pH-Sensitive Polymeric Vesicles from Coassembly of Amphiphilic Cholate Grafted Poly(l-lysine) and Acid-Cleavable Polymer-Drug Conjugate

Herein we report a coassembly method toward the preparation of pH-sensitive polymeric vesicular aggregates, using comb-shaped amphiphilic polymers, i.e., cholate grafted poly(l-lysine) (PLL-CA), with an amphiphilic poly(ethylene glycol)-doxorubicin conjugate (PEG-DOX). Because the drug conjugate includes a low-pH labile bond, i.e., benzoic imine, the permeability of the coassembled polymeric vesicles can be tuned by changing either the PLL-CA/PEG-DOX weight ratio or the environmental pH from 7.4 to 6.5. Furthermore, at lower pH values such as 5.0, the vesicles destabilize. The pH sensitivity leads to enhanced uptake of the vesicles by cancer cells (MCF-7) under a condition close to the extracellular environment of solid tumor (pH = 6.5) and subsequent efficient endosome escape after the endocytosis.     

Preparation of electrospun luminescent polyimide/europium nanofibers by simultaneous in situ sol-gel and imidization processes

Comicellization of a star block copolymer poly(ε-caprolactone)-block-poly(diethylamino)ethyl methacrylate (S(PCL-b-PDEAEMA)) and a linear block copolymer methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) (mPEG-b-PCL) was developed to enhance the stability and lower the cytotoxicity of the micelles. The two copolymers self-assembled into the mixed micelles with a common PCL core surrounded by a mixed PDEAEMA/mPEG shell in aqueous solution. This core-shell structure was transformed to the core-shell-corona structure at high pH due to the collapse of the PDEAEMA segment. The properties of the polymeric micelles were greatly dependent on the weight ratio of the two copolymers and the external pH. As increasing the mPEG-b-PCL content, the size and the zeta potential of the mixed micelles were lowered while the pH-dependent stability and the biocompatibility were improved. Moreover, an increase in pH accelerated the release of indomethacin (IND) from the mixed micelles in vitro. These results augured that the mixed micelles could be applied as a stable pH-sensitive release system.     

Synthesis and characterization of amphiphilic triblock polymers by copper mediated living radical polymerization

2-Dimethylaminoethyl methacrylate (DMAEMA) and 2-diethylaminoethyl methacrylate (DEAEMA) block copolymers have been synthesized by using poly(ethylene glycol), poly(tetrahydrofuran) (PTHF) and poly(ethylene butylenes) macroinitiators with copper mediated living radical polymerization. The use of difunctional macroinitiator gave ABA block copolymers with narrow polydispersities (PDI) and controlled number average molecular weights (M_n’s). By using DMAEMA, polymerizations proceed with excellent first order kinetics indicative of well-controlled living polymerization. Online ¹H NMR monitoring has been used to investigate the polymerization of DEAEMA. The first order kinetic plots for the polymerization of DEAMA showed two different rate regimes ascribed to an induction period which is not observed for DMAEMA. ABA triblock copolymers with DMAEMA as the A blocks and PTHF or PBD as B blocks leads to amphiphilic block copolymers with M_n’s between 22 and 24 K (PDI 1.24-1.32) which form aggregates/micelles in solution. The critical aggregation concentrations, as determined by pyrene fluorimetry, are 0.07 and 0.03 g dm⁻¹ for PTHF- and PBD-containing triblocks respectively.     

PLMA‐b‐POEGMA amphiphilic block copolymers: Synthesis and self‐assembly in aqueous media

The synthesis and self‐assembly properties in aqueous solutions of novel amphiphilic block copolymers composed of one hydrophobic poly (lauryl methacrylate), (PLMA) block and one hydrophilic poly (oligo ethylene glycol methacrylate) (POEGMA) block are reported. The block copolymers were prepared by RAFT polymerization and were molecularly characterized by size exclusion chromatography, NMR and FT‐IR spectroscopy, and DSC. The PLMA‐b‐POEGMA amphiphilic block copolymers self‐assemble in nanosized complex nanostructures resembling compound micelles when inserted in aqueous media, as supported by light scattering and TEM measurements. The encapsulation and release of the model, hydrophobic, nonsteroidal anti‐inflammatory drug indomethacin in the polymeric micelles is also investigated. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 155–163     

pH敏感型mPEG-Hz-PLA聚合物纳米载药胶束的制备

以合成的含有腙键的聚乙二醇大分子(mPEG-Hz-OH)为引发剂,以丙交酯为单体引发开环聚合反应,并通过调整投料比,制备出3种不同分子量的含腙键的生物可降解嵌段聚合物(mPEG-Hz-PLA).将腙键引入到聚合物的骨架中,以此构建聚合物胶束并作为pH敏感型纳米药物载体.制备的pH敏感型胶束的CMC值等于或低于5.46×10-4 mg/m L,DLS和TEM显示粒径均小于100 nm,且粒径分布均匀.非pH敏感型胶束在不同pH下的粒径变化不明显,而pH敏感型胶束在酸性环境下(pH=4.0和pH=5.0)胶束粒径出现了明显变化.以阿霉素为模型药物制备了pH敏感型载药胶束,其粒径比空白胶束大(100~200 nm),且粒径分布均匀.药物释放实验表明pH敏感型载药胶束随着释放介质pH降低累积释药量增高.MTT实验表明空白胶束对HeLa细胞和RAW264.7细胞几乎没有抑制作用,而载阿霉素的胶束对2种细胞的抑制作用都随着剂量的增大和时间的延长而增强.     

P(MMA-co-MAh)-g-mPEG的合成及环境敏感性

采用偶合接枝法在甲基丙烯酸甲酯(MMA)和马来酸酐(MAh)无规共聚物上接枝不同含量的聚乙二醇单甲醚(mPEG), 合成具有pH敏感和温度敏感的两亲接枝共聚物P(MMA-co-MAh)-g-mPEG, 并对其进行了红外光谱和核磁共振波谱表征. 通过紫外-可见分光光度计测量了接枝共聚物水溶液的透光率, 结果表明, 接枝聚合物的水溶液呈现低临界溶解温度(LCST), 其LCST值对环境pH值和无机盐等因素敏感, 并可通过控制亲水侧链含量来调节.     

Synthesis,self-assembly,and pH-responsive drug release of PHMEMA-PEG-PHMEMA ABA triblock copolymers

Abstract

A series of tertiary amine containing PHMEMA-PEG-PHMEMA ABA triblock copolymers were synthesized by atom transfer radical polymerization (ATRP) using bromine-capped poly(ethylene glycol) (Br-PEG-Br) and 2-(hexamethyleneimino)ethyl methacrylate (HMEMA) as macro-initiator and monomers, respectively. The chemical structures and molecular weights of triblock copolymers were characterized by ¹H NMR and gel permeation chromatography (GPC). The self-assembly behaviors of copolymers in different pH conditions were studied by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Triblock copolymers self-assembled into micelles in water (pH 7.4) and the micelles disassembled at acidic pH (pH 5.0). Anticancer drug doxorubicin (DOX) was used as a drug model and physically encapsulated into polymeric micelles. The drug release of DOX-loaded polymeric micelles was pH-responsive; the drug-loaded micelles that had higher contents of tertiary amine in polymer pendant groups showed faster release speed. In addition, the drug-loaded micelles showed excellent inhibition efficacy against HeLa cells in vitro.     

Brush-type amphiphilic diblock copolymers from "living"/controlled radical polymerizations and their aggregation behavior

Two brush-type amphiphilic diblock copolymers, poly(poly(ethylene glycol)methyl ether methacrylate-block-polystyrene) (P(PEGMA)-b-PS) and poly(glycidyl methacrylate)-block-poly(poly(ethylene glycol)methyl ether methacrylate) (P(GMA)-b-P(PEGMA)) were synthesized, respectively, via consecutive atom-transfer radical polymerizations (ATRPs) and reversible addition-fragmentation chain-transfer (RAFT) polymerizations. The diblock copolymers were characterized by gel permeation chromatography (GPC), (1)H nuclear magnetic resonance (NMR) spectroscopy, and FT-IR spectroscopy. The aggregation behavior of the two amphiphilic diblock copolymers in water was also studied. Scanning electron and transmission electron microscopic images revealed that spherical micelles (40-80 nm in diameter) from self-assembly of the P(PEGMA)-b-PS copolymers and wormlike micelles (60-120 nm in length and 20-30 nm in diameter) from self-assembly of the P(GMA)-b-P(PEGMA) copolymers were prevalent. The spherical P(PEGMA)-b-PS micelles could self-assemble gradually into giant aggregates of several micrometers in diameter.     

pH/enzyme/light triple-responsive vesicles from lysine-based amphiphilic diblock copolymers

We report the synthesis of pH- and enzyme-responsive amphiphilic diblock copolymers through reversible addition-fragmentation chain transfer polymerization of a lysine-derived methacrylate monomer comprising p-nitrobenzyl carbamate (pNBC) functionality using a poly(ethylene glycol)-modified macro-chain transfer agent. Depending on the hydrophobic block length, the diblock copolymers self-assemble to form spherical micelles, wormlike micelles, and bilayered vesicles in the aqueous solution. The responsive behaviors of the polymeric vesicles to pH, enzyme, and light are investigated in detail. As the pH lowers to pH 5.0, the polymeric vesicles undergo a morphological transition from vesicles to spherical micelles. In the presence of nitroreductase and a cofactor NADH, the decomposition of pNBC releases the ε-NH₂ of the lysine moiety and hence induces the generation of the vesicles with crosslinked membranes at pH 7.4. Moreover, owing to the degradation of pNBC moiety under UV irradiation, the polymeric vesicles also demonstrate a photo-responsive feature. As the irradiation time prolongs, it is observed a light-triggered morphological transition from vesicles to wormlike micelles with network-like structures.     

Synthesis of self-assemble pH-responsive cyclodextrin block copolymer for sustained anticancer drug delivery

Well-defined p H-responsive poly(ε-caprolactone)-graft-β-cyclodextrin-graft-poly(2-(dimethylamino)ethylmethacrylate)-co-poly(ethylene glycol) methacrylate amphiphilic copolymers(PCL-g-β-CD-g-P(DMAEMA-co-PEGMA)) were synthesized using a combination of atom transfer radical polymerization(ATRP),ring opening polymerization(ROP) and "click" chemistry.Successful synthesis of polymers was confirmed by Fourier transform infrared spectroscopy(FTIR),proton nuclear magnetic resonance(1H-NMR),and gel permeation chromatography(GPC).Then,the polymers could selfassemble into micelles in aqueous solution,which was demonstrated by dynamic light scattering(DLS) and transmission electron microscopy(TEM).The p H-responsive self-assembly behavior of these copolymers in water was investigated at different p H values of 7.4 and 5.0 for controlled doxorubicin(DOX) release,and these results revealed that the release rate of DOX could be effectively controlled by altering the p H,and the release of drug loading efficiency(DLE) was up to 88%(W/W).CCK-8 assays showed that the copolymers had low toxicity and possessed good biodegradability and biocompatibility,whereas the DOX-loaded micelles remained with high cytotoxicity for He La cells.Moreover,confocal laser scanning microscopy(CLSM) images revealed that polymeric micelles could actively target the tumor site and the efficient intracellular DOX release from polymeric micelles toward the tumor cells further confirmed the anti-tumor effect.The DOX-loaded micelles could easily enter the cells and produce the desired pharmacological action and minimize the side effect of free DOX.These results successfully indicated that p H-responsive polymeric micelles could be potential hydrophobic drug delivery carriers for cancer targeting therapy with sustained release.     

阴离子型含氟两亲接枝共聚物的合成及其胶束化行为研究

以聚乙二醇甲醚甲基丙烯酸酯(MPEGMA)为大分子单体,甲基丙烯酸六氟丁酯(HFMA)、对苯乙烯磺酸钠(NaSS)为共聚单体,采用大分子单体接枝共聚法,制备了一种阴离子型含氟两亲接枝共聚物P( HFMA-co-NaSS) -g-PEG.利用FTIR、1H-NMR和19F-NMR对共聚物的分子结构进行了表征.表面张力法测...     

Self‐assembly of amphiphilic ABA random triblock copolymers in water

Self‐assembly of amphiphilic ABA random triblock copolymers in water serves as a novel approach to create unique structure micelles connected with flexible linkages. The ABA triblock copolymers consist of amphiphilic random copolymers bearing hydrophilic poly(ethylene glycol) and hydrophobic dodecyl pendants as the A segments and a hydrophilic poly(ethylene oxide) (PEO) as the middle B segment. The A block is varied in dodecyl methacrylate content of 20%–50% and degree of polymerization (DP) of 100‐200. By controlling the composition and DP of the A block, various architectures can be tailor‐made as micelles in water: PEO‐linked double core unimer micelles, PEO‐looped unimer or dimer micelles, and multichain micelles. Those PEO‐linked or looped micelles further exhibit thermoresponsive solubility in water. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 313–321     

Investigation of pH-responsive properties of polymeric micelles with a core-forming block having pendant cyclic ketal groups

In this study, three kinds of amphiphilic block copolymers, termed MPEG-block-PDMMA, MPEG-block-PCPMA, and MPEG-block-PMPMA, which were composed of one hydrophilic monomethoxy poly(ethylene glycol) (MPEG) block and one hydrophobic polyacrylate block bearing pendant six-member cyclic ketal groups, were synthesized by atom transfer radical polymerization (ATRP). These polymers can disperse in aqueous media to self-assemble into micellar aggregates with a spherical core-shell structure with mean diameter below 300 nm. The stimuli-responsiveness of polymeric micelles from MPEG-block-PDMMA was detected by fluorescence-probe technique at pH 3.5 and 37 °C. The effect of chemical architecture and composition of the polymers on the pH-responsive properties of polymeric micelles was also studied. A combination of pH and temperature to trigger release behavior of these polymeric micelles was discussed by comparing the encapsulated molecule release ability under various pH and temperature conditions and analyzing chemical structural changes of the polymer before and after the triggering.     

Fabrication of tailorable pH responsive cationic amphiphilic microgels on a microfluidic device for drug release

Cationic, amphiphilic microgels of differing compositions based on hydrophilic, pH, and thermoresponsive 2‐(dimethylamino)ethyl methacrylate (DMAEMA) and hydrophobic, nonionic n‐butyl acrylate (BuA) are synthesized using a lab‐on‐a‐chip device. Hydrophobic oil‐in‐water (o/w) droplets are generated via a microfluidic platform, with the dispersed (droplet) phase containing the DMAEMA and BuA, alongside the hydrophobic cross‐linker, ethylene glycol dimethacrylate, and a free radical initiator in an organic solvent. Finally, the hydrophobic droplets are photopolymerized via a UV light source as they traverse the microfluidic channel to produce the cationic amphiphilic microgels. This platform enables the rapid, automated, and in situ production of amphiphilic microgels, which do not match the core‐shell structure of conventionally prepared microgels but are instead based on random amphiphilic copolymers of DMAEMA and BuA between the hydrophobic cross‐links. The microgels are characterized in terms of their swelling and encapsulation abilities, which are found to be influenced by both the pH response and the hydrophobic content of the microgels. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 59–66     

End‐linked amphiphilic polymer conetworks: Synthesis by sequential atom transfer radical polymerization and swelling characterization

Conetworks based on end‐linked homopolymers and amphiphilic gradient copolymers were synthesized by the atom transfer radical polymerization (ATRP) of 2‐(dimethylamino)ethyl methacrylate (DMAEMA, hydrophilic monomer), methyl methacrylate (MMA, hydrophobic monomer), and ethylene glycol dimethacrylate (EGDMA, hydrophobic cross‐linker). Sequential, rather than step‐wise polymerizations, were performed to enhance the livingness of the polymerization, particularly for the end‐linking step, and to ultimately obtain conetworks based on gradient rather than pure block copolymers. Amphiphilic conetworks based on end‐linked MMA‐DMAEMA‐MMA gradient copolymers of different compositions were successfully synthesized as confirmed by the narrow molecular weight distributions of the linear precursors, the rigidity of the amphiphilic conetwork products and the low sol‐fraction extracted from the conetworks. Similarly successful was the ATRP synthesis of an end‐linked conetwork based on a DMAEMA‐MMA statistical copolymer and of a randomly cross‐linked conetwork that resulted from the simultaneous terpolymerization of DMAEMA, MMA and EGDMA. An amphiphilic conetwork based on an end‐linked DMAEMA‐MMA‐DMAEMA gradient copolymer presented a less rigid, mucous‐like, texture. The degrees of swelling (DS) in tetrahydrofuran of all the conetworks were higher than those measured in pure water, whereas the aqueous DS values increased by lowering the pH and increasing the DMAEMA content of the conetworks. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 1878–1886, 2010     

pH-induced micelle formation of poly(histidine-co-phenylalanine)-block-poly(ethylene glycol) in aqueous media

Poly[(L-histidine)-co-(L-phenylalanine)]-block-poly(ethylene glycol) (HF-b-PEG) diblock copolymers were synthesized to be used for preparation of pH-sensitive polymeric micelles. First, HF block was synthesized by ring opening copolymerization of L-histidine and L-phenylalanine N-carboxyanhydride, and then the resulting copolymer was coupled with PEG. The pKa value of diblock copolymer can be controlled by adjusting the histidine/phenylalanine ratio in HF block. It is observed that the block copolymers form micelles in aqueous media and that the micelles are spherical in shape with a unimodal distribution. The micelle is formed at pH higher than pKa of block copolymer while it is not formed at lower pH. This is because the protonation of histidine residue in the HF block converts the hydrophobic core into hydrophilic one at lower pH. Acid-Base titration profile of HF41(5600)-b-PEG, HF56(5500)-b-PEG, H(5100)-b-PEG and 0.1 N NaCl.     

Syntheses and characterization of statistical and block fluorinated copolymers with linear and star-like architectures via ATRP

The synthesis of a fluorinated macroinitiator for copper-catalyzed atom transfer radical polymerization (ATRP) is reported, as well as its use for the controlled living polymerization of poly(propylene glycol) methacrylate (PPGM) in MEK at 80 °C. The ATRP system used was efficient for polymerization of the functionalized monomer and the molecular weight of the polymer estimated by NMR spectroscopy was in close agreement with the theoretical molecular weight, as expected for controlled processes. The statistical copolymerization of PPGM or methyl ether poly(ethylene glycol) methacrylate (MPEGMA) with a perfluoroalkyl ethyl methacrylate by copper-mediated ATRP was also investigated and led to copolymers with essentially random incorporation of monomers. The syntheses and characterization of star-like homopolymers of MPEGMA or the fluorinated monomer via ATRP are also reported, as well as an amphiphilic star-like block copolymer containing ethyleneglycol units as the core and fluorinated moieties in the shell. The micellar behavior of this copolymer was investigated as a function of the external environment.     

Multicompartment micelles from hyperbranched star-block copolymers containing polycations and fluoropolymer segment

In this Article, we have investigated the self-assembly of a series of amphiphilic hyperbranched star-block copolymers to form multicompartment micelles in acidic aqueous solution (pH 3.0) or in a dimethylformamide/water (pH 3.0) mixture. These hyperbranched star-block copolymers were prepared via oxyanion-initiated polymerization process, using hydroxyl-terminated hyperbranched poly[3-ethyl-3-(hydroxymethyl)oxetane] (HP) as a macroinitiator precursor with multi-reactive sites. It was turned into oxyanion end-capped macroinitiator through the reaction with potassium hydride, and followed by a sequential addition of 2-(N,N-dimethylamino)ethyl methacrylate (DMAEMA) and 2,2,3,3,4,4,5,5-octafluoropentyl methacrylate (OFPMA). The resultant HP-star-PDMAEMA-b-POFPMA copolymers were characterized via 1H NMR, 19F NMR, and gel permeation chromatography (GPC). The analyses of transmission electron microscopy (TEM), dynamic light scattering (DLS), and microelectrophoresis confirmed that these copolymers could directly self-organize into supramolecular multicompartment micelles with different diameters, depending on the length of the PDMAEMA segment, which can be protonated in acidic aqueous medium. The measurement of the zeta potential gave further evidence of the aggregating structures for the multicompartment micelles.     

Synthesis of amphiphilic copolymer having acid‐labile bicyclo bisoxazolidine in the side chain for controlled release of fragrance aldehyde

A metharylate monomer having an octanal‐derived bicyclo bisoxazolidine (BBOX) moiety was synthesized and was radically copolymerized with a methacrylate having a hydrophilic poly(ethylene glycol) chain to obtain an amphiphilic copolymer having the BBOX moieties as hydrophobic side chains. The BBOX moieties were stable for 7 days at pH 7.0, whereas they were gradually hydrolyze at pH 5.0 to release octanal continuously for 7 days, confirming the potential applicability of the copolymer to a polymeric pro‐fragrance that can release aldehyde‐type fragrance molecules slowly for a long period. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

SYNTHESIS OF AMPHIPHILIC COMB-SHAPED COPOLYMERS USED FOR SURFACE MODIFICATION OF PVDF MEMBRANES

The synthesis of a novel amphiphilic comb-shaped copolymer consisting of a main chain of styrene-(N-(4- hydroxyphenyl) maleimide)(SHMI) copolymer and poly(ethylene glycol) methyl ether methacrylate(PEGMA) side groups was achieved by atom transfer radical polymerization(ATRP).The amphiphilic copolymers were characterized by ~1H-NMR, Fourier transform infrared(FTIR) spectroscopy and gel permeation chromatography(GPC).From thermogravimetric analysis (TGA),the decomposition temperature of SHMI-g-PEGMA is low...