Formation Of Block Copolymer Micelles Research Articles

Dual Thermal- and Oxidation-Responsive Polymers Synthesized by a Sequential ROP-to-RAFT Procedure Inherently Temper Neuroinflammation.

This study is about multiple responsiveness in biomedical materials. This typically implies "orthogonality" (i.e., one response does not affect the other) or synergy (i.e., one increases efficacy or selectivity of the other), but an antagonist effect between responses may also occur. Here, we describe a family of very well-defined amphiphilic and micelle-forming block copolymers, which show both oxidative and temperature responses. They are produced via successive anionic ring-opening polymerization of episulfides and RAFT polymerization of dialkylacrylamides and differ only in the ratio between inert (N,N-dimethylacrylamide, DMA) and temperature-sensitive (N,N-diethylacrylamide, DEA) units. By scavenging Reactive Oxygen Species (ROS), these polymers are anti-inflammatory; through temperature responsiveness, they can macroscopically aggregate, which may allow them to form depots upon injection. The localization of the anti-inflammatory action is an example of synergy. An extensive evaluation of toxicity and anti-inflammatory effects on in vitro models, including BV2 microglia, C8D30 astrocytes and primary neurons, shows a link between capacity of aggregation and detrimental effects on viability which, albeit mild, can hinder the anti-inflammatory potential (antagonist action). Although limited in breadth (e.g., only in vitro models and only DEA as a temperature-responsive unit), this study suggests that single-responsive controls should be used to allow for a precise assessment of the (synergic or antagonist) potential of double-responsive systems.

Effect of Core-Crosslinking on Protein Corona Formation on Polymeric Micelles.

Most nanomaterials acquire a protein corona upon contact with biological fluids. The magnitude of this effect is strongly dependent both on surface and structure of the nanoparticle. To define the contribution of the internal nanoparticle structure, protein corona formation of block copolymer micelles with poly(N-2-hydroxypropylmethacrylamide) (pHPMA) as hydrophilic shell, which are crosslinked-or not-in the hydrophobic core is comparatively analyzed. Both types of micelles are incubated with human blood plasma and separated by asymmetrical flow field-flow fractionation (AF4). Their size is determined by dynamic light scattering and proteins within the micellar fraction are characterized by gel electrophoresis and quantified by liquid chromatography-high-resolution mass spectrometry-based label-free quantitative proteomics. The analyses reveal only very low amounts of plasma proteins associated with the micelles. Notably, no significant enrichment of plasma proteins is detectable for core-crosslinked micelles, while noncrosslinked micelles show a significant enrichment of plasma proteins, indicative of protein corona formation. The results indicate that preventing the reorganization of micelles (equilibrium with unimers) by core-crosslinking is crucial to reduce the interaction with plasma proteins.

Micelle-Forming Block Copolymers Tailored for Inhibition of P-gp-Mediated Multidrug Resistance: Structure to Activity Relationship.

Multidrug resistance (MDR) is often caused by the overexpression of efflux pumps, such as ABC transporters, in particular, P-glycoprotein (P-gp). Here, we investigate the di- and tri- block amphiphilic polymer systems based on polypropylene glycol (PPO) and copolymers of (N-(2-hydroxypropyl)methacrylamide) (PHPMA) as potential macromolecular inhibitors of P-gp, and concurrently, carriers of drugs, passively targeting solid tumors by the enhanced permeability and retention (EPR) effect. Interestingly, there were significant differences between the effects of di- and tri- block polymer-based micelles, with the former being significantly more thermodynamically stable and showing much higher P-gp inhibition ability. The presence of Boc-protected hydrazide groups or the Boc-deprotection method did not affect the physico-chemical or biological properties of the block copolymers. Moreover, diblock polymer micelles could be loaded with free PPO containing 5–40 wt % of free PPO, which showed increased P-gp inhibition in comparison to the unloaded micelles. Loaded polymer micelles containing more than 20 wt % free PPO showed a significant increase in toxicity; thus, loaded diblock polymer micelles containing 5–15 wt % free PPO are potential candidates for in vitro and in vivo application as potent MDR inhibitors and drug carriers.

Spatial Control of Mechanical Properties and Surface Topography in a Photoreactive Block Copolymer Hydrogel

A simple method for spatially directed mechanical reinforcement and surface feature introduction on a photoactive block copolymer-based thermoplastic elastomer hydrogel is presented. The hydrogel material comprises two primary spherical micelle-forming block copolymer species: photoactive ω-anthracenylpolystyrene-b-poly(ethylene oxide) diblock copolymer (SO-anth) and polystyrene-b-poly(ethylene oxide)-b-polystyrene triblock copolymer (SOS). The PEO midblock of the SOS triblock copolymer species provides a physical tether between adjacent micelles, increasing mechanical robustness (modulus) with addition of bridging SOS chains. The photoactive SO-anth diblock copolymer contains a terminal anthracene unit capable of dimerization by application of 365 nm light to induce a [4 + 4] photocycloaddition. The ability to photocouple chain termini populating the outer shell of the hydrophilic micelle coronas produces additional SOS triblock copolymer in situ. While the initial population of SOS tethers act to form a...

Classical Challenges in the Physical Chemistry of Polymer Networks and the Design of New Materials.

Polymer networks are widely used from commodity to biomedical materials. The space-spanning, net-like structure gives polymer networks their advantageous mechanical and dynamic properties, the most essential factor that governs their responses to external electrical, thermal, and chemical stimuli. Despite the ubiquity of applications and a century of active research on these materials, the way that chemistry and processing interact to yield the final structure and the material properties of polymer networks is not fully understood, which leads to a number of classical challenges in the physical chemistry of gels. Fundamentally, it is not yet possible to quantitatively predict the mechanical response of a polymer network based on its chemical design, limiting our ability to understand and characterize the nanostructure of gels and rationally design new materials. In this Account, we summarize our recent theoretical and experimental approaches to study the physical chemistry of polymer networks. First, our understanding of the impact of molecular defects on topology and elasticity of polymer networks is discussed. By systematically incorporating the effects of different orders of loop structure, we develop a kinetic graph theory and real elastic network theory that bridge the chemical design, the network topology, and the mechanical properties of the gel. These theories show good agreement with the recent experimental data without any fitting parameters. Next, associative polymer gel dynamics is discussed, focusing on our evolving understanding of the effect of transient bonds on the mechanical response. Using forced Rayleigh scattering (FRS), we are able to probe diffusivity across a wide range of length and time scales in gels. A superdiffusive region is observed in different associative network systems, which can be captured by a two-state kinetic model. Further, the effects of the architecture and chemistry of polymer chains on gel nanostructure are studied. By incorporating shear-thinning coiled-coil protein motifs into the midblock of a micelle-forming block copolymer, we are able to responsively adjust the gel toughness through controlling the nanostructure. Finally, we review the development of novel application-oriented materials that emerge from our enhanced understanding of gel physical chemistry, including injectable gel hemostats designed to treat internal wounds and engineered nucleoporin-like polypeptide (NLP) hydrogels that act as biologically selective filters. We believe that the fundamental physical chemistry questions articulated in this Account will provide inspiration to fully understand the design of polymer networks, a group of mysterious yet critically important materials.

Tumor-targeted micelle-forming block copolymers for overcoming of multidrug resistance

New amphiphilic diblock polymer nanotherapeutics serving simultaneously as a drug delivery system and an inhibitor of multidrug resistance were designed, synthesized, and evaluated for their physico-chemical and biological characteristics. The amphiphilic character of the diblock polymer, containing a hydrophilic block based on the N-(2-hydroxypropyl)methacrylamide copolymer and a hydrophobic poly(propylene oxide) block (PPO), caused self-assembly into polymer micelles with an increased hydrodynamic radius (Rh of approximately 15nm) in aqueous solutions. Doxorubicin (Dox), as a cytostatic drug, was bound to the diblock polymer through a pH-sensitive hydrazone bond, enabling prolonged circulation in blood, the delivery of Dox into a solid tumor and the subsequent stimuli-sensitive controlled release within the tumor mass and tumor cells at a decreased pH. The applicability of micellar nanotherapeutics as drug carriers was confirmed by an in vivo evaluation using EL4 lymphoma-bearing C57BL/6 mice. We observed significantly higher accumulation of micellar conjugates in a solid tumor because of the EPR effect compared with similar polymer-drug conjugates that do not form micellar structures or with the parent free drug. In addition, highly increased anti-tumor efficacy of the micellar polymer nanotherapeutics, even at a sub-optimal dose, was observed. The presence of PPO in the structure of the diblock polymer ensured, during in vitro tests on human and mouse drug-sensitive and resistant cancer cell lines, the inhibition of P-glycoprotein, one of the most frequently expressed ATP-dependent efflux pump that causes multidrug resistance. In addition, we observed highly increased rate of the uptake of the diblock polymer nanotherapeutics within the cells. We suppose that combination of unique properties based on MDR inhibition, stimuli sensitiveness (pH sensitive activation of drug), improved pharmacokinetics and increased uptake into the cells made the described polymer micelle a good candidate for investigation as potential drug delivery system.

Encapsulation of Nanoparticles During Polymer Micelle Formation: A Dissipative Particle Dynamics Study.

The formation of block copolymer micelles with and without hydrophobic nanoparticles is simulated using dissipative particle dynamics. We use the model developed by Spaeth et al. [ Spaeth , J. R. , Kevrekidis , I. G. , and Panagiotopoulos , A. Z. J. Chem. Phys. 2011 , 134 ( (16) ) 164902 ], and drive micelle formation by adjusting the interaction parameters linearly over time to represent a rapid change from organic solvent to water. For different concentrations of added nanoparticles, we determine characteristic times for micelle formation and coagulation, and characterize micelles with respect to size, polydispersity, and nanoparticle loading. Four block copolymers with different numbers of hydrophobic and hydrophilic polymer beads, are examined. We find that increasing the number of hydrophobic beads on the polymer decreases the micelle formation time and lowers polydispersity in the final micelle distribution. Adding more nanoparticles to the simulation has a negligible effect on micelle formation and coagulation times, and monotonically increases the polydispersity of the micelles for a given polymer system. The presence of relatively stable free polymer in one system decreases the amount of polymer encapsulating the nanoparticles, and results in an increase in polydispersity and the number of nanoparticles per micelle for that system, especially at high nanoparticle concentration. Longer polymers lead to micelles with a more uniform nanoparticle loading.

Effect of Polymer Micelles on Antifungal Activity of Geranylorcinol Compounds against Botrytis cinerea

Herein, we explore the potential use of two micelle-forming block copolymers, i.e., Pluronic F-127 and poly(ethylene oxide)-b-poly(caprolactone), for application of fungicide agents. The polymer effect on the in vitro fungicide activity of a series of geranyl orcinol derivatives against Botrytis cinerea has been assessed. The results show that, for all test compounds, the incorporation into micelles, formed by Pluronic F-127, produces a great enhancement of the inhibitory effect on the growth of B. cinerea. For some compounds, at the lowest tested concentration (50 ppm), the percentage of inhibition increases significantly (from 0-10 to 80-90%) when the application is made using a polymer solution instead of an ethanol/water mixture. The synthesis and structural determination of a series of eight geranylphenols/diacetates, which were used as fungicide agents, are also discussed. These results suggest that polymer micelles are promising systems for application of crop-protecting agents.

Block copolymer micelle formation in a solvent good for all the blocks

To produce desired aggregate structures of copoly- mers, the copolymer is usually first dissolved in a common solvent that dissolves all the blocks. However, a solvent hav- ingtheexact samesolubilitytoalltheblocksofacopolymeris rare. Hence, it is extremely important to know whether the block copolymer forms micelle in a common solvent, and if it does, to know the micelle's structure. In this study, we used polystyrene-b-poly(4-vinylpyridine) (PS-b-P4VP) dissolved in dimethyl formamide (DMF) as a model system to address block copolymer micelle formation and its structure in a solvent good for all the blocks as DMF dissolves both PS and P4VP. Our atomic force microscopy (AFM) and cryogenic-transmission electron microscopy (cryo-TEM) results clearly demonstrated that PS-b-P4VP with a wide range of molecular weight and P4VP composition in DMF forms a spherical micelle. Furthermore, contact angle measurements and TEM results clearly show that the micelle has a PS core and a P4VP corona. In com- paring the dry micelle and the micelle in DMF, we discovered that the micelle core is significantly swelled by DMF. Our findings suggest that soft-core micelles widely exist for block copolymers in solvents good for all the blocks but with significant selectivity between different blocks.

Block Copolymer Micelles with an Intermediate Star‐/Flower‐Like Structure Studied by 1H NMR Relaxometry

1H NMR relaxation is used to study the self‐assembly of a double thermoresponsive diblock copolymer in dilute aqueous solution. Above the first transition temperature, at which aggregation into micellar structures is observed, the trimethylsilyl (TMS)‐labeled end group attached to the shell‐forming block shows a biphasic T2 relaxation. The slow contribution reflects the TMS groups located at the periphery of the hydrophilic shell, in agreement with a star‐like micelle. The fast T2 contribution corresponds to the TMS groups, which fold back toward the hydrophobic core, reflecting a flower‐like micelle. These results confirm the formation of block copolymer micelles of an intermediate nature (i.e., of partial flower‐like and star‐like character), in which a part of the TMS end groups folds back to the core due to hydrophobic interactions. image

Effects of Solvent Quality and Degree of Polymerization on the Critical Micelle Temperature of Poly(ethylene oxide-b-n-butyl methacrylate) in Ionic Liquids

Block copolymers are attractive building blocks for designing micelles having complex shapes and functionality, but experimental investigations into the detailed thermodynamics of block copolymer micellization have been constrained. In this work, we take advantage of the favorable solvent properties of ionic liquids to study the thermodynamics of block copolymer micelle formation. Specifically, we investigate the effects of solvent quality and degree of polymerization on the critical micelle temperature (cmt) of poly(ethylene oxide-b-n-butyl methacrylate) (PEO-b-PnBMA) in mixtures of two ionic liquids: 1-butyl-3-methylimidazolium:bis(trifluoromethylsulfonyl)imide ([BMIm][TFSI]) and 1-ethyl-3-methylimidazolium:TFSI ([EMIm][TFSI]). The solvent quality for the core-forming block of the block copolymer, PnBMA, is varied over a wide range by blending the two ionic liquids in different ratios, resulting in a large variation in the cmt of PEO-b-PnBMA. It is shown that the interaction parameter between the solvent and PnBMA at the cmt is approximately constant for all of the ionic liquid mixtures. The enthalpies and entropies of micelle formation also do not vary with ionic liquid composition, suggesting that the nature of the polymer/solvent and solvent/solvent interactions do not change much as the ionic liquid composition is varied despite the large change in solvent quality. Furthermore, the cmt is shown to depend on the degree of polymerization of PnBMA as predicted by theory.

Disulfide Cross-Linked Phosphorylcholine Micelles for Triggered Release of Camptothecin

A series of block copolymers based on 2-methacryloyloxyethyl phosphorylcholine (MPC) were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. Incorporation of dihydrolipoic acid (DHLA) into the hydrophobic block led to formation of block copolymer micelles in water. The micelles were between 15 and 30 nm in diameter, as characterized by dynamic light scattering (DLS), with some size control achieved by adjusting the hydrophobic/hydrophilic balance. Cross-linked micelles were prepared by disulfide formation, and observed to be stable in solution for weeks. The micelles proved amenable to disassembly when treated with a reducing agent, such as dithiothreitol (DTT), and represent a potential delivery platform for chemotherapeutic agents. As a proof-of-concept, camptothecin (CPT) was conjugated to the polymer scaffold through a disulfide linkage, and release of the drug from the micelle was monitored by fluorescence spectroscopy. These CPT-loaded prodrug micelles showed a reduction in release rate compared to physically encapsulated CPT. The use of disulfide conjugation facilitated drug release under reducing conditions, with a half-life (t1/2) of 5.5 h in the presence of 3 mM DTT, compared to 28 h in PBS. The toxicity of the micellar prodrugs was evaluated in cell culture against human breast (MCF7) and colorectal (COLO205) cancer cell lines.

Micellar Formation and Organization in Thin Film Polymer Blends

We study the formation and organization of micelles, of polystyrene-b-poly(2-vinylpyridine) (PS-b-P2VP) diblock copolymer chains, in thin film hosts composed of (1) blends of long and short chain polystyrenes, PSL and PSS, of degrees of polymerization PL and PS, respectively (PS < PL), and (2) blends of PSL and a homopolymer with which it is compatible, tetramethyl bisphenol-A polycarbonate (TMPC), of degree of polymerization PTMPC (PTMPC < PL). The role of competing entropic and enthalpic interactions on the block copolymer micelle formation and organization is examined. We show that the average size of the micelle cores, Dcore, decreased with increasing weight fraction of the shorter chain PS component in PS(PS = 125)/PS(PL = 15400) mixtures, for PL≫NPS, NPS is the degree of polymerization of the PS block (the micelle corona). Dcore also decreased with increasing weight fraction of TMPC in TMPC(PTMPC = 122)/PS(PL = 15400) mixtures. The values of Dcore in the TMPC/PSL hosts were smaller than those in PSS/PSL mixtures, for the same TMPC, or PSS, weight fractions (PS ≈ PTMPC). This is due to more extensive mixing between the TMPC host chains, compared to the PSS chains, and the micelle corona. Furthermore, we show that the size and the organization of the micelles within the films may be controlled independently, through changing the relative fractions of PSS or TMPC and the value of PL. The fraction of TMPC, or PSS, mixed with the corona decreased as PL decreased from PL = 15400 to smaller values.

Effect of chain rigidity on block copolymer micelle formation and dissolution as observed by 1H-NMR spectroscopy

Amphiphilic copolymers poly(methyl methacrylate-b-acrylic acid), poly(methyl methacrylate-b-methacrylic acid), poly(methyl acrylate-b-acrylic acid) and poly(methyl acrylate-b-methacrylic acid) were prepared by reversible addition fragmentation chain-transfer (RAFT) polymerization. The hydrophilic polyacid blocks were either synthesized directly or formed by the hydrolysis of poly(tert-butyl acrylate) or poly(tert-butyl methacrylate) blocks. The hydrophobic blocks consisted of either the more rigid, high glass transition temperature (Tg) poly(methyl methacrylate) or more flexible, low Tg poly(methyl acrylate) material. The hydrophilic blocks were either poly(methacrylic acid) (rigid, high Tg) or poly(acrylic acid) (flexible, low Tg). The micellization behavior of the polymers was studied by proton nuclear magnetic resonance (1H-NMR) spectroscopy in mixtures of 1,4-dioxane-d8 and D2O. All four polymers were soluble in neat dioxane. In solutions of higher water content, the polymers with the more rigid hydrophobic blocks formed into micelles as was evidenced by broadening of the resonances resulting from the protons in those blocks. At moderate water concentration (25–50%), dissolution of the micelles was observed upon heating the solution. No micellization was observed in polymers containing the less rigid poly(methyl acrylate) hydrophobic block regardless of the identity of the hydrophilic block. As further evidence of micellization formation and dissolution, the spin-lattice (T1) and spin-spin (T2) relaxation times of protons in the hydrophobic and hydrophilic blocks were measured. Significant differences in the relaxation times as functions of temperature and solvent concentration were observed between the hydrophilic and hydrophobic blocks of the micelle-forming polymers.

Controlling the Self-Assembly Structure of Magnetic Nanoparticles and Amphiphilic Block-Copolymers: From Micelles to Vesicles

We report how to control the self-assembly of magnetic nanoparticles and a prototypical amphiphilic block-copolymer composed of poly(acrylic acid) and polystyrene (PAA-b-PS). Three distinct structures were obtained by controlling the solvent-nanoparticle and polymer-nanoparticle interactions: (1) polymersomes densely packed with nanoparticles (magneto-polymersomes), (2) core-shell type polymer assemblies where nanoparticles are radially arranged at the interface between the polymer core and the shell (magneto-core shell), and (3) polymer micelles where nanoparticles are homogeneously incorporated (magneto-micelles). Importantly, we show that the incorporation of nanoparticles drastically affects the self-assembly structure of block-copolymers by modifying the relative volume ratio between the hydrophobic block and the hydrophilic block. As a consequence, the self-assembly of micelle-forming block-copolymers typically produces magneto-polymersomes instead of magneto-micelles. On the other hand, vesicle-forming polymers tend to form magneto-micelles due to the solubilization of nanoparticles in polymer assemblies. The nanoparticle-polymer interaction also controls the nanoparticle arrangement in the polymer matrix. In N,N-dimethylformamide (DMF) where PS is not well-solvated, nanoparticles segregate from PS and form unique radial assemblies. In tetrahydrofuran (THF), which is a good solvent for both nanoparticles and PS, nanoparticles are homogeneously distributed in the polymer matrix. Furthermore, we demonstrated that the morphology of nanoparticle-encapsulating polymer assemblies significantly affects their magnetic relaxation properties, emphasizing the importance of the self-assembly structure and nanoparticle arrangement as well as the size of the assemblies.

Micelle Formation and Gelation of (PEG−P(MA-POSS)) Amphiphilic Block Copolymers via Associative Hydrophobic Effects

A series of well-defined amphiphilic di- and triblock copolymers have been synthesized, using atom transfer radical polymerization, with poly(ethylene glycol) (PEG) and poly(methacrylisobutyl polyhedral oligomeric silsesquioxane) P(MA-POSS) as the hydrophilic and hydrophobic blocks, respectively. The detailed self-assembly behavior of the amphiphilic macromolecules in aqueous media was studied using both static and dynamic light scattering (SLS and DLS) techniques. The evolution of block copolymer micelle formation in THF/water mixture (20/80 v/v) was monitored as the THF evaporated from the solvent mixture. Initially the block copolymer chains existed as unimers in solution, followed by the formation of smaller aggregates (R(h) < 2 nm) after 30 min, eventually growing in size to reach an equilibrium size when all the THF evaporated within 24 h. The micelles formed by the block copolymers were found to be kinetically unstable (not frozen); i.e., they tended to revert to individual copolymer chains on dilution. The hydrodynamic radii, R(h), of the micelles varied with the degree of polymerization (DP) of the hydrophobic P(MA-POSS); for example, for PEG(5K)-b-P(MA-POSS), an increase from R(h) approximately 13.3 +/- 1.1 nm to R(h) approximately 17.5 +/- 1.4 nm was observed with a nominal change in the DP of P(MA-POSS) from 4 to 6. The micelles formed by the triblock copolymers (P(MA-POSS)-b-PEG(10K)-b-P(MA-POSS)) were comparable in size to the diblock copolymer micelles; e.g., R(h) approximately 14.0 +/- 1.3 nm was found for P(MA-POSS)(4)-b-PEG(10K)-b-P(MA-POSS)(4). The micellar structures created by the triblocks in aqueous media were "flowerlike", where the PEG middle block adopted a loop conformation in the micelle corona. In addition to micelles, larger aggregates formed by P(MA-POSS)-b-PEG(10K)-b-P(MA-POSS) were also detected in solution. The larger aggregates may suggest a contribution from some PEG blocks adopting an extended conformation with one end dangling in solution, causing gelation at higher copolymer concentrations via intermicellar interactions. The P(MA-POSS)(4)-b-PEG(10K)-b- P(MA-POSS)(4) formed a gel in water at approximately 8.8 wt % copolymer concentration. No gel formation by diblock copolymers was observed; however, the addition of a small amount of triblock copolymer to an aqueous solution of diblock copolymer results in gel formation. Finally, rheological behavior of the obtained gels was also investigated.

Spontaneous Generation of Amphiphilic Block Copolymer Micelles with Multiple Morphologies through Interfacial Instabilities

We introduce a method for the formation of block copolymer micelles through interfacial instabilities of emulsion droplets. Amphiphilic polystyrene-block-poly(ethylene oxide) (PS-PEO) copolymers are first dissolved in chloroform; this solution is then emulsified in water and chloroform is extracted by evaporation. As the droplets shrink, the organic solvent/water interface becomes unstable, spontaneously generating a new interface and leading to dispersion of the copolymer as micellar aggregates in the aqueous phase. Depending on the composition of the copolymer, spherical or cylindrical micelles are formed, and the method is shown to be general to polymers with several different hydrophobic blocks: poly(1,4-butadiene), poly(-caprolactone), and poly(methyl methacrylate). Using this method, hydrophobic species dissolved or suspended in the organic phase along with the amphiphilic copolymer can be incorporated into the resulting micelles. For example, addition of PS homopolymer, or a PS-PEO copolymer of different composition and molecular weight, allows the diameter and morphology of wormlike micelles to be tuned, while addition of hydrophobically coated iron oxide nanoparticles enables the preparation of magnetically loaded spherical and wormlike micelles.

PH-Responsive Copolymer Assemblies for Controlled Release of Doxorubicin

pH-Responsive drug carriers have the potential to provide selective drug release at therapeutic targets including tumors and in acidic intracellular vesicles such as endosomes and lysosomes. We have developed a new approach to the design of acid-sensitive micelles by incorporating hydrophobic acetal groups on the core block of a micelle-forming block copolymer. Hydrolysis of the acetals at mildly acidic pH is designed to reveal polar groups on the core-forming block, thus changing its solubility and disrupting the micelle, triggering drug release. The anticancer drug doxorubicin (DOX) was encapsulated in these pH-sensitive micelles, and the acetal hydrolysis rates and DOX release rates were determined in the pH range of 4.0 to 7.4 and were compared to those of control systems. The micelle disruption was investigated by dynamic light scattering. The in vitro toxicities of the empty and DOX-loaded micelles were determined, and the intracellular fate of the encapsulated DOX was compared to free DOX using fluorescence confocal microscopy.

Toroidal Triblock Copolymer Assemblies

A stable phase of toroidal, or ringlike, supramolecular assemblies was formed by combining dilute solution characteristics critical for both bundling of like-charged biopolymers and block copolymer micelle formation. The key to toroid versus classic cylinder micelle formation is the interaction of the negatively charged hydrophilic block of an amphiphilic triblock copolymer with a positively charged divalent organic counterion. This produces a self-attraction of cylindrical micelles that leads to toroid formation, a mechanism akin to the toroidal bundling of semiflexible charged biopolymers such as DNA. The toroids can be kinetically trapped or chemically cross-linked. Insight into the mechanism of toroid formation can be gained by observation of intermediate structures kinetically trapped during film casting.

Novel micelle-forming block copolymer composed of poly ($epsiv;-caprolactone) and poly(vinyl pyrrolidone)

The well-defined poly (ε-caprolactone) (PCL)/poly(vinyl pyrrolidone) (PVP) diblock copolymers were synthesized through combining radical polymerization of VP and the controlled coordination–insertion ring-opening polymerization of CL using an aluminum alkoxide macroinitiator formed from the equimolar reaction of triethylaluminum with hydroxy-terminated PVP (PVP-OH). The molecular characterization of PCL/PVP diblock copolymers was confirmed through 1H NMR spectroscopy and GPC analysis. Polymeric micelles composed of PCL as a hydrophobic core and PVP as a hydrophilic shell were prepared by a diafiltration method. The micellar properties such as sizes, shapes, and critical micelle concentrations (CMC) were investigated with a dynamic light scattering (DLS) spectrometer, transmission electron microscope (TEM) and spectrofluorimeter. The sizes of micelles ranged from 30 to 80 nm in average size. The novel micelles formed from the well-defined PCL/PVP diblock copolymers seem to be feasible as novel promising carriers in biomedical and pharmaceutical applications.