双组分复合胶束的形成及其胶束结构的研究进展

概述了采用两种不同共聚物共混的方式制备多组分复合胶束的方法。共混不仅引入了新的胶束组分,还增加了胶束的可调节参数,由此得到的复合胶束具有不同于之前单一组分胶束的特殊结构。复合胶束的功能结构更富于变化,可以适应更多的功能需求。复合胶束的形成受到很多方面的影响,本文介绍了几种具有代表性的复合胶束结构的形成方式和结构特征,如复合核、复合冠、核-壳-冠胶束结构等。它们分别具有独特的稳定性、药物控释性能和刺激响应性。展望了这些具有新颖胶束结构的复合胶束可能在药物传输体系中具有的新功能。复合结构有望实现协同载药、胶束通道释药和药物的可控释放等,将在药物控制释放领域发挥巨大的作用。     

Nano-container assembled thin films with time-programmed release of hydrophobic dyes

We introduce an all nano-container assembled multilayer thin films for controlling the release of hydrophobic functional materials. Two complementary charged block copolymer micelles were used as a nano-container for layer-by-layer assembly of thin films. Block copolymer micelles were composed of positively charged hairy polystyrene-block-poly(4-vinylpyridine) and negatively charged hairy (long corona region relative to the hydrophobic core part) or crew-cut (huge hydrophobic core chains, compared with the hydrophilic corona region) polystyrene-block-poly(acrylic acid) micelles. Two different fluorescent dye-incorporated block copolymer micelles multilayer films deconstructed when rehydrated in physiological condition, phosphate buffer saline solutions, releasing block copolymer micelles as a hydrophobic material carrier, suggesting that the detachment behavior of block copolymer micelles integrated into the multilayer films differs according to layer-by-layer assembled block copolymer micelle combinations. These results indicate the suitability of thin films for applications including the controlled release of hydrophobic materials. Atomic force microscope analysis suggested the successful preparation of block copolymer micelles. Film growth and release of fluorescence dyes were monitored by UV-Vis spectra.     

Stimuli responsive associative polyampholytes based on ABCBA pentablock terpolymer architecture

A poly(methyl methacrylate)–poly(acrylic acid)–poly(2-vinyl pyridine)–poly(acrylic acid)–poly(methyl methacrylate) (PMMA–PAA–P2VP–PAA–PMMA), ABCBA pentablock terpolymer was synthesized by “living” anionic polymerization and was studied in aqueous media at different pH conditions in the presence of MeOH. By tuning the pH and/or the solvent selectivity and dielectric constant of the medium, reversible hydrogels of different nature were formed. At low pH the hydrogel is based on a three dimensional network comprising PMMA hydrophobic cores (physical crosslinks) interconnected by complex bridging (elastically active) chains constituted of positively charged P2VP and non-ionic PAA segments. At high pH the hydrogel is transformed reversibly to a negatively charged network the bridging chains of which comprise ionized PAA segments interrupted by hydrophobic P2VP blocks, swellable on MeOH addition. Furthermore, we found conditions for the formation of flower-like micelles of different topologies and nature like core–shell–corona micelles with positively charged corona (pH < 2), multicompartment micelles comprising P2VP and PMMA hydrophobic domains (pH 8.3, low MeOH content), micelles constituted of a centrosymmetric compartmentalized core and PAA negatively charged corona (pH 8.3, 30%, 40% MeOH), and core–shell micelles of PMMA cores (pH 8.3, 50% MeOH).     

Thermoresponsive core-shell-corona micelles of poly(ethyleneglycol)-b-poly(N-isopropylacrylamide)-b-polystyrene

Core-shell-corona micelles with a thermoresponsive shell self-assembled by triblock copolymer of poly(ethyleneglycol)-b-poly(N-isopropylacrylamide)-b-polystyrene (PEG₄₅-b-PNIPAM₁₆₈-b-PS₄₆) are studied by ¹H NMR, light scattering and atomic force microscopy. The thermoresponsive triblock copolymer, which has a relatively short hydrophobic PS block, can disperse in water at room temperature to form core-shell-corona micelles with the hydrophobic PS block as core, the thermoresponsive PNIPAM block as shell and the hydrophilic PEG block as corona. At temperature above lower critical solution temperature (LCST) of the PNIPAM block, the PNIPAM chains gradually collapse on the PS core to shrink the size and change the structure of the resultant core-shell-corona micelles with temperature increasing. It is found that there possibly exists an interface between the PNIPAM shell and PEG corona of the core-shell-corona micelles at temperature above LCST of the PNIPAM block.     

In vitro degradability and stability of hydrophobically modified pH‐sensitive micelles using MPEG‐grafted poly(β‐amino ester) for efficient encapsulation of paclitaxel

Methoxypoly(ethylene glycol)‐grafted poly(β‐amino ester) was synthesized for the fabrication of pH‐sensitive micelles, and these micelles were modified with deoxycholic acid to facilitate the hydrophobic interaction between the micellar core and paclitaxel. The micelle properties were studied by dynamic light scattering and fluorescence spectrometry. An in vitro degradation study showed that the synthesized polymers degraded hydrolytically within 24 h under physiological conditions. The stability of paclitaxel‐loaded pH‐sensitive micelles was evaluated in vitro. The introduced deoxycholic acid more stabilized the micelles at pH 7.4 compared to the micelles without modification. But the pH‐sensitive region of the micelles was lowered from pH 6.8 to pH 5.8. These results indicate that pH‐sensitive micelles with improved stability have great potential as hydrophobic drug carriers for tumor targeting. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Polymer mediated formation of corona-embedded gold nanoparticles in block polyelectrolyte micelles

Micelles having a hydrophobic core of poly(tert-butylstyrene) and a hydrophilic corona of poly(sodium sulfamate/carboxylate-isoprene) anionic polyelectrolyte, were formed through self-assembly of the diblock copolymer poly[tert-butylstyrene-b-sodium (sulfamate/carboxylate-isoprene)] (BS-SCI) in water. HAuCl₄, as the metal precursor, was preferentially dissolved and coordinated into the corona of the micelles. Au nanoparticles were formed within the corona block by subsequent reduction of Au³⁺ to Au⁰ without introducing any reducing agent, since the amine group of the corona block acts as both the reducing and stabilizing agent. The kinetics of the Au reduction reaction was followed by UV-vis spectroscopy by direct observation of the exact position and the intensity of the surface plasmon resonance band of created Au nanoparticles. The colloidal stability and structural response of the BS-SCI/Au nanohybrid was studied as a function of pH, ionic strength and temperature by dynamic light scattering (DLS). Additional information on the structure of the hybrid systems and the metal nanoparticle characteristics were gathered by UV-vis spectroscopy, atomic force microscopy (AFM) and transmission electron microscopy (TEM). Taking into account the polyelectrolyte nature and biocompatibility of the SCI corona of the BS-SCI/Au nanoassembly, the interactions with a model globular protein (lysozyme) were investigated, aiming at exploring the potential application of such hybrid colloids in protein assay protocols.     

Synthesis and characterization of brush copolymers based on methoxy poly(ethylene glycol) and poly(ε‐caprolactone)

Brush copolymers composed of methoxy poly(ethylene glycol) (MPEG) and poly(ε‐caprolactone) (PCL) have been synthesized by the ring‐opening polymerization of ε‐caprolactone initiated by hydroxyl function of thermally esterified MPEG‐citrate in presence of stannous octoate. Citric acid (CA) acts as spacer between brush‐like MPEG and the long chain of PCL. Existence of hydrophobic domains as cores of the micelles were characterized by ¹H NMR spectroscopy and further confirmed with fluorescence technique using pyrene as a probe. Critical micelle concentration (CMC) of the synthesized copolymer decreased from 0.019 to 0.0031 mg/mL on increasing the fraction of PCL. Along with the physicochemical study, the brush copolymers were explored for the preparation of nanoparticles by nanoprecipitation technique. The morphology and geometry of micelles were investigated by using DLS, AFM, and TEM. Hydrodyanamic dimensions of micelles were around 118 and 178 nm with the core size of 8–10 nm, which further aggregated to form secondary micelle of 60–90 nm. Such assembled polymeric micelles with its flexible dendritic MPEG corona could hold a promise for the immobilization (encapsulation) of hydrophobic drugs and subsequently promote sustained release so that it can be a good vehicle for anti‐cancer drug deliverance. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Double-responsive core-shell-corona micelles from self-assembly of diblock copolymer of poly(t-butyl acrylate-co-acrylic acid)-b-poly(N-isopropylacrylamide)

Self-assembly of poly(t-butyl acrylate-co-acrylic acid)-b-poly(N-isopropylacrylamide) [P(tBA-co-AA)-b-PNIPAM], which was obtained from part hydrolysis of PtBA-b-PNIPAM synthesized by sequential atom transfer radical polymerization (ATRP) was studied. Thermo- and pH-responsive core-shell-corona (CSC) micelles with different structures were formed from (PtBA-co-PAA)-b-PNIPAM in aqueous solution. At pH 5.8 and 25 °C, the block copolymer self-assembled into spherical core-shell micelles with hydrophobic PtBA segments as the core, hydrophilic PAA/PNIPAM segments as the mixed shell. Increasing temperatures, core-shell micelles converted into CSC micelles with PtBA as the core, collapsed PNIPAM as the shell and soluble PAA as the corona. Moreover, decreasing pH at 25 °C, PAA chains collapsed onto the core resulting in CSC micelles with PtBA as the core, PAA as the shell and PNIPAM as the corona.     

Sheddable micelles based on disulfide-linked hybrid PEG-polypeptide copolymer for intracellular drug delivery

A novel reduction-sensitive sheddable micelle based on disulfide-linked hybrid PEG-polypeptide mPEG-SS-Pleu was demonstrated for intracellular drug delivery. These micelles are composed of an mPEG shell and polypeptide core, characterized by FT-IR, ¹H NMR, fluorescence techniques, TEM, and DLS. Interestingly, they would undergo a fast sheddable process when encounter the reduction sensitive condition, indicated by the aggregation phenomena in the presence of DTT, a reduction agent, which could cleave the disulfide bond between the micellar core and shell and consequently leading to the aggregation of hydrophobic core. Cytotoxicity study revealed that copolymers in this system have good biocompatibility and their self-assembled micelles showed a high drug loading efficiency for DOX, a hydrophobic drug model, and released DOX quantitatively in response to the intracellular level of reducing potential. Cellular uptake experiments demonstrated that the fluorescently labeled micelles could be successfully internalized into human liver carcinoma HepG2 cells, evidenced by confocal laser scanning microscopy. Above results indicate that the copolymers may have great potential in drug delivery to achieve improved cancer therapy.     

pH-Sensitive Micelles Based on Double-Hydrophilic Poly(methylacrylic acid)-Poly(ethylene glycol)-Poly(methylacrylic acid) Triblock Copolymer

pH-sensitive micelles with hydrophilic core and hydrophilic corona were fabricated by self-assembling of triblock copolymer of poly(methylacrylic acid)-poly(ethylene glycol)-poly(methylacrylic acid) at lower solution pH. Transmission electron microscopy and laser light scattering studies showed micelles were in nano-scale with narrow size distribution. Solution pH value and the micelles concentration strongly influenced the hydrodynamic radius of the spherical micelles (48–310 nm). A possible mechanism for the formation of micelles was proposed. The obtained polymeric micelle should be useful for biomedical materials such as carrier of hydrophilic drug.     

Visualization of degradable worm micelle breakdown in relation to drug release

Spherical micelles and spherical vesicles have been extensively studied as carriers of hydrophobic drugs, but highly elongated polymer-based worm micelles might also serve the same purpose if release mechanisms are integrated. Degradable amphiphilic copolymers of poly(ethylene oxide)-block-polycaprolactone, PEO-b-PCL, are labeled here with hydrophobic dye and shown by fluorescence microscopy to assemble into highly flexible worm micelles. Degradation-induced morphological transitions from worms to spheres are quantitated in terms of decreasing contour lengths. The hydrophobic core of PCL can carry hydrophobic drugs in addition to dyes, as illustrated here by loading efficiency, storage, and degradation-coupled release of a model hydrophobic anti-cancer drug, taxol. From this, it can be estimated that single worm micelle about 10 μm long is additionally estimated to carry and release enough taxol to kill a single cell. The transition-coupled release is explained in part by the fact that worms have a larger volume-to-area ratio compared to spheres of the same radius.     

Reversibly light-responsive micelles constructed via a simple modification of hyperbranched polymers with chromophores

Reversibly light-responsive and biocompatible micelles with an appropriate size were constructed from an amphiphilic spiropyran-containing hyperbranched polyphosphate (denoted as HPHEEP-SP). The polymer was conveniently synthesized based on the modification of a biodegradable hyperbranched polyphosphate with carboxyl-containing spiropyran molecules. HPHEEP-SP can self-assemble to biocompatible micelles with an average diameter of 186.3 nm and a critical micelle concentration of 0.052 mg mL^?1. After 5 min of UV irradiation, the diameter of the micelles decreased gradually to about 100 nm, which is ascribed to the transformation of hydrophobic spiropyran to hydrophilic merocyanine. Subsequent exposure the micelles to visible light, the diameter of the micelles was restored. Model drug coumarin 102 was then encapsulated into the micelles successfully. Light-controlled release and re-encapsulation behaviours were lastly demonstrated by fluorescence spectroscopy. This study provides a convenient way to construct smart nanocarriers for controlled release and re-encapsulation of hydrophobic drugs.     

Synthesis and physicochemical characterization of amphiphilic block copolymers bearing acid-sensitive orthoester linkage as the drug carrier

Amphiphilic block copolymers bearing an acid-sensitive orthoester linkage, composed of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic poly(γ-benzyl L-glutamate) (PBLG), were prepared as the carrier capable of selectively releasing the hydrophobic drug at the mildly acidic condition. Diblock copolymers with various lengths of PBLG were synthesized via ring opening polymerization of benzyl glutamate NCA in the presence of the acid-labile PEG as a macroinitiator. Owing to their amphiphilicities, the copolymers formed spherical micelles in aqueous conditions, and their particle sizes (22-106 nm in diameter) were dependent on the block length of PBLG. These nanoparticles were stable in the physiological buffer (pH 7.4), whereas they were readily decomposed under the acidic condition. In particular, the block copolymer with a smaller hydrophobic portion was rapidly disassembled under the acidic condition. Doxorubicin (DOX), chosen as the model anti-cancer drug, was effectively encapsulated into the hydrophobic core of the micelles using the solvent casting method. The loading efficiency depended on the hydrophobic block length of the copolymer; i.e., the longer hydrophobic block allowed for loading of larger amounts of the drug. In vitro release studies demonstrated that DOX was slowly released from the pH-sensitive micelles in the physiological buffer (pH 7.4), whereas the release rate of DOX significantly increased under the acidic condition (pH 5.0). From the in vitro cytotoxicity test, it was found that DOX-loaded pH-sensitive micelles showed higher toxicity to SCC7 cancer cells than DOX-loaded micelles without the orthoester linker. These results suggest that the amphiphilic block copolymer bearing the orthoester linkage is useful for pH-triggered delivery of the hydrophobic drug.     

Functionalized micelles from new ABC polyglycidol-poly(ethylene oxide)-poly(d,l-lactide) terpolymers

New ABC type terpolymers of poly(ethoxyethyl glycidyl ether)/poly(ethylene oxide)/poly(d,l-lactide) were obtained by multi-mode anionic polymerization. After successive deprotection of the ethoxyethyl groups from the first block, highly hydroxyl functionalized copolymers of polyglycidol/poly(ethylene oxide)/poly(d,l-lactide) were obtained. These copolymers form elongated ellipsoidal micelles by direct dissolution in water. The micelles consist of a poly(d,l-lactide) core and stabilizing shell of polyglycidol/poly(ethylene oxide). The hydroxyl groups of polyglycidol blocks situated at the micelle surface provide high functionality, which could be engaged in further chemical modification resulting in a potential drug targeting agents. The micellization process of the copolymers in aqueous media was studied by hydrophobic dye solubilization, static and dynamic light scattering, and transmission electron microscopy.     

New macromolecular carriers for drugs. I. Preparation and characterization of poly(oxyethylene-b-isoprene-b-oxyethylene) block copolymer aggregates

This work describes the formation of discrete micelles (? 0.1 μm) from ABA poly(oxyethylene-b-isoprene-b-oxyethylene) block copolymers in water. An efficient labeling of the micelles by polymerization of [¹⁴C]-styrene within the hydrophobic core is also described. These micellar nanoparticles are being considered as promising materials for controlled release and/or site-specific drug delivery systems. In experimental animals the micelles remained in circulation with a half-life in excess of 50 h. Our results demonstrate the advantages of using block copolymers for the preparation of “perfect” biocompatible surfaces such as are required for well-tolerated, long-circulating particulate drug carriers.     

Self‐assembly and drug delivery behaviors of thermo‐sensitive poly(t‐butyl acrylate)‐b‐poly(N‐isopropylacrylamide) micelles

Self‐assembly of thermo‐sensitive poly (t‐butyl acrylate)‐b‐poly(N‐isopropylacrylamide) (PtBA‐ b‐PNIPAM) micelles in aqueous medium and its applications in controlled release of hydrophobic drugs were described. PtBA‐b‐PNIPAM was synthesized by atom transfer radical polymerization and aggregated into thermo‐sensitive core‐shell micelles with regular spheres in water, which was confirmed by ¹H‐NMR, fluorescence spectroscopy, transmission electron microscopic (TEM), and UV–vis spectroscopic techniques. The critical micelle concentration of micelles decreased with the increase of the hydrophobic components. The anti‐inflammation drug naproxen (NAP) was loaded as the model drug into polymeric micelles, which showed a dramatic thermo‐sensitive fast/slow switching behavior around the lower critical solution temperature (LCST). When the temperature was enhanced above LCST, release of NAP from core‐shell micelles was accelerated ascribed to the temperature‐induced deformation of micelles. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

pH-responsive nanosized-micelles based on poly(monomethylitaconate)-co-poly(dimethylaminoethyl methacrylate) and cholesterol side chains effect on pH change-induced release of piroxicam

Novel double hydrophilic poly(monomethylitaconate)-co-poly(N,N-dimethylaminoethyl methacrylate) (PMMI-co-PDMAEMA) synthesized via free radical polymerization of corresponding monomers with defined molar ratios in the presence of K₂S₂O₈ as an initiator in an aqueous solution. The resulting copolymer was subsequently converted to a cholesterol conjugate (PMMICholC₆-co-PDMAEMA) by esterification reaction with 6-cholesteryl-1-hexanol (CholC₆). Two copolymers self-assembled into micelles by simply adjusting the solution pH at room temperature. The non-conjugated polymer had a sharp transition at pH 5. TEM and DLS studies showed that both micelles were spherical in shape with a mean diameter around 85 and 26 nm, respectively. Piroxicam (PX) as a hydrophobic model drug was encapsulated into micelles. The results indicated that PMMICholC₆-co-PDMAEMA micelles were able to load more amounts of drug than PMMI-co-PDMAEMA micelles which could be attributed to the strong hydrophobic interactions of cholesterol molecules in the core. In vitro release studies demonstrated that PX release from PMMI-co-PDMAEMA micelles was significantly fast at physiological pH compared with mildly acidic pH 4.5. However, at pH 4.5, PMMICholC₆-co-PDMAEMA micelles, with core-shell-corona structure, released loaded drug molecules faster than pH 7.4 which contained a relatively steady drug release profile. In summary, cholesterol-modified micelles could be introduced as stable and effective pH responsive nanocarriers to make a promising system for enhancing the efficacy of hydrophobic drugs in cancer cells for improved cancer therapy.     

AIE-Featured Redox-Sensitive Micelles for Bioimaging and Efficient Anticancer Drug Delivery

In the present study, an amphiphilic polymer was prepared by conjugating methoxy poly(ethylene glycol) (mPEG) with tetraphenylethene (TPE) via disulfide bonds (Bi(mPEG-S-S)-TPE). The polymer could self-assemble into micelles and solubilize hydrophobic anticancer drugs such as paclitaxel (PTX) in the core. Combining the effect of TPE, mPEG, and disulfide bonds, the Bi(mPEG-S-S)-TPE micelles exhibited excellent AIE feature, reduced protein adsorption, and redox-sensitive drug release behavior. An in vitro intracellular uptake study demonstrated the great imaging ability and efficient internalization of Bi(mPEG-S-S)-TPE micelles. The excellent anticancer effect and low systemic toxicity were further evidenced by the in vivo anticancer experiment. The Bi(mPEG-S-S)-TPE micelles were promising drug carriers for chemotherapy and bioimaging.     

Temperature-responsive multilayered micelles formed from the complexation of PNIPAM-b-P4VP block-copolymer and PS-b-PAA core–shell micelles

Multilayered micelles with a polystyrene (PS) core, a swollen poly(acrylic acid) (PAA)/poly(4-vinyl pyridine) (P4VP) complex shell and a poly(4-vinyl pyridine)-block-poly(isopropyl acryl amide) (P4VP-b-PNIPAM) block-copolymer corona was synthesized by complexation between PNIPAM₅₃-b-P4VP₁₀₉ block-copolymers and the PS₁₂₀-b-PAA₄₇ diblock-copolymer core–shell micelles in ethanol due to the hydrogen bonding between the AA units and 4VP units. The surface of the micelle has been modified and a temperature sensitive block PNIPAM was introduced into the corona of the micelles. After being dialyzed against acidic water, PNIPAM corona would collapse onto the PAA/P4VP shell and the excessive P4VP shell would extend into the acidic solution to form the corona reversed micelles when the micelle aqueous solution was heated to 45 °C. The whole process was performed using dynamic light scattering (DLS), static light scattering (SLS), atom force microscope (AFM) and nuclear magnetic resonance (NMR).     

Synthesis of sharply thermo and PH responsive PMA-b-PNIPAM-b-PEG-b-PNIPAM-b-PMA by RAFT radical polymerization and its schizophrenic micellization in aqueous solutions

Sharply thermo- and pH-responsive pentablock terpolymer with a core-shell-corona structure was prepared by RAFT polymerization of N-isopropylacrylamide and methacrylic acid monomers using PEG-based benzoate-type of RAFT agent. The PEG-based RAFT agent could be easily synthesized by dihydroxyl-capped PEG with 4-cyano-4-(thiobenzoyl) sulfanylpentanoic acids, using esterification reaction. This pentablock terpolymer was characterized by ¹H NMR, FT-IR, and GPC. The PDI was obtained by GPC, indicating that the molecular weight distribution was narrow and the polymerization was well controlled. The thermo- and pH-responsive micellization of the pentablock terpolymer in aqueous solution was investigated using ?uorescence spectroscopy technique, UV–vis transmittance, and TEM. The LCST of pentablock terpolymer increased (over 50 °C) compared to the NIPAM homopolymer (~32 °C), due to the incorporation of the hydrophilic PEG and PMA blocks in pentablock terpolymer (PNIPAM block as the core, PEG the block and the hydrophilic PMA block as the shell and the corona). Also, pH-dependent phase transition behavior shows at a pH value of about ~5.8, according to pKa of MAA. Thus, in acidic solution at room temperature, the pentablock terpolymer self-assembled to form core–shell–corona micelles, with the hydrophobic PMA block as the core, the PNIPAM block and the hydrophilic PEG block as the shell and the corona, respectively.