POLYMERIC MICELLES
Introduction
What Are Polymeric Micelles?. Polymeric micelles are usually nanosized spheres having an inner core and outer corona, which differ in polarity. The
structures of the micelles are mainly assembled from amphiphilic block copolymers, which undergo phase separation in selective solvents as a result of the
solubility difference between core- and corona-forming blocks.
Polymeric micelles usually have a three-dimensional core–coronas architecture with a solid hydrophobic core and a hydrophilic corona in aqueous solution
(1). The typical structure of polymeric micelles is shown in Figure 1. The block
copolymers can also be self-assembled in organic solvents due to the different
solubilities of different blocks (2,3). The sizes of polymeric micelles are usually
between 10 and 100 nm (4,5). However, large compound micelles can be formed,
which have a bigger size than typical polymeric micelles (6–8). Compared with
lipid micelles, the polymeric micelles are more stable, more easily designable,
and have more chemical modification possibilities (9).
In recent years, nanostructured materials such as polymeric micelles have
attracted growing attention due to their potential applications in drug and gene
delivery (10–17), nanoreactors and biomineralization, and so on. The unique
core–corona structure of polymeric micelles can be easily formed by self-assembly
of amphiphilic polymers, which is one of the most attractive fields in polymer science in recent years (11,18–28).
Pioneering work in the area of polymeric micelles has been extensively performed and excellently reviewed in recent years by Wooley (1), Armes (5) and
their co-workers, as well as many other groups. For example, in 2006 O’Reilly
and co-workers have reviewed the area of cross-linked block copolymer micelles
(1). In 2007, Read and Armes reviewed the progress in shell cross-linked micelles
(5). In 2008, Amiji and co-workers classified the stimuli-responsive nanocarriers
for drug and gene delivery (29). In 2008, Kwon and co-workers highlighted the
application of block copolymer micelles for cancer therapy (30). In 2009, Satoh detailed the preparation and encapsulation-release properties of novel amphiphilic
hyperbranched unimolecular micelles (31). In 2009, Kataoka and co-workers describe the progress that has been made in the field of polymeric nanomedicine
that brings the science closer to clinical realization of nanopolymeric therapeutics for its application in cancer treatment (32). This highlights the very active
and growing research activities in the field of polymeric micelles. In this review, we aim to introduce the basic concepts and the recent advances in the
1
c 2012 John Wiley & Sons, Inc. All rights reserved.
Encyclopedia of Polymer Science and Technology. Copyright 2
POLYMERIC MICELLES
Fig. 1. Typical structure of an amphiphilic block copolymer micelle. Blue: hydrophilic
chains forming the coronas; Green: hydrophobic chains forming the solid core.
preparation and application of polymeric micelles. Polymeric micelles that respond to external stimuli such as pH, temperature, redox, and light to afford a
change in structure, morphology, or controlled release event are also introduced.
Finally, we summarize the current limitations and the perspective in the preparation and application of polymeric micelles.
Polymeric vesicles are similar to polymeric micelles. However, the main difference lies in the structure. Polymeric micelles have a solid, hydrophobic core,
which is usually used for encapsulation of hydrophobic drugs in the hydrophobic
core. Different from this, polymeric vesicles have a hollow structure that can be
used for encapsulating the hydrophilic drug in the cavity and the hydrophobic
drug in the hydrophobic membrane. For the detailed advances in the polymer
vesicles, readers are referred to other review articles (9,33).
Most of block copolymers used in self-assembly can be synthesized by using
controlled radical polymerization (CRP) techniques such as reversible addition
fragmentation chain transfer (RAFT) polymerization, atom transfer radical polymerization (ATRP), and so on. Among them, ATRP is one of the most powerful
and versatile CRP processes. It enables precise control over molecular weight,
molecular weight distribution, and functionality (34). It can be carried out in a variety of solvents and conditions, even in water at room temperature. It is tolerant
to most functional groups (34). RAFT polymerization is another powerful technique for the preparation of well-defined copolymers. Specifically, water-soluble,
stimuli-responsive block, graft, and star copolymers have become especially significant in targeted delivery of diagnostic and therapeutic agents (35).
A wide range of polymers with complex structure such as linear, star-like,
graft, comb, and ring-like polymers has been synthesized, as shown in Figure 2.
The only limitation of the macromolecular design is the creativity and imagination of the researchers (34,36). The polymeric micelles are mainly self-assembled
by amphiphilic block copolymers, which phase separate in selective solvents
due to the different solubility between different blocks (37). In this article, we
mainly focus on the polymeric micelles self-assembled through amphiphilic block
copolymers.
POLYMERIC MICELLES
3
Fig. 2. Various complex polymer structures that can be achieved via ATRP or RAFT, (a)
linear; (b) graft; (c) brush or comb; (d) ring; (e) star An Bn ; (f) star-block (AB)n ; (g) AB2
star; (h) palm tree ABn ; (i) dumb-bell (pom-pom); and (j) H-shaped B2 AB2 . Adapted from
Prog. Polym. Sci., Vol. no. 37, A. Gregory and M. H. Stenzel, Complex polymer architecture via RAFT polymerization: From fundamental process to extending the scope using
click chemistry and nature’s building blocks. Page No. 38–105, Copyright (2012), with permission from Elsevier.
Self-Assembly of Block Copolymer into Micelles in Solution. Two
methods are generally used to self-assemble polymers into micelles: organicsolvent-free method (or a dialysis method) and solvent-switch method (or a direct dissolution method), as shown in Figure 3. Water is a widely used solvent
for self-assembly of polymers by the organic-solvent-free method. After dissolved
in water, the hydrophobic chains of the amphiphilic copolymers form the core
of the micelle, whereas the hydrophilic chains form the micelle coronas. However, only a limited number of polymers can be self-assembled by this method.
In contrast, a solvent-switch method has been widely used where water-miscible
organic cosolvents such as THF, DMF, methanol, DMSO, and dioxane are used to
dissolve polymers with frequent dialysis or evaporation to remove the organic solvent. The choice of the method for self-assembly depends on the solubility of the
polymer in water. Moreover, the organic cosolvents usually have great impact on
the morphology of self-assemblies because they are related to the self-assembly
behavior of a core-forming block (39,40). Even for the same block copolymer, it
may form polymer micelles, cylinders, or vesicles just because it is self-assembled
in different solvents (40). In the solvent-switch method, the size, size distribution, and morphology of the micelles are determined by both the organic solvent
4
POLYMERIC MICELLES
Fig. 3. Major methods for self-assembling block copolymers into polymeric micelles in
solution: direct dissolution method and the dialysis method. Adapted from Colloid Surf.
B, Vol. no. 16, C. Allen, D. Maysinger, and A. Eisenberg, Nano-engineering block copolymer aggregates for drug delivery, Page No. 3–27, Copyright (1999) with permission from
Elsevier.
and sometimes by the rate of water dropping to the copolymer solvent mixture
(41,42).
The spontaneous formation of micelles can be explained on the basis of free
energy theory. The decrease in the free energy of a system is the major driving
force for the self-assembly of amphiphilic copolymers into micelles. After the removal of the cosolvent by dialysis or evaporation, the hydrophobic chains become
incompatible in aqueous solution by forming the core of the micelle to reduce the
interface energy. In addition, the hydrophobic core is protected from water by the
hydrophilic coronas. This effect is often called the hydrophobic effect (1).
Critical Micelle Concentration. In colloidal and surface chemistry, the
critical micelle concentration (CMC) is defined as the concentration of surfactants
above which micelles form and almost all additional surfactants added to the
system go to micelles (41).
In polymer self-assembly, the process of self-assembling amphiphilic block
copolymers into micelles is a thermodynamically driven and reversible process,
which is similar to the surfactants. However, CMCs of polymers are much lower
than surfactants.
Why Is CMC Important?. When the polymer concentration is lower than
CMC, the copolymer exists in aqueous solutions as individual chains. The selfassembly process begins when the concentration of the copolymer reaches a specific value called CMC. The chemical nature and length ratio of hydrophilic and
hydrophobic chains determine the CMC value (4). Also the value of the CMC for a
given polymer in a given medium depends on temperature, pressure, the presence
and concentration of other surface-active substances, and electrolytes.
POLYMERIC MICELLES
5
The CMC is a thermodynamically stable parameter of the polymeric micelles in solution. If the concentration of the polymer is lower than the CMC, only
single chains exist in the solution but it starts to self-assemble into micelles when
the concentration is above CMC. It is essential to stabilize the micelles especially
for drug delivery application because the micelles will disassociate into individual molecules upon dilution in the bloodstream (the concentration below CMC),
which may cause nontargeted drug release and toxicity (41,43).
The Measurement of CMC. The CMC of the copolymer is usually estimated by using the following methods: fluorescence spectroscopic method, UVabsorption spectroscopy method, surface tension method, and so on (43–50).
In the fluorescence spectroscopic method, a hydrophobic florescence probe
such as pyrene or N-phenyl-1-naphthylamine (PNA), which can be partitioned
preferably in the micelle core, is used to conduct the test (43,48,50,51). This
method is based on the solvent dependence of vibrational band intensities in
pyrene monomer fluorescence (46). Above the CMC, the high hydrophobicity of
pyrene molecules is solubilized in the micelle cores, which may lead to the sharp
change in fluorescence absorption compared with the concentration below CMC.
The concentration of the changing point is the CMC.
The UV-absorption spectroscopy method is somewhat as same as the fluorescence spectroscopic method. This method is based on the tautomerism of small
molecules added to the micelle solution, which can be easily detected by UVabsorption spectroscopy (46). When the concentration of the polymer reaches the
CMC, the conformation of the small molecule will change because of the solubility
of the small molecules in the micelle core.
Another simple method for determining the value of the CMC is the surface
tension method, in which the surface tension of the polymeric micelles has a remarkable change when the concentration reaches the CMC. No extra molecules
are added in the solution (44,45).
Other methods in recent years have also been developed to measure the
value of CMC such as static light scattering (47) and electrical conductivity methods (46). All the methods for measuring CMC depend on the physical property
transition of the solution when the concentration of the polymer reaches to a certain point where the polymeric micelles start to form.
Stabilization of Polymeric Micelles. Below the CMC, or under other
conditions such as the removal of solvent, polymeric micelles may dissociate or
deform. Therefore, it is essential to stabilize polymeric micelles under certain
circumstances. There are two general ways to solidify polymer micelles. One is
introducing extra small cross-linkers to cross-link the micelle core or coronas.
The other is self-cross-linking the micelle core if the block copolymer has selfcross-linkable groups.
The first method has been widely reported, usually based on the esterification, amidation, quaternization, epoxy-amine chemistry between polymer
micelle and cross-linkers (5,52–54). For example, cross-linkers such as bis(2iodoethoxy)ethane (BIEE) and diamines, divinyl sulfone (DVS) allow crosslinking via quaternization, esterification, or Michael addition under mild conditions in aqueous solution (5), and other small molecules are introduced to the
polymeric micelles solution (5). The advantage of this method is that it is very
simple and feasible.
6
POLYMERIC MICELLES
Fig. 4. Schematic of the preparation of hybrid nanospheres by the self-assembly of reactive diblock copolymers. The light gray corona represents the PEO, the dark gray core is
the PTMSPMA, and the black core is the hybrid sphere for the polyorganosiloxane from
the gelation process. Adapted from Ref. 54, copyright 2005, with permission from John
Wiley and Sons.
Besides copolymers, homopolymers can also from polymeric micelles
(55). For example, noncovalently connected micelles (NCCM) with poly(4)vinylpyridine) (PVPy) as the coronas and hydroxyl-containing polystyrene as the
core were formed in a selective solvent mixture for PVPy by interpolymer hydrogen bonding. The micelles were locked in by the quaternization of PVPy with the
cross-linker of 1,4-dibromobutane.
Usually, the morphology of polymer micelles before and after cross-linking
does not change, depending on the cross-linking chemistry and conditions. However, very recently, it was reported that the introduction of a small cross-linker
may significantly destroy self-assembled nanostructure such as polymer vesicles
(56), which suggested that much attention should be paid to the polymer micelles
if solidified by extra cross-linkers.
The second strategy is self-cross-linking the micelle core without the addition of any extra cross-linkers. The reactive groups are engineered into the
polymer before self-assembly. For example, the polymer micelles can be crosslinked upon UV light radiation either by dimerization of poly[(2-cinnamoylethyl
methacrylate) (2,57), or polymerization of poly(isoprene) (58), in the micelle core.
In 2005, Du and Chen reported a novel polymeric micelle self-assembled in
methanol and water solvent based on PEO113 -b-PTMSPMA206 block copolymer,
as shown in Figure 4. The core of the micelle consists of PTMSPMA, which can
undergo in situ sol–gel reactions because of the trimethoxysilane groups in the
core of the micelles (54), Other cross-linkable moieties can also be incorporated
into the polymer. The disadvantage of this strategy is that only a limited number
of polymers can be self-cross-linked.
Polymeric micelles can be stabilized either thermodynamically or kinetically. Thermodynamic stability of polymeric micelles means that the micelles are
formed when the concentration of copolymers is above CMC. In turn, they will
disassociate into individual polymer molecules if the concentration of the copolymer is below CMC. However, the micelle system may still be kinetically stabilized
even if the concentration is below its CMC under the condition that the micelle
core is large and the core material is below the T g or it is crystalline and thus
physically cross-linked (41).
The thermodynamic stability of polymeric micelles is determined by many
factors, some of which are the nature and length of the core-forming block, a
length of the hydrophilic block, the ratio of hydrophilic/hydrophobic chains, and
POLYMERIC MICELLES
7
the presence of hydrophobic solubilizates (41). The nature of the self-assembly
process and the property of the copolymer also allow for significant versatility
in the chemical nature of the polymer micelles and thus permit fine-tuning of
the material properties, shapes, and sizes (1). For example, the micelle core composition can be varied to include glassy, crystalline, or fluid-like materials and
the corona can be positively- or negatively-charged or neutral which are considered to have a significant influence on the thermodynamic stability of polymeric
micelles (1).
The stability of polymeric micelles can be influenced by high temperature,
low concentrations (below CMC), or certain changes in the solvent property (1,5),
One fundamental problem of the block copolymer micelles is their spontaneous
dissociation at concentrations below CMC. So cross-linking the micelle cores or
shells will achieve stability of the polymeric micelles with respect to infinite dilution or certain changes in solvent conditions (5). Covalent and noncovalent crosslinking of the micelle cores or coronas provides an effective means to stabilize the
polymeric micelles (1,5).
In a related work, Wooley and co-workers first reported the shell crosslinking micelles of a block copolymer of polystyrene and poly(4-vinyl pyridine),
PS-b-P4VP. Shell cross-linking of the micelles was achieved by radical oligomerization of the pendent styrenyl groups on the coronal P4VP blocks in a THF–
water mixture (52). Many other cross-linking strategies have been developed.
For example, cross-linkers such as bis(2-iodoethoxy)ethane (BIEE), diamines and
DVS allow cross-linking via quaternization, esterification, or Michael addition
under mild conditions in aqueous solution (5), and other small molecules are introduced to the polymeric micelles solution (5). The advantage of this method is
that it is very simple and feasible. What is more, the Click chemistry is another
valid method to cross-link polymeric micelles (59). Other examples will be discussed in the following section.
Functionalization of Polymeric Micelles. The introduction of functionality at various segments within polymer micelles can be achieved by tailoring
diverse ligands to the polymer chain to meet the requirement in real applications. For a two-layered, core–corona polymeric micelles self-assembled by block
copolymer, there are three major classes of functional domains (Fig. 5), and of
course the number of unique fictionalization sites increases with the complexity
of a nanoparticle structure (1).
In the simplest, diblock copolymer core–shell morphology, the first class of
nanoparticles contain functional groups at the surface of the particle (via either
surface or shell functionalization), allowing for the targeted and directed delivery of the vehicle to a particular site. In the second class, the substituents are
located at the core–shell interface for cross-linking of the corona or for further
functionality. For the last class, the reactive groups located in the hydrophobic
core domain or at the hydrophobic polymer for core cross-linking or introducing
further functionality (1).
These introducing groups can be used as selective and reactive handles and
can be made to work cooperatively to allow for the further tailoring of these materials toward specific applications such as drug delivery and nanoreactors. Another particular advantage of conjugation special ligands to the polymer chains
lies in the areas of biological application such as diagnostic and therapeutic
8
POLYMERIC MICELLES
Fig. 5. Illustration of the possible locations of functionalization within a spherical diblock
polymeric micelle. Adapted from Ref. 1 with permission of The Royal Society of Chemistry.
products. The functionalization of polymer chains with saccharides, peptides,
oligonucleotides, targeting ligands, antibodies, and other moieties has received
great interest as a good method to generate structures capable of polyvalent, specific binding interactions. As a result, the introduction of these functionalities
into the polymeric micelles is of increasing potentials and application (1).
Classification of Polymeric Micelles
There are various ways to classify the polymeric micelles. In traditional classification, generally, there are two kinds of micelles: star-like and crew-cut micelles (40,60), which are also named as regular and reverse micelles. Whether
the micelles belong to star-like or crew-cut micelles depends on the relative
block lengths of the block copolymers. If the micelle core is much smaller than
the corona, such assemblies are defined as star-like micelles. Another kind of
micelles, the crew-cut micelles, has a bulky core and a relatively short corona
(40,60). Both the star-like and crew-cut micelles have been deeply explored recently because of their variable structure and potential applications.
Another classification is based on the morphology of the micelles, for example, spherical, tubular, worm-like, ring-like, and spiral micelles.
Figure 6 shows the different morphologies of polymeric micelles prepared
using the self-assembly method. Figure 6c is a kind of spherical micelles selfassembled by using a PEO–PGMA–PDEA triblock copolymer with subsequent
shell cross-linking. PEO chains form the outer coronas of the micelles, whereas
POLYMERIC MICELLES
9
Fig. 6. (a) Cylindrical micelles self-assembled from PI250 -PFS50 . Adapted from Ref. 5,
copyright 2007, with permission of The Royal Society of Chemistry. (b) Tubular micelles
by PS-b-PAA (40); Adapted from with permission from Ref. 40. Copyright (1999) American
Chemical Society. (c) Spherical micelles by PEO113 -PGMA50 -PDEA65 . Adapted from Ref. 5
with permission of The Royal Society of Chemistry. (d) Worm-like micelles by PDMA165 b-PNIPAM202 . Adapted from with permission from Ref. 61. Copyright (2009) American
Chemical Society. See the full name of block copolymers in the Glossary section.
PDMA forms the core of the micelles and the PGMA segment serves as the linkage shell between the core and the coronas.
The spherical micelles are most conventional ones that have been deeply
explored in recent years. The application of spherical micelles in drug and gene
delivery and nanoreactors will be discussed in a later section. Polymeric micelles
with other morphologies, for example, cylinder (Fig. 6a), tube (Fig. 6b), and wormlike (Fig. 6d) have also been explored by other researchers.
Amphiphilic polymers can self-assemble into a variety of nanostructures,
such as micelles, vesicles, and cylinders (5,40,61,62). Recently, the preparation of
micelles with more complex nanostructures such as toroids, disks, multicompartment structures (63), and Janus and patchy particles has showed great interest
due to their special structure and applications (64). For example, multicompartment micelles are an intriguing class of self-assembled aggregates with subdivided solvophobic cores. These micelles have unique morphological and sequestration properties because they have multiple distinct chemical environments being in close proximity within one nanostructure. This special structure can be
used as the carrier to deliver multiple incompatible drug payloads.
Anisotropic micelles can be classified according to their morphologies, as
shown in Figure 7: (1) Janus micelles, (2,3) Janus–Janus micelles, (4) Janus
multicompartment micelles, (5) patchy Janus micelles, (6) multicompartment micelles, (7) patchy multicompartment micelles, and (8) patchy micelles (64).
Factors Mediating the Morphology of Polymeric Micelles
The following factors contribute to the control of the self-assembled morphology of
polymers: the hydrophilic/hydrophobic ratio, the concentration of the polymer in
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POLYMERIC MICELLES
Fig. 7. Schematic representation of anisotropic polymer micelles: (1) Janus micelles, (2,3)
Janus–Janus micelles, (4) Janus multicompartment micelles, (5) patchy Janus micelles,
(6) multicompartment micelles, (7) patchy multicompartment micelles, (8) patchy micelles.
Adapted from Ref. 64 with permission of The Royal Society of Chemistry.
solution, and the solvent properties such as the type of organic solvent, the ratio
of organic solvent/water, salt concentration, solution pH, and temperature (65).
Among these factors, the volume ratio of the hydrophilic to hydrophobic block is
proposed to be an important parameter in the self-assembly process. The solvent
compatible block has a swollen tendency to form the exterior structures of the
aggregates, whereas the solvent incompatible block trends to form the interior
parts (Fig. 8). Whether the block copolymers form vesicles or micelles can be explained on the basis of the following equation: The packing parameter, p, is used
to distinguish the type of self-assemblies formed by amphiphiles (66,67):
p=
v
alc
where v is the volume occupied by the densely packed copolymer block (hydrophobic for aqueous media); lc is the statistical critical length normal to interface, which correlates with the contour length of the polymer chain; and a is
an effective cross-sectional area per the amphiphilic block copolymer molecule
at the interface (66,67). Amphiphiles with p below 1/3 form spherical micelles.
When p is between 1/3 and 1/2, amphiphiles form micelles with the spherical to
POLYMERIC MICELLES
11
Fig. 8. Aggregates self-assembled by amphiphilic block copolymers at different packing parameters, p. The block copolymer can form spherical micelles at p < 1/3, whereas
when packing parameters, 1/3 < p < 1/2 the polymer may form worm-like micelles. Vesicles or other complex structures the copolymer will self-assemble into when the packing
parameters, p > 1/2 (68). Adapted from Prog. Polym. Sci., Vol. no. 35, M. Motornov, Y.
Roiter, I. Tokarev, and S. Minko, Stimuli-response nanoparticles, nanogels, and capsules
for integrated multifunctional intelligent systems, Page No. 174–211, Copyright (2010)
with permission from Elsevier.
cylindrical (worm-like) morphology. If p values are between 1/2 and 1, a gradual
variation from a cylindrical micelle through vesicles (also called polymersomes in
the case of block copolymer vesicles) to a planar bilayer at p = 1 is expected. When
the packing parameter is p > 1, more complex systems of the inverted aggregates
may form (66,68).
However, these ratios are not definitive design features and often exceptions
to these guidelines are observed because having multiple morphologies. It should
be stressed that it is in balance between all the free energy contributions to the
self-assembly and also kinetic factors that determine the morphology of the final nanostructure. The hydrophilic/hydrophobic ratio is an important factor but
never the only determining parameter (9). For example, spherical micelles, vesicles, lamellae, flower-like vesicles, large compound vesicles, and perforated genus
vesicles can be made from the same block copolymer assembled under different
conditions (9).
Various morphologies can coexist in the self-assembly process of the block
copolymers. McCormick and co-workers found that spherical and worm-like micelles both existed by controlling the pH and concentration of the solution using
PDMA165 -b-PNIPAM202 block copolymer (61). Du and Chen reported the formation of the vesicles by the PEO-b-PTMSPMA block copolymer in a methanol–
water solvent mixture. Before the exclusive vesicles appeared, micelles, short
rods, and lamellae were observed as the coexisted morphologies when the water content increased gradually (69). Very recently, we observed the transition
12
POLYMERIC MICELLES
from polymer micelles to vesicles upon increasing the solution pH, with clear coexistence of micelles and vesicles at intermediate pH (70).
What’s more, the polydispersity of the polymer has also a great influence
on the final morphology of the micelles. For example, Hillmyer and co-workers
prepared several sets of poly(ethylene-alt-propylene)-b-poly(DL-lactide) diblock
copolymers with controlled molecular weights, compositions, and polydispersity
indices. They found that the domain spacing increased with increasing polydispersity and demonstrated that an increase in polydispersity at the constant polylactide composition can result in a change in morphology for compositionally
asymmetric diblock copolymers (71). Other studies on the effects of molecular
weight distribution on diblock copolymer self-assembly have been reported by
Matsushita and co-workers (72–74).
Stimuli-Responsive Polymeric Micelles
Polymeric micelles are good candidates for drug and gene delivery, nanoreactors,
and templates, and so on. It is important for the polymeric micelles to respond to
external stimuli such as a change in pH, oxidation/reduction, light, and temperature to release drugs in targeted tumor cells.
pH-Responsive Micelles. It is of great interest to use pH-responsive
nanoparticles for controlled release and encapsulation in vivo because of the wide
range of pH gradients present in biological and physiological systems. In general,
the pH-responsive property of a polymer is obtained via the protonation and deprotonation cycle of a weak polybase and/or weak polyacid in the block copolymers
at different pH (9). The variable pH can also induce the conformation changes in
the copolymers that may lead to the transformation of the self-assembled aggregates (75,76). Both block copolymers and synthetic block copolypeptides have
been used to make pH-responsive polymer vesicles or micelles (9).
For example, tumor-targeting polymer micelles had been prepared
on the basis of folic acid (FA)-functionalized diblock copolymers containing 2-(methacryloyloxy)-ethyl phosphorylcholine (MPC) and either 2(dimethylamino)ethyl methacrylate (DMA) or 2-(diisopropylamino) ethyl
methacrylate (DPA) (77). The FA-MPC30 -DMA50 block copolymer (Fig. 9) was
first dissolved in water at pH 2 and then added pH 8–9 water to form polymeric
micelles. These FA-functionalized MPC–DMA diblock copolymers are good
candidates for gene therapy and the drug delivery due to the cell-targeting agent
FA (77). In many types of cancer cells, the folate receptor has an elevated level
than the normal cells. Folic acid has a strong binding affinity functions with
the folate receptor. Once inside the cancer cells, the relatively low pH ∼ 5.0
will dissociate the responsive micelles and release the drugs. Therefore, these
pH-triggered polymeric micelles with a FA-targeting agent will have a great
potential in clinical applications (1,77).
Redox-Responsive Micelles. There is significant interest in the preparation of nanostructures that respond to a change in redox environment. Polymeric micelles with a redox-responsive property have also attracted researchers
in recent years (9). For example, a new type of sheddable micelle was prepared
on the basis of the biodegradable disulfide linked dextran-b-poly(ε-caprolactone)
POLYMERIC MICELLES
13
Fig. 9. Structure of FA-MPC-DMA block copolymer (77). Adapted with permission from
Ref. 77. Copyright (2005) American Chemical Society.
diblock copolymer (Dex-SS-PCL) for intracellular drug delivery (doxorubicin,
DOX) incorporated, (Fig. 10) (78). It is well known that the disulfide bond breaks
in the presence of a reducing agent. The polymeric micelles are stable without
the reducing agent for a long time, whereas they will undergo a fast shedding
process when subjected to reduction conditions (glutathione (GSH), a reductive
agent, at a higher level in a cancer cell than that in a normal cell in vivo), which
was demonstrated by the distinct changes in size and rapid drug release (78).
Light-Responsive Micelles. Compared to pH- or redox- responsive micelles, light-responsive micelles offer the advantage in the controlled release of
encapsulated molecules, that no extra chemical additives are needed to induce the
response. Zhao recently reviewed characteristics of light-responsive amphiphilic
copolymers, whose micellar aggregates can be disrupted by light exposure and
their application as delivery vehicles (79). The dissociation of these structures
can be reversibly and irreversibly achieved upon illumination with UV–vis or
near IR light (9).
The basic concept for the preparation of light-responsive polymer micelles
is to incorporate a chromophore into the structure of the hydrophobic block,
whose photoreaction can result in a conformational or structural change (trans
to cis) that shifts the hydrophilic/hydrophobic balance toward the destabilization
of micelle structure. The most commonly used chromophore is liquid crystalline
azobenzenes (LC-Azo). Its rod-like trans configuration makes it more stable than
its cis form, which stabilizes the structure of the LC phase, whereas its cis isomer
is bent and tends to destabilize the phase structure of the mixture (80). Upon UV
irradiation, the trans configuration isomerizes into its cis form. The cis form is
not thermodynamically stable and usually goes back to its trans form within several hours. This transition rate significantly increases (to several minutes) upon
visible light irradiation (9).
A new kind of light-breakable polymeric micelle was prepared on the basis
of an amphiphilic diblock copolymer whose structure is shown in Figure 11. The
hydrophilic block is PEO, whereas the hydrophobic block is a polymethacrylate
bearing a pyrene moiety in the side group (PPy). The micelles were finally formed
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POLYMERIC MICELLES
Fig. 10. DOX-loaded Dex-SS-PCL micelles are readily prepared with high drug loading
efficiency; following endocytosis, dextran shells are shed off due to cleavage of the intermediate disulfide bond triggered by GSH tripeptide, which results in fast destabilization
of micelles and quantitative release of DOX in the cytosol and into the cell nucleus (78).
Adapted with permission from Ref. 78. Copyright (2010) American Chemical Society.
with PEO coronas and a PPy core. Polymer micelles dissociate on the UV light
irradiation because the chemical bond breaking detaches the chromophore from
the polymer and transforms the hydrophobic block into a hydrophilic block (81).
Another kind of both light- and pH-sensitive polymeric micelles is reported
in 2012 (76). The azobenzene-containing block copolymer PEO-b-P(DEA-statPPHMA) was synthesized by ATRP (Fig. 12). The block copolymer can selfassemble into vesicles in aqueous solution at pH 8 and turn into micelles at pH 3
(Fig. 13). The same phenomenon (vesicles to micelles transition) can be observed
on addition of β-cyclodextrin (β-CD) to the PEO-b-P(DEA-co-PPHMA) solution at
pH 8. After adding β-CD into the solution, both UV and visible light can also
induce the reversible micelle-to-vesicle transition because of the photoinduced
trans-to-cis isomerization of azobenzene units (76).
Thermo-Responsive Micelles. A block copolymer may self-assemble
into polymeric micelles in aqueous solution if the hydrophilicity or hydrophobicity
of one segment of the copolymer can by changing temperature. It is well known
that N-isopropylacrylamide (NIPAM) is a thermo-responsive monomer and its
polymer (PNIPAM) has a LCST, which depends on the molecular weight, end
POLYMERIC MICELLES
15
Fig. 11. (a) Schematic illustration of light-induced detachment of dye pendant groups,
resulting in the hydrophobic-to-hydrophilic switch. (b) Chemical structure of the pyrenecontaining amphiphilic diblock copolymer and its photosolvolysis under UV light irradiation. Adapted with permission from Ref. 81. Copyright (2005) American Chemical Society.
Fig. 12. Synthesis of PEO-b-P(DEA-stat-PPHMA) copolymer by ATRP. Adapted from
Ref. 76, copyright 2012, with permission from John Wiley and Sons.
groups, and the overall composition of block copolymer (82–84). An amphiphilic
block copolymer with a PNIPAM block may be used to make polymer micelles and
other morphologies in pure water simply by varying the solution temperature (9).
For example, novel diblock copolymers comprising thermoresponsive segments of poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) [P(NIPAM-coDMAAm)] and hydrophobic segments of poly(D,L-lactide) were synthesized by
a combination of RAFT and ring-opening polymerization. The block copolymer
16
POLYMERIC MICELLES
Fig. 13. Multistimuli-responsive micelle-to-vesicle transition. Adapted from Ref. 76,
copyright 2012, with permission from John Wiley and Sons.
Fig. 14. (a) Synthesis of P(NIPAM-co-DMAAm)-b-PLA diblock copolymers. (b) Conversion of thermo-responsive polymer termini and formation of polymeric micelles. Adapted
with permission from Ref. 85. Copyright (2009) American Chemical Society.
can self-assemble into micelles, which showed great sensitivity to the temperature. The thermo-responsive micelles obtained from these polymers were approximately 25 nm when below the LCST of 40◦ C, and their sizes increased to
an average of approximately 600 nm above the LCST due to aggregation of the
micelles (Fig. 14) (85).
In related work, Liu and co-workers also reported thermo-sensitive unimolecular star polymer micelles as templates for the in situ preparation of silver
nanoparticles. The unimolecular micelles also showed a good thermo-sensitive
property with a LCST around 32◦ C (83).
Dual or multiresponsive polymeric micelles offer more control over the
drug release system. For example, both pH- and temperature-sensitive polymer
micelles were prepared (75). A PNIPAM-b-PAA diblock copolymer was synthesized by using RAFT polymerization in methanol. PNIPAM is a temperatureresponsive polymer with a LCST of ∼32◦ C in aqueous solutions (82–84), whereas
the PAA block is pH sensitive. The PAA-b-PNIPAM block copolymers form micelles with PAA coronas and a PNIPAM core when pH >4 and T > T c , whereas it
forms reverse micelles with a PAA core and PNIPAM coronas when pH < 4 and
T < T c . In other conditions, the block copolymer can form other nanostructures
or even gels (Fig. 15) (75).
POLYMERIC MICELLES
17
Fig. 15. pH- and temperature-responsive aggregate formation for PNIPAM-b-PAA diblock copolymer in aqueous solution. Adapted with permission from Ref. 75. Copyright
(2004) American Chemical Society.
Applications
Drug and Gene Delivery. One of the most important applications of the
polymeric micelles is drug and gene delivery (12–17,86–92). The method of drug
incorporation mostly depends on the method for the micelle preparation and the
particular block copolymer in the solution. If the micelles are formed by direct
dissolution in water, the hydrophobic drug and the polymer can be added into
the water together in order that the drug can be incorporated in the micelle core
(93). If the micelles are prepared by using the dialysis method, then the drug
is added with the copolymer to the common organic solvent and then dialysis is
conducted to remove the organic solvent and free drug (93). Figure 16 shows the
two different methods to incorporate drugs into polymeric micelles.
Multifunctional polymeric micelles with a cancer-targeting capability for
controlled drug delivery and efficient magnetic resonance imaging (MRI) contrast
characteristics have been reported in 2006 (87). The hydrophobic drug such as
DOX can be loaded in the core of the micelles, whereas the hydrophilic micelle
coronas are connected with some targeting ligand that can be recognized by the
particular tissue or cell. What’s more, the iron oxide is also introduced to the core
of the micelles for efficient MRI (87). The structure of the micelles is shown in
Figure 17.
Except for the application of the polymeric micelles in drug delivery, the
micelles can also be used in gene delivery (88,94). In 2008, Lin and co-workers
reported an intelligent gene delivery systems based on the PEO–PDMA polymeric micelles (88). The structure of the block copolymer is shown in Figure 18.
The block copolymer can self-assemble into micelles with PDMA as the core and
PEO as the coronas. In body fluid circumstance at pH ∼7.4, the PDMA core absorbs positive charge due to the protonation of their tertiary amine groups so the
18
POLYMERIC MICELLES
Fig. 16. Methods for loading drugs into polymeric micelles.
Fig. 17. Multifunctional nanomedicine platform for targeted drug delivery. Adapted with
permission Ref. 87. Copyright (2006) American Chemical Society.
plasmid DNA with negative charge will easily appeal to the micelle core. This
intelligent gene delivery system has great potential in clinic.
By now, as far as we know, at least four kinds of polymeric micelles have
been approved for clinical trials, such as drug vehicles, including Genexol-PM,
SP1049C, NK911, and NC-6004 (95,96).
For Genexol-PM, the polymeric micelles were self-assembled by PEO-b-PLA
diblock copolymers with the biodegradable and hydrophobic PLA as the core and
hydrophilic and biocompatible PEO as the coronas. The diameter of the micelles
is around 20–50 nm. The hydrophobic drug, paclitaxel, which is a taxane derived from the Pacific yew tree that has a wide spectrum of antitumor activity
POLYMERIC MICELLES
19
Fig. 18. Illustration of the process of PEO-b-PDMA polymeric micelles incorporated with
plasmid DNA. Adapted with permission from Ref. 88. Copyright (2008) American Chemical Society.
Fig. 19. Formulation of polymeric micelle loaded Genexol-PM.
(97,98), is preferred to stay in the micelle core to form the Genexol-PM product.
Figure 19 shows the whole process of the formulation of polymeric micelle based
Genexol-PM. Genexol-PM was found to have threetime higher maximum tolerated dose (MTD) in nude mice, and the biodistribution of Genexol-PM showed
2–3 fold higher levels in various tissues including liver, spleen, kidney, lung, and
more importantly in tumors.
Another vital product that has been approved for clinical trials is NK 911
(99). NK911 is a novel supramolecular nanocarrier designed for the enhanced
delivery of DOX and is one of the successful polymeric micelle systems, which
exhibits an efficient accumulation in solid tumors in mice (99). The polymeric
micelles consist of PEG-b-poly(aspartic acid) block copolymers conjugated with
DOX. PEG is believed to form the outer coronas of the micelle, whereas the
poly(aspartic acid) segments form the micelle core to entrap DOX (99). The drug
delivery systems have longer plasma half-lives, accumulate in tumors more effectively because of the EPR effect, and exhibit a stronger antitumor activity
20
POLYMERIC MICELLES
Fig. 20. Spatial and temporal control of drug distribution using tunable pH-sensitive
polymeric micelles. Adapted from Pharmaceut. Res., Vol. 27, 2010, 2330–2342, PEG-poly
(amino acid) block copolymer micelles for tunable drug release, A. Ponta, with kind permission from Springer Science and Business Media.
than free DOX when administered in mice (99). The NK911 nanocarrier is a kind
of pH-sensitive polymeric micelles that has been studied by some researchers
(100). Figure 20 shows the design and the control of drug delivery to tumor microenvironment using these tunable pH-sensitive polymeric micelles (100). The
polymeric micelles with tunable drug release may provide good methods for both
early-prompt and late-prolonged chemotherapeutic treatment (101).
The third product is SP1049C. SP1049C is a novel anticancer product containing DOX and two nonionic pluronic block copolymers micelles. In preclinical
studies, SP1049C demonstrated increased efficacy compared to free DOX (102).
The fourth system that has been approved for clinical trial is NC-6004 (103).
NC-6004 is a kind of cisplatin-incorporating polymeric micelles consisting of Cisplatin (cis-dichlorodiammineplatinum (II) (CDDP, which is a key drug in the
chemotherapy for cancer, including lung, gastrointestinal, and genitourinary cancer) and PEG-b-P(Glu). PEG serves as the hydrophilic chain, which constitutes
the outer coronas of the micelles, whereas the P(Glu) segments form the micelle
core to incorporate CDDP (103).
In addition, polymeric carriers with sufficient amount of drugs to the tumor
site have always been an important requirement for polymer–drug conjugates.
However, the loading capacity of the polymeric micelles acting as a drug vehicle is
often limited (104), usually less than 40% (101,105,106). Therefore, development
of polymeric micelles with a higher payload becomes necessary. Another challenge
of polymeric micelles in the drug delivery application is to use more products
in the clinic because it needs additional measures to prove the clinical benefits.
However, it usually takes a long time and much cost. Although polymeric micelles
have great potentials in drug delivery, the optimization of the system toward
clinical applications is really a great challenge based on the above discussion
POLYMERIC MICELLES
21
Fig. 21. Hollow nanosphere is formed using PS-PAA-PEO micelles as templates. Adapted
from J. Colloid Interf. Sci., Vol. No. 307, M. Sasidharan, N. Gunawardhana, H. N. Luitel,
T. Yokoi, M. Inoue, et al., Novel LaBO3 hollow nanospheres of size 34 ± 2 nm templated by
polymeric micelles, Page No. 51–57, Copyright (2012) with permission from Elsevier.
(104). Genexol-PM, SP1049C, NK911, and NC-6004 are four kinds of promising
products. However, the use of polymeric micelles as drug delivery units is still
limited, which raises a vital question to chemists, biologists, and doctors.
Nanoreactors. The polymeric micelles are widely used as the template
for biomineralization. For example, as shown in Figure 21, PS-PAA-PEO triblock self-assembles into micelles with a core–shell–corona architecture, which
serves as an efficient soft template for fabrication of LaBO3 hollow particles using sodium borohydride (NaBH4 ) and LaCl3 ·7H2 O as the precursors (107). In this
nanotemplate, the PS core serves as the template of the void space of hollow particle, the anionic PAA block (shell) acts as a reaction field for absorbing the La3+
ions, and the PEO block (corona) stabilizes the polymer–lanthanum composite
particles (107). After calcinations, the LaBO3 hollow sphere is achieved. LaBO3
hollow nanospheres are good candidates for their lithium-ion battery (LIBs)
applications.
In 2010, Du and co-workers reported a novel patchy multicompartment micelles by direct dissolution of a primary amine based triblock copolymer, PEO-bPCL-b-PAMA in water with PCL chains forming the micelle cores and the PEO
and PAMA chains forming patchy or hemispherical coronas (108). The patchy micelles can be used as templates to deposit silica on the PCL core adopting water
insoluble tetramethyl orthosilicate (TMOS) as the silica source. The deposition
reaction is catalyzed by cationic polymer chains PAMA. Therefore, the silica only
aggregates on the PAMA hemispheres without touching the PEO hemispheres
(Fig. 22). In this article, the researchers provided a good method for revealing the
structure of the Janus micelles using the TMOS as a silica source. The TMOS also
played the role of the staining agent so that the patchy micelles can be observed
in the TEM (Fig. 23). TMOS trends to aggregate in PAMA hemispherical coronas
of micelles because of the catalysis of PAMA chains in a sol–gel reaction.
22
POLYMERIC MICELLES
Fig. 22. Formation of Janus micelles by dissolution of the PEO-b-PCL-b-PAMA triblock
copolymer in pure water at pH 5 and 60◦ C. The Janus micelles are stabilized when cooled
to 20◦ C. Selective sol–gel reactions occurred in the PAMA-corona-rich hemisphere after
adding TMOS. Adapted from Ref. 108 with permission of The Royal Society of Chemistry.
In addition, polymer micelles can be used for the mediation of titanium
dioxide nanoparticles (109). Nakashima and co-workers reported the hollow silica nanospheres by the sol–gel reactions confined to the middle shell of PS-bPVP-b-PEO micelles and subsequent calcinations (110). In 2011, hollow titania
nanospheres were prepared on the basis of polystyrene-block-poly(acrylic acid)block-poly(ethylene oxide) (PS-b-PAA-b-PEO) triblock copolymer micelles using
titanium(IV) butoxide as a titanium precursor, exhibiting excellent electrochemical properties in lithium ion rechargeable batteries such as high capacity, very
low irreversible capacity loss, and high cycling performance (111). In 2011, Zhao
and co-workers used a PEO-b-PS diblock copolymer to synthesize large-pore ordered mesoporous TiO2 in a ligand-assisted assembly (112). In addition, a range
of hollow metal oxide spheres such as niobium pentoxide, cerium oxide, and vanadia can be mediated by polymer micelles (113).
Characterization
The morphology of the polymeric micelles can be observed via TEM, SEM and
AFM. Of the three above-mentioned techniques, TEM is most widely adopted
because the diameter of the micelles is much small usually around 10–100 nm
and the morphology can be better revealed by TEM. To get a good TEM image, the
aqueous micelle solution is often stained to enhance the contrast of the polymeric
micelles. Dynamic light scattering (DLS) and static light scattering (SLS) are
POLYMERIC MICELLES
23
Table 1. Relationship between R g /R h Value
and Morphology (114)
Rg /Rh value
Morphology
1.2
∼1
0.7–1
0.7
Cylinders
Vesicles
Vesicles or micelles
Micelles
Fig. 23. TEM images of silicified micelles prepared from a PEO43 -b-PCL63 -b-PAMA73 triblock copolymer in water at pH 5 (a) and pH 7 (b): Janus micelles with no patches (eg,
particles 1 and 3); Janus micelles with different patches (particles 2, 3–8); patchy multicompartment micelles (particles in panel b). The arrows indicate two chemically segregated hemispheres comprising PEO chains (white) and PAMA chains (black). In panel a,
some unlabeled particles are also believed to be Janus micelles (eg, particle 9) but are
simply viewed at a different angle. Others are patchy multicompartment micelles (eg, particle 10 and particles in the top-left corner). Adapted from Ref. 108 with permission of The
Royal Society of Chemistry.
adopted to measure the hydrodynamic radius (Rh ) and radius of gyration (Rg )
of the polymeric micelles, and on the basis of the DLS and SLS tests, we can
preliminary judge whether the aggregates self-assemble into micelles, vesicles,
or other agglomerations based on the Rg /Rh value, as shown in Table 1 (9,68).
Problems and Challenge
Although the rapid progress in the preparation of smart and functional polymeric
micelles in recent years, some general issues still exist in this area. The first issue is the large-scale preparation. As we know, most of polymeric micelles are
prepared in dilute solution in the laboratory, which is really difficult to meet
the industrial demand for large production. Besides the scaling-up issue, another question that should be paid much attention is the cytotoxicity of polymeric
micelles for biomedical use. Noncytotoxic polymeric materials are the essential
24
POLYMERIC MICELLES
requirement when the polymeric micelles are used in clinics. Furthermore, polymers with biocompatible and biodegradable properties are preferred. However,
only a few polymers are allowed to be used in vivo such as PEO, PLA, PCL, and
so on (97,99,102,103).
Summary and Prospective
Polymeric micelles are diverse materials that can be used in many fields such as
nanoreactors and drug, gene delivery. In this review, we briefly introduced some
basic knowledge of polymeric micelles, which include the definition, the preparation, the classification, and the applications of polymeric micelles. The research
on smart polymeric micelles, for example, pH-responsive, thermo-responsive,
redox-responsive, and light-responsive micelles has highly developed in recent
years. One of the future research work is to focus on improving the biocompatibility and biodegradability of the polymeric micelles for their use in biomedical
applications. For the nanoreactor application, the method to form micelles should
be optimized to meet the large-scale demands. The design of multifunctional polymeric micelles is another prospective trend. Significant work in the field of polymeric micelles should also be directed to the more efficient, less costly, and timeconsuming preparation of these materials.
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JIANZHONG DU
HANG LU
Tongji University, Shanghai
People’s Republic of China
Glossary
ATRP
BIEE
CDDP
CMC
CRP
Dex
DLS
DOX
DVS
DPA
DMAAm
EPR
FA
LCST
GSH
Glu
MRI
MPC
MTD
P4VP
PAA
PAMA
PCL
PDEA
PDMA
PEO
PFS
PGMA
PI
PLA
atom transfer radical polymerization
bis(2-iodoethoxy)ethane
cis-dichlorodiammineplatinum
critical micelle concentration
controlled radical polymerization
dextran
dynamic light scattering
doxorubicin
divinyl sulfone
2-(diisopropylamino) ethyl methacrylate
N, N-dimethylacrylamide
enhanced permeation and retention
folic acid
lower critical solution temperature
glutathione
glutamic acid
magnetic resonance imaging
2-(methacryloyloxy)-ethyl phosphorylcholine
maximum tolerated dose
poly(4-vinyl pyridine)
poly(acrylic acid)
poly(2-aminoethyl methacrylate)
poly(ε-caprolactone)
poly(2-(diethylamino)ethyl methacrylate)
poly(N, N-dimethylaminoethyl methacrylate)
poly[2-(dimethylamino)ethyl methacrylate];
poly(ethylene oxide)
polyferrocenyldimethylsilane
poly(glycerol monomethacrylate)
polyisoprene
poly(lactic acid)
POLYMERIC MICELLES
PMA
PNA
PNIPAM
PPHMA
PS
PTMSPMA
PVPy
NCCM
RAFT
SLS
TMOS
UCST
β-CD
poly(methyl acrylate)
N-phenyl-1-naphthylamine
poly(N-isopropylacrylamide)
6-(4-phenylazo phenoxy)hexyl methacrylate
polystyrene
poly[3-(trimethoxysilyl)propyl methacrylate]
poly(4-vinylpyridine)
noncovalently connected micelles
reversible addition–fragmentation chain transfer
static light scattering
tetramethyl orthosilicate
upper critical solution temperature
β-cyclodextrin
29