Supplementary Table 2: Some polymeric and particulate nanomaterials under investigation as therapeutic platforms
Supplementary Table 1. Representative systemic anti-cancer nanomedicines in clinical trials1-3
A: Selected anti-cancer “Nanomedicines” with FDA approval for marketing
Platform
Novel particle reformulations
Description
Albumin coated paclitaxel particles
Nanocrystalized form of megestrol acetate
Liposome encapsulated daunorubicin particles
PEG-Liposome encapsulated doxorubicin particles
Name
Abraxane
Megace ES
Daunosome
Doxil
PEGylated proteins
PEG-asparaginase
PEG-interferon alpha2b
PEG-G-CSF colony stimulating factor
Oncaspar
PEG-Intron, PEGASYS
Neulasta
B: Selected anti-cancer “Nanomedicines” in clinical trials
Platform
Liposome
Description
Immunoliposome-doxorubicin targeting gastric cancer epitope via F(ab’)2
Encapsulated oxaliplatin; targeting via trasferrin
Encapsulated plasmid p53 gene; targeting via anti-transferrin receptor mAb
fragment
Name
MCC-465
MBP-426
SGT-53
Polymeric micelles
PEG-poly lactide copolymer encapsulating paclitaxel
Pluorinic-based copolymer encapsulating doxorubicin
PEG-poly aspartic acid copolymer encapsulating doxorubicin
PEG-poly aspartic acid copolymer encapsulating paclitaxel
PEG-poly glutamic acid copolymer encapsulating cisplatin
Genexol-PM
SP1049C
NK911
NK105
NC-6004
Polymer-drug Conjugates
Poly glutamate-paclitaxel
Poly glutamate-camptothecin
HPMA copolymer-platinium
HPMA copolymer derivative-platinum
HPMA copolymer-doxorubicin
HPMA copolymer-doxorubicin; targeting via galactosamine
Methacryloylglycynamide-camptothecin
HPMA copolymer-paclitaxel
Dextran-doxorubicin
Carboxymethyl dextran-exatecan mesylate (Topoisomerase I inhibitor)
PEG-camptothecin
PEG-irinotecan
PEG-SN38 (camptothecin metabolite)
Cyclodextrin-siRNA; targeting via transferrin
Cyclodextrin-camptothecin
XYOTAX
CT-2106
AP5280
AP5346
FCE28068
FCE28069
MAG-CPT/PNU166148
PNU166945
AD-70, DOX-OXD
DE-310
Pegamotecan
NKTR-102
EZN-2208
CALAA-01
IT-101/Cyclosert
Nanomaterial
I. Polymers
Description
Advantages
Disadvantages
Warheads appended
a. Dendrimers
Branched polymer composed of cores and
repeating branching units. Various compositions
available (polyamido-amine, polylysine,
polypropylene etc.) with choice of core and
surface groups
•
•
•
•
•
Highly multivalent
High water solubility
Controllable synthesis
Encapsulation of warhead within core
Improves solubility of poorly soluble drugs
•
•
•
•
Charge-dependent toxicity
Can be polydisperse
Charge-dependent hemolysis
Cost
•
•
•
•
•
Methotrexate
Placlitaxel
Doxorubicin
Etoposide
campothecin
b. Poly(lactic acid) (PLA)
Linear polymer, often combined with other units
to form copolymers (i.e. pylene glycol, glycolic
acid, polyethylene glycol)
Linear polymer
•
•
•
•
•
•
•
•
•
•
Biocompatible/biodegradable
Improves solubility
FDA approved for certain uses
Biocompatible/biodegradable
FDA approved for certain uses
Phase I/II/III trial
Biocompatible
Improves biodistribution profile of other particles
Use in humans as formulation additive
Can be used to form micellar structures to encapsulate
drugs
•
Polydisperse
•
•
Paclitaxel
Campothecin
6
•
Polydisperse
•
•
Paclitaxel
Campothecin
3,5
•
Polydisperse
•
•
Campothecin
Doxorubicin
3,5
1
c. Polyglutamic acid (PGA)
Refs
3, 5, 11
•
•
•
•
5-FU
siRNA
NSAIDs
Antibiotics
12-18, 21-25
d. PEG (polyethylene glycol)
Linear polymer. Often improves in vivo half-life
and biodistribution of other polymers.
e. Cyclodextrin
Linear polymer
•
•
•
Biocompatible
FDA approved for certain uses
Phase I trials
•
Polydisperse
•
•
Campothecin
Doxorubicin
f. Stylene maleic anhydride
Linear copolymer
•
•
•
•
•
•
•
Polydisperse
Route of administration (intratumor)
Not biodegradable
Neocarzinostatin (protein with anti tumor activity)
Linear copolymer
FDA approved when conjugated with neocarzinostatin
for treatment of hepatocellular carcinoma
Biocompatible
Improves solubility of poorly soluble drugs
Phase I/II trials
•
g. N-(2-hydroxypropyl) methacrylimide
(HPMA) copolymers
•
•
•
Doxorubicin
Campothecin
Paclitaxel
h. Poly(lactic-co-glycolic acid) (PLGA)
Linear copolymer composed of lactic
acid/glycolic acid units.
Polydisperse
•
Biocompatibility not yet determined
•
•
•
•
Paclitaxel
Doxorubicin
Platinium
Doxorubicin
7,8
Specialized polymeric particles of various
compositions synthesized from molds
Biocompatible/biodegradable
Improves solubility of poorly soluble drugs
FDA approved for certain uses
Monodisperse
Size/geometry precisely controllable
Encapsulation of warhead within core
•
i. PRINT particles
•
•
•
•
•
•
•
•
•
•
•
•
•
Can be heated by external radiofrequency
Relatively inert
Magnetically active (MR imaging)
Can be heated by external radiofrequency
Limited toxicity
Wide range of absorption/emission properties
Potentially favorable biocompatibility
•
Biocompatibility not yet determined in
many applications
Liver accumulation
•
Radiofrequency (thermoablation)
43-48
•
•
Radiofrequency (thermoablation)
26, 27, 32
•
Pharmacology not well known
•
With gold coating absorb NIR (thermoablation)
30, 49
•
•
•
Relatively monodisperse
Size/geometry controllable
Wide range of absorption/emission properties
•
•
Possible toxicity of metal cores
Pharmacology not well known
•
Currently only used for imaging
28, 31, 50-53
•
•
•
•
•
•
•
•
Surface modifiable (covalent or non-covalent)
High aspect ratio
Scalable
Chemically inert
Rapid clearance
Relatively inert
Stable structure
Mondisperse
•
•
Polydisperse
Toxicity without functionalization
Toxicity
Non biodegradable
Limited surface sites available
Methotrexate
Doxorubicin
Radiofrequency (thermoablation)
Radionuclide (225Ac, 125I )
siRNA
Paclitaxel
36-39, 54-59
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Daunorubicin
Doxorubicin (Doxil)
Platinum
Vincristine
Doxorubicin
1, 62
1, 63
•
Combrestatin + Doxorubicin
64
•
Varied but mostly biologic (eg. Gene therapy)
65
• Cisplatin/carboplatin
• 5-FU
5, 11
3, 5, 9-11
19, 20
II. Metallic and other Particles
a. Gold nanoparticles
Colloidal gold, gold nanoshells gold nanorods
b. Superparamagnetic iron oxide(SPIO);
Cross-linked iron oxide (CLIO)
particles
c. Silica nanoparticles
FexOy nanoparticles
d. Quantum dots
Semiconducting silica nanocrystals with unique
absorption/emission properties often used in
imaging. Can be synthesized as core/shell
particles.
Semiconducting nanocrystals composed of
inorganic cores and surrounding metal shells
with unique absorption/emission properties
often used in imaging
III. Carbon
a. Carbon nanotubes
Graphene sheet cylinder with single or multiple
walls
b. C60, C80 (Bucky balls)
Spherical carbon-based structure composed of
alternating five and six-membered aromatic
rings.
60, 61
IV. Bioinspired
a. Liposomes
Synthetic lipid bilayered sphere
•
•
Encapsulation of warhead within core
FDA approved uses already
•
•
•
Polydisperse
In vivo stability
Hepato-splenic clearance
b. Micelle/Nanoemulsion
Synthetic single layer phospholipid-based
sphere
Particle composed of concentric lipidic sphere
shells
•
Encapsulation of warhead within core
•
Encapsulation of more than one warhead within shells
•
•
•
•
Polydisperse
In vivo stability
Difficult to engineer
Cost
Engineered virus
•
Exploit specificity of viruses to delivery warhead
•
•
Oncogenicity
Bystander toxicity
c. Nanocells
d. Viruses
Supplementary Table 2. A diverse set of particulate nano-materials has served as drug platforms.4 Perhaps the most widely used polymer is
polyethylene glycol (PEG), which is known to modulate in vitro solubility and increase blood half-life by reducing aggregation, preventing rapid
renal clearance, decreasing uptake by the reticuloendothelial system in the liver, spleen and bone marrow, and reduce potential immunogenicity.5
As such, PEG moieties are often appended to many of the nano-materials listed in Supplementary Tables 1 and 2. While linear polymers (e.g.
polylactic acid, polyglutamate) have themselves been used as drug carriers,6 they can also be combined at varying ratios to form copolymers with
new properties and tertiary structures. Doxorubicin has been successfully incorporated into poly(lactic-co-glycolic acid) copolymers to improve in
vivo oral bioavailability of the drug in rats and lower the toxicity observed otherwise.5,7,8 Since doxorubicin is used to treat of a wide range of
cancers, there is broad scope of treatment opportunities of such formulations. Linear copolymer N-(2-hydroxypropyl)methacrylamide conjugates
are currently in clinical trials as potential treatment for a wide range of cancers.5,9–11 These copolymers are generally biocompatible, non-toxic and
non-immunogenic, while augmenting the in vivo solubility and biodistribution of chemotherapeutics, such as doxorubicin, campothecin, paclitaxel,
which have been used to treat various solid tumor types in clinical trials including lung, breast, and liver cancers.5 Stylene maleic anhydride
copolymer covalently conjugated with neocarzinostatin, a potent chromoprotein that causes DNA damage, has shown potent anti-tumor activity
and has been FDA-approved for hepatocellular carcinoma.3
Polymers encapsulating existing drugs are generally formulation changes and may differ significantly from polymers covalently conjugated with
drugs with regard to stability in vivo. Agents engineered from dendrimer platforms have supported these differences.12 Dendrimers are star-like
branched polymers synthesized either from a common core from which the branches emerge (divergent), or from branching dendrons which are
subsequently conjugated to a common core (convergent).13–16 Because of their controlled synthesis, dendrimers are considered monodisperse as
compared to linear polymers which are quite polydisperse (that is, of many sizes). Monodispersity of the starting material favorably impacts the
reproducibility of results, especially once surface modifications—including various targeting, therapeutic and imaging agents—are made and the
construct is introduced in vivo.12,17–23 The molecular weight and, more importantly, charge of dendrimers determine in vitro and in vivo behavior
and cytotoxicity.22,24,25
Metallic and other particles, including iron oxides, quantum dots and silica nanoparticle dots have mostly been applied to imaging (e.g.
intracellular structures, in vivo visualization of lymphatics and breast cancer xenografts26–30). In addition, methods for surface modification of these
particles can be employed to both target and deliver a therapeutic agent. The major advantage of quantum dots is their size-dependent
fluorescence that can be excited at a wide range of wavelengths, with negligible photobleaching.31 Superparamagnetic iron oxide (SPIO) and crosslinked iron oxide (CLIO) particles have been used for MRI, as well as for therapeutic strategies.32,33 Coating of these particles with biocompatible
polymers such as dextran or PEG, has helped thwart some charge-dependent toxicities in vivo. The ability of iron oxide and gold particles to heat
upon introduction of a high power external radiofrequency, is a novel characteristic that can be used for thermoablation once these particles are
targeted to tumor sites.32,34
The highly unusual properties of both single walled and multi-walled carbon nanotubes have also led these agents to become important as
potential therapeutics. The π-bonding system inherent to these structures can be exploited to induce hyperthermia using external radiofrequency,
resulting in thermoablation of the tumor35. The inherent extremely high aspect ratios (lengths 50–1000 times the widths) allows for a significant
surface area upon which to append multiple functional ligands, imaging agents and cytotoxics, making them ideal carriers. Containment within
tubes, adsorption of moieties to the side walls of tubes, and covalent modifications at either tube side-walls or at the ends are all possible.36
Nanotubes have been non-covalently functionalized with PEG and vascular targeting peptides37 and covalently modified with whole proteins, and
chelating agents to both target and deliver an imaging or therapeutic radionuclide.38,39 Other modifications include the addition of toxins40,
radioisotopes,38 and imaging agents for diagnostics.41,42
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