Satpathy M, Wang L, Zielinski R, Qian W, Lipowska M, Capala J, et al.
Active targeting using HER-2-affibody-conjugated nanoparticles
enabled sensitive and specific imaging of orthotopic HER-2 positive
ovarian tumors. Small 2014;10:544-55.
511. Satpathy M, Zielinski R, Lyakhov I, Yang L. Optical imaging of
ovarian cancer using HER-2 affibody conjugated nanoparticles.
Methods Mol Biol 2015;1219:171-85.
512. Muyldermans S, Lauwereys M. Unique single-domain antigen binding
fragments derived from naturally occurring camel heavy-chain
antibodies. J Mol Recognit 1999;12:131-40.
513. Muyldermans S. Nanobodies: Natural single-domain antibodies. Annu
Rev Biochem 2013;82:775-97.
514. Desmyter A, Spinelli S, Roussel A, Cambillau C. Camelid nanobodies:
Killing two birds with one stone. Curr Opin Struct Biol 2015;32C:1-8.
515. Vaneycken I, D'Huyvetter M, Hernot S, De Vos J, Xavier C, Devoogdt
N, et al. Immuno-imaging using nanobodies. Curr Opin Biotechnol
2011;22:877-81.
516. De Vos J, Devoogdt N, Lahoutte T, Muyldermans S. Camelid singledomain antibody-fragment engineering for (pre)clinical in vivo
molecular imaging applications: Adjusting the bullet to its target. Expert Opin Biol Ther 2013;13:1149-60.
517. Saerens D, Ghassabeh GH, Muyldermans S. Single-domain antibodies
as building blocks for novel therapeutics. Curr Opin Pharmacol
2008;8:600-8.
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
518. D'Huyvetter M, Xavier C, Caveliers V, Lahoutte T, Muyldermans S,
Devoogdt N. Radiolabeled nanobodies as theranostic tools in targeted
radionuclide therapy of cancer. Expert Opin Drug Deliv
2014;11:1939-54.
519. Kijanka M, Dorresteijn B, Oliveira S, van Bergen en Henegouwen PM.
Nanobody-based cancer therapy of solid tumors. Nanomedicine (Lond)
2015;10:161-74.
520. Keyaerts M, Xavier C, Heemskerk J, Devoogdt N, Everaert H, Ackaert
C, et al. Phase I study of 68Ga-HER2-nanobody for PET/CT assessment
of HER2 expression in breast carcinoma. J Nucl Med 2016;57:27-33.
521. Iqbal U, Albaghdadi H, Luo Y, Arbabi M, Desvaux C, Veres T, et al.
Molecular imaging of glioblastoma multiforme using anti-insulin-like
growth factor-binding protein-7 single-domain antibodies. Br J Cancer
2010;103:1606-16.
522. Van de Broek B, Devoogdt N, D'Hollander A, Gijs HL, Jans K, Lagae
L, et al. Specific cell targeting with nanobody conjugated branched gold
nanoparticles for photothermal therapy. ACS Nano 2011;5:4319-28.
523. Zaman MB, Baral TN, Jakubek ZJ, Zhang J, Wu X, Lai E, et al. Singledomain antibody bioconjugated near-IR quantum dots for targeted
cellular imaging of pancreatic cancer. J Nanosci Nanotechnol
2011;11:3757-63.
524. Tomanek B, Iqbal U, Blasiak B, Abulrob A, Albaghdadi H, Matyas JR,
et al. Evaluation of brain tumor vessels specific contrast agents for
glioblastoma imaging. Neuro Oncol 2012;14:53-63.
525. Sukhanova A, Even-Desrumeaux K, Kisserli A, Tabary T, Reveil B,
Millot JM, et al. Oriented conjugates of single-domain antibodies and
quantum dots: Toward a new generation of ultrasmall diagnostic
nanoprobes. Nanomedicine 2012;8:516-25.
526. Fatehi D, Baral TN, Abulrob A. In vivo imaging of brain cancer using
epidermal growth factor single domain antibody bioconjugated to nearinfrared quantum dots. J Nanosci Nanotechnol 2014;14:5355-62.
527. Hafian H, Sukhanova A, Turini M, Chames P, Baty D, Pluot M, et al.
Multiphoton imaging of tumor biomarkers with conjugates of singledomain antibodies and quantum dots. Nanomedicine 2014;10:1701-9.
528. Brazhnik K, Nabiev I, Sukhanova A. Oriented conjugation of singledomain antibodies and quantum dots. Methods Mol Biol
2014;1199:129-40.
529. Zarschler K, Zscheppang K, Kapplusch F, Cordes N, Stephan H.
Single-domain antibodies: Next-generation targeting vectors for
molecular imaging. Nucl Med Biol 2014;41:628.
530. Zarschler K, Prapainop K, Mahon E, Rocks L, Bramini M, Kelly PM, et
al. Diagnostic nanoparticle targeting of the EGF-receptor in complex
biological conditions using single-domain antibodies. Nanoscale
2014;6:6046-56.
531. Rousserie G, Grinevich R, Brazhnik K, Even-Desrumeaux K, Reveil B,
Tabary T, et al. Detection of carcinoembryonic antigen using singledomain or full-size antibodies stained with quantum dot conjugates.
Anal Biochem 2015;478:26-32.
532. Vincke C, Loris R, Saerens D, Martinez-Rodriguez S, Muyldermans S,
Conrath K. General strategy to humanize a camelid single-domain
antibody and identification of a universal humanized nanobody
scaffold. J Biol Chem 2009;284:3273-84.
533. Hu M, Zhang K. The application of aptamers in cancer research: An upto-date review. Future Oncol 2013;9:369-76.
534. Sun H, Zhu X, Lu PY, Rosato RR, Tan W, Zu Y. Oligonucleotide
aptamers: New tools for targeted cancer therapy. Mol Ther Nucleic
Acids 2014;3:e182.
535. Xiao Z, Farokhzad OC. Aptamer-functionalized nanoparticles for
medical applications: Challenges and opportunities. ACS Nano
2012;6:3670-6.
536. Reinemann C, Strehlitz B. Aptamer-modified nanoparticles and their use in
cancer diagnostics and treatment. Swiss Med Wkly 2014;144:w13908.
537. Bagalkot V, Zhang L, Levy-Nissenbaum E, Jon S, Kantoff PW, Langer
R, et al. Quantum dot-aptamer conjugates for synchronous cancer
imaging, therapy, and sensing of drug delivery based on bifluorescence resonance energy transfer. Nano Lett 2007;7:3065-70.
1699
538. Wang AZ, Bagalkot V, Vasilliou CC, Gu F, Alexis F, Zhang L, et al.
Superparamagnetic iron oxide nanoparticle-aptamer bioconjugates for
combined prostate cancer imaging and therapy. ChemMedChem
2008;3:1311-5.
539. Javier DJ, Nitin N, Levy M, Ellington A, Richards-Kortum R.
Aptamer-targeted gold nanoparticles as molecular-specific contrast
agents for reflectance imaging. Bioconjug Chem 2008;19:1309-12.
540. Walter JG, Petersen S, Stahl F, Scheper T, Barcikowski S. Laser
ablation-based one-step generation and bio-functionalization of gold
nanoparticles conjugated with aptamers. J Nanobiotechnol 2010;8:21.
541. Kim D, Jeong YY, Jon S. A drug-loaded aptamer-gold nanoparticle
bioconjugate for combined CT imaging and therapy of prostate cancer.
ACS Nano 2010;4:3689-96.
542. Yu MK, Kim D, Lee IH, So JS, Jeong YY, Jon S. Image-guided prostate
cancer therapy using aptamer-functionalized thermally cross-linked superparamagnetic iron oxide nanoparticles. Small 2011;7:2241-9.
543. Demeritte T, Fan Z, Sinha SS, Duan J, Pachter R, Ray PC. Gold
nanocage assemblies for selective second harmonic generation imaging
of cancer cell. Chemistry 2014;20:1017-22.
544. Lian S, Zhang P, Gong P, Hu D, Shi B, Zeng C, et al. A universal
quantum dots-aptamer probe for efficient cancer detection and targeted
imaging. J Nanosci Nanotechnol 2012;12:7703-8.
545. Tang L, Yang X, Dobrucki LW, Chaudhury I, Yin Q, Yao C, et al.
Aptamer-functionalized, ultra-small, monodisperse silica nanoconjugates for targeted dual-modal imaging of lymph nodes with metastatic
tumors. Angew Chem Int Ed Engl 2012;51:12721-6.
546. Hu H, Dai A, Sun J, Li X, Gao F, Wu L, et al. Aptamer-conjugated
Mn3O4@SiO2 core-shell nanoprobes for targeted magnetic resonance
imaging. Nanoscale 2013;5:10447-54.
547. Alibolandi M, Abnous K, Ramezani M, Hosseinkhani H, Hadizadeh F.
Synthesis of AS1411-aptamer-conjugated CdTe quantum dots with
high fluorescence strength for probe labeling tumor cells. J Fluoresc
2014;24:1519-29.
548. Latorre A, Posch C, Garcimartin Y, Celli A, Sanlorenzo M, Vujic I, et
al. DNA and aptamer stabilized gold nanoparticles for targeted delivery
of anticancer therapeutics. Nanoscale 2014;6:7436-42.
549. Dam DH, Culver KS, Odom TW. Grafting aptamers onto gold
nanostars increases in vitro efficacy in a wide range of cancer cell types.
Mol Pharm 2014;11:580-7.
550. Hwang DW, Ko HY, Lee JH, Kang H, Ryu SH, Song IC, et al. A
nucleolin-targeted multimodal nanoparticle imaging probe for tracking
cancer cells using an aptamer. J Nucl Med 2010;51:98-105.
551. Li N, Larson T, Nguyen HH, Sokolov KV, Ellington AD. Directed
evolution of gold nanoparticle delivery to cells. Chem Commun (Camb)
2010;46:392-4.
552. Choi J, Park Y, Choi EB, Kim HO, Kim DJ, Hong Y, et al. Aptamerconjugated gold nanorod for photothermal ablation of epidermal
growth factor receptor-overexpressed epithelial cancer. J Biomed Opt
2014;19:051203.
553. Melancon MP, Zhou M, Zhang R, Xiong C, Allen P, Wen X, et al.
Selective uptake and imaging of aptamer- and antibody-conjugated
hollow nanospheres targeted to epidermal growth factor receptors
overexpressed in head and neck cancer. ACS Nano 2014;8:4530-8.
554. Savla R, Taratula O, Garbuzenko O, Minko T. Tumor targeted quantum
dot-mucin 1 aptamer-doxorubicin conjugate for imaging and treatment
of cancer. J Control Release 2011;153:16-22.
555. Sa LT, Pessoa C, Meira AS, da Silva MI, Missailidis S, Santos-Oliveira
R. Development of nanoaptamers using a mesoporous silica model
labeled with 99mTc for cancer targeting. Oncology 2012;82:213-7.
556. Zhang C, Ji X, Zhang Y, Zhou G, Ke X, Wang H, et al. One-pot
synthesized aptamer-functionalized CdTe:Zn 2 + quantum dots for
tumor-targeted fluorescence imaging in vitro and in vivo. Anal Chem
2013;85:5843-9.
557. Lin Z, Ma Q, Fei X, Zhang H, Su X. A novel aptamer functionalized
CuInS2 quantum dots probe for daunorubicin sensing and near infrared
imaging of prostate cancer cells. Anal Chim Acta 2014;818:54-60.
1700
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
558. Pirollo KF, Chang EH. Does a targeting ligand influence nanoparticle
tumor localization or uptake? Trends Biotechnol 2008;26:552-8.
559. Jansch M, Stumpf P, Graf C, Ruhl E, Muller RH. Adsorption kinetics of
plasma proteins on ultrasmall superparamagnetic iron oxide (USPIO)
nanoparticles. Int J Pharm 2012;428:125-33.
560. Maffre P, Brandholt S, Nienhaus K, Shang L, Parak WJ, Nienhaus GU.
Effects of surface functionalization on the adsorption of human serum
albumin onto nanoparticles – a fluorescence correlation spectroscopy
study. Beilstein J Nanotechnol 2014;5:2036-47.
561. Lesniak A, Fenaroli F, Monopoli MP, Åberg C, Dawson KA, Salvati A.
Effects of the presence or absence of a protein corona on silica
nanoparticle uptake and impact on cells. ACS Nano 2012;6:5845-57.
562. Salvati A, Pitek AS, Monopoli MP, Prapainop K, Bombelli FB, Hristov
DR, et al. Transferrin-functionalized nanoparticles lose their targeting
capabilities when a biomolecule corona adsorbs on the surface. Nat
Nanotechnol 2013;8:137-43.
563. Docter D, Westmeier D, Markiewicz M, Stolte S, Knauer SK, Stauber
RH. The nanoparticle biomolecule corona: Lessons learned – challenge
accepted? Chem Soc Rev 2015;44:6094-121.
564. Walkey CD, Chan WC. Understanding and controlling the interaction
of nanomaterials with proteins in a physiological environment. Chem
Soc Rev 2012;41:2780-99.
565. Lundqvist M, Stigler J, Elia G, Lynch I, Cedervall T, Dawson KA.
Nanoparticle size and surface properties determine the protein corona
with possible implications for biological impacts. Proc Natl Acad Sci U
S A 2008;105:14265-70.
566. Gunawan C, Lim M, Marquis CP, Amal R. Nanoparticle–protein
corona complexes govern the biological fates and functions of
nanoparticles. J Mater Chem B 2014;2:2060-83.
567. Saptarshi SR, Duschl A, Lopata AL. Interaction of nanoparticles with
proteins: Relation to bio-reactivity of the nanoparticle. J Nanobiotechnol 2013;11:26.
568. Deng ZJ, Liang M, Monteiro M, Toth I, Minchin RF. Nanoparticleinduced unfolding of fibrinogen promotes Mac-1 receptor activation
and inflammation. Nat Nanotechnol 2011;6:39-44.
569. Tenzer S, Docter D, Rosfa S, Wlodarski A, Kuharev J, Rekik A, et al.
Nanoparticle size is a critical physicochemical determinant of the
human blood plasma corona: A comprehensive quantitative proteomic
analysis. ACS Nano 2011;5:7155-67.
570. Schäffler M, Semmler-Behnke M, Sarioglu H, Takenaka S, Wenk A, Schleh
C, et al. Serum protein identification and quantification of the corona of 5, 15
and 80 nm gold nanoparticles. Nanotechnology 2013;24:265103.
571. Kreyling WG, Fertsch-Gapp S, Schäffler M, Johnston BD, Haberl N,
Pfeiffer C, et al. In vitro and in vivo interactions of selected
nanoparticles with rodent serum proteins and their consequences in
biokinetics. Beilstein J Nanotechnol 2014;5:1699-711.
572. Benetti F, Fedel M, Minati L, Speranza G, Migliaresi C. Gold
nanoparticles: Role of size and surface chemistry on blood protein
adsorption. J Nanopart Res 2013;15:1-9.
573. Mahmoudi M, Sheibani S, Milani AS, Rezaee F, Gauberti M,
Dinarvand R, et al. Crucial role of the protein corona for the specific
targeting of nanoparticles. Nanomedicine (Lond) 2015;10:215-26.
574. Rejman J, Oberle V, Zuhorn IS, Hoekstra D. Size-dependent
internalization of particles via the pathways of clathrin- and
caveolae-mediated endocytosis. Biochem J 2004;377:159-69.
575. Salvati A, Åberg C, dos Santos T, Varela J, Pinto P, Lynch I, et al.
Experimental and theoretical comparison of intracellular import of
polymeric nanoparticles and small molecules: Toward models of uptake
kinetics. Nanomedicine 2011;7:818-26.
576. Mitragotri S, Lahann J. Physical approaches to biomaterial design. Nat
Mater 2009;8:15-23.
577. Petros RA, DeSimone JM. Strategies in the design of nanoparticles for
therapeutic applications. Nat Rev Drug Discov 2010;9:615-27.
578. Decuzzi P, Godin B, Tanaka T, Lee SY, Chiappini C, Liu X, et al. Size
and shape effects in the biodistribution of intravascularly injected
particles. J Control Release 2010;141:320-7.
579. Ge C, Du J, Zhao L, Wang L, Liu Y, Li D, et al. Binding of blood
proteins to carbon nanotubes reduces cytotoxicity. Proc Natl Acad Sci
U S A 2011;108:16968-73.
580. Hu W, Peng C, Lv M, Li X, Zhang Y, Chen N, et al. Protein coronamediated mitigation of cytotoxicity of graphene oxide. ACS Nano
2011;5:3693-700.
581. Lesniak A, Salvati A, Santos-Martinez MJ, Radomski MW, Dawson
KA, Åberg C. Nanoparticle adhesion to the cell membrane and its effect
on nanoparticle uptake efficiency. J Am Chem Soc 2013;135:1438-44.
582. Kim JA, Salvati A, Aberg C, Dawson KA. Suppression of nanoparticle
cytotoxicity approaching in vivo serum concentrations: Limitations of
in vitro testing for nanosafety. Nanoscale 2014;6:14180-4.
583. Wang F, Yu L, Monopoli MP, Sandin P, Mahon E, Salvati A, et al. The
biomolecular corona is retained during nanoparticle uptake and protects
the cells from the damage induced by cationic nanoparticles until
degraded in the lysosomes. Nanomedicine 2013;9:1159-68.
584. Kim JA, Aberg C, Salvati A, Dawson KA. Role of cell cycle on the
cellular uptake and dilution of nanoparticles in a cell population. Nat
Nanotechnol 2012;7:62-8.
585. Åberg C, Kim JA, Salvati A, Dawson KA. Theoretical framework for
nanoparticle uptake and accumulation kinetics in dividing cell
populations. EPL (Europhys Lett) 2013;101:38007.
586. Kim JA, Åberg C, de Cárcer G, Malumbres M, Salvati A, Dawson KA.
Low dose of amino-modified nanoparticles induces cell cycle arrest.
ACS Nano 2013;7:7483-94.
587. Walczyk D, Bombelli FB, Monopoli MP, Lynch I, Dawson KA. What
the cell “sees” in bionanoscience. J Am Chem Soc 2010;132:5761-8.
588. Doane TL, Burda C. The unique role of nanoparticles in nanomedicine:
Imaging, drug delivery and therapy. Chem Soc Rev 2012;41:2885-911.
589. Caruso F, Hyeon T, Rotello VM. Nanomedicine. Chem Soc Rev
2012;41:2537-8.
590. Frangioni JV. New technologies for human cancer imaging. J Clin
Oncol 2008;26:4012-21.
591. Bradbury MS, Pauliah M, Zanzonico P, Wiesner U, Patel S.
Intraoperative mapping of sentinel lymph node metastases using a
clinically translated ultrasmall silica nanoparticle. Wiley Interdiscip
Rev Nanomed Nanobiotechnol 2015.
592. Sun X, Cai W, Chen X. Positron emission tomography imaging using
radiolabeled inorganic nanomaterials. Acc Chem Res 2015;48:286-94.
593. Pant K, Gröger D, Bergmann R, Pietzsch J, Steinbach J, Graham B, et
al. Synthesis and biodistribution studies of 3H- and 64Cu-labeled
dendritic polyglycerol and dendritic polyglycerol sulfate. Bioconjug
Chem 2015;26:906-18.
594. Kircher MF, Gambhir SS, Grimm J. Noninvasive cell-tracking
methods. Nat Rev Clin Oncol 2011;8:677-88.
595. Kiessling F. Noninvasive cell tracking. Handb Exp Pharmacol
2008:305-21.
596. Klein S, Dell'Arciprete ML, Wegmann M, Distel LV, Neuhuber W,
Gonzalez MC, et al. Oxidized silicon nanoparticles for radiosensitization of
cancer and tissue cells. Biochem Biophys Res Commun 2013;434:217-22.
597. Zhu X, Chi X, Chen J, Wang L, Wang X, Chen Z, et al. Real-time
monitoring in vivo behaviors of theranostic nanoparticles by contrastenhanced T1 imaging. Anal Chem 2015;87:8941-8.
598. Tian Q, Hu J, Zhu Y, Zou R, Chen Z, Yang S, et al. Sub-10 nm
Fe3O4@Cu2-xS core-shell nanoparticles for dual-modal imaging and
photothermal therapy. J Am Chem Soc 2013;135:8571-7.
599. Bechet D, Auger F, Couleaud P, Marty E, Ravasi L, Durieux N, et al.
Multifunctional ultrasmall nanoplatforms for vascular-targeted interstitial photodynamic therapy of brain tumors guided by real-time MRI.
Nanomedicine 2015;11:657-70.
600. Yoo B, Ma K, Zhang L, Burns A, Sequeira S, Mellinghoff I, et al.
Ultrasmall dual-modality silica nanoparticle drug conjugates: Design,
synthesis, and characterization. Bioorg Med Chem 2015;23:7119-30.
601. Zhang X, Chibli H, Mielke R, Nadeau J. Ultrasmall gold-doxorubicin
conjugates rapidly kill apoptosis-resistant cancer cells. Bioconjug
Chem 2011;22:235-43.
K. Zarschler et al / Nanomedicine: Nanotechnology, Biology, and Medicine 12 (2016) 1663–1701
602. Kwatra D, Venugopal A, Anant S. Nanoparticles in radiation therapy:
A summary of various approaches to enhance radiosensitization in
cancer. Transl Cancer Res 2013;2:330-42.
1701
603. Sancey L, Lux F, Kotb S, Roux S, Dufort S, Bianchi A, et al. The use of
theranostic gadolinium-based nanoprobes to improve radiotherapy
efficacy. Br J Radiol 2014;87:20140134.