In situ fabrication of paclitaxel‐loaded core‐crosslinked micelles via thiol‐ene “click” chemistry for reduction‐responsive drug release

In this study, a facile method to fabricate reduction‐responsive core‐crosslinked micelles via in situ thiol‐ene “click” reaction was reported. A series of biodegradable poly(ether‐ester)s with multiple pendent mercapto groups were first synthesized by melt polycondensation of diol poly(ethylene glycol), 1,4‐butanediol, and mercaptosuccinic acid using scandium trifluoromethanesulfonate [Sc(OTf)₃] as the catalyst. Then paclitaxel (PTX)‐loaded core‐crosslinked (CCL) micelles were successfully prepared by in situ crosslinking hydrophobic polyester blocks in aqueous media via thiol‐ene “click” chemistry using 2,2′‐dithiodiethanol diacrylate as the crosslinker. These PTX‐loaded CCL micelles with disulfide bonds exhibited reduction‐responsive behaviors in the presence of dithiothreitol (DTT). The drug release profile of the PTX‐loaded CCL micelles revealed that only a small amount of loaded PTX was released slowly in phosphate buffer solution (PBS) without DTT, while quick release was observed in the presence of 10.0 mM DTT. Cell count kit (CCK‐8) assays revealed that the reduction‐sensitive PTX‐loaded CCL micelles showed high antitumor activity toward HeLa cells, which was significantly higher than that of reduction‐insensitive counterparts and free PTX. This kind of biodegradable and biocompatible CCL micelles could serve as a bioreducible nanocarrier for the controlled antitumor drug release. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 99–107     

Reduction‐responsive poly (ethylene glycol)‐dexamethasone biarm conjugate and its self‐assembled nanomicelles: Preparation,physicochemical characterization,and thiol‐triggered drug release

In this study, a reduction‐responsive poly (ethylene glycol)‐dexamethasone biarm conjugate was synthesized as intracellular targeted drug delivery carriers. The hydroxyl end group of methoxy poly (ethylene glycol) (mPEG) was modified to introduce a biarm structure with bioreducible disulfide bond and amine end groups. Dexamethasone (Dex) as a nuclear targeting moiety was conjugated to the amine end groups of mPEG biarm derivatives, mPEG‐(NH₂)₂ or mPEG‐(ss‐NH₂)₂, with or without bioreducible disulfide bonds. The bioreducible and nonreducible mPEG‐Dex biarm conjugates, R‐mPEG‐Dex and N‐mPEG‐Dex, were synthesized and characterized by various analytical methods, proton nuclear magnetic resonance (¹H‐NMR), Fourier transform infraredspectroscopy (FT‐IR), dynamic light scattering (DLS), and fluorescence measurements. Amphiphilic mPEG‐Dex conjugates self‐assembled in aqueous solutions to form nanoparticles (NPs) with a size range of 130 to 150 nm, and their critical micelle concentrations (CMCs) were determined to be 12.4 and 15.3 mg/L, respectively, for bioreducible and nonreducible ones. The R‐mPEG‐Dex NPs maintained good colloidal stability in the presence of bovine serum albumin (BSA) for more than 1 week but demonstrated a significant change in colloidal stability in the presence of dithiothreitol (DTT). In DTT‐containing phosphate‐buffered saline (PBS), the bioreducible NPs showed not only reduction‐responsive destabilization with PEG shedding but also thiol‐dependent drug release profile. Our observations indicated that the R‐mPEG‐Dex NPs have a promising prospective as an efficient nanocarrier for intracellular targeted delivery of various anticancer drugs.     

Synthesis and self‐assembling of poly(N‐isopropylacrylamide‐block‐poly(L‐lactide)‐block‐poly(N‐isopropylacrylamide) triblock copolymers prepared by combination of ring‐opening polymerization and atom transfer radical polymerization

Novel thermo‐responsive poly(N‐isopropylacrylamide)‐block‐poly(l ‐lactide)‐block‐poly(N‐isopropylacylamide) (PNIPAAm‐b‐PLLA‐b‐PNIPAAm) triblock copolymers were successfully prepared by atom transfer radical polymerization of NIPAAm with Br‐PLLA‐Br macroinitiator, using a CuCl/tris(2‐dimethylaminoethyl) amine (Me₆TREN) complex as catalyst at 25 °C in a N,N‐dimethylformamide/water mixture. The molecular weight of the copolymers ranges from 18,000 to 38,000 g mol^?1, and the dispersity from 1.10 to 1.28. Micelles are formed by self‐assembly of copolymers in aqueous medium at room temperature, as evidenced by ¹H NMR, dynamic light scattering (DLS) and transmission electron microscopy (TEM). The critical micelle concentration determined by fluorescence spectroscopy ranges from 0.0077 to 0.016 mg mL^?1. ¹H NMR analysis in selective solvents confirmed the core‐shell structure of micelles. The copolymers exhibit a lower critical solution temperature (LCST) between 32.1 and 32.8 °C. The micelles are spherical in shape with a mean diameter between 31.4 and 83.3 nm, as determined by TEM and DLS. When the temperature is raised above the LCST, micelle size increases at high copolymer concentrations due to aggregation. In contrast, at low copolymer concentrations, decrease of micelle size is observed due to collapse of PNIPAAm chains. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3274–3283     

Dendron‐like poly(ε‐benzyloxycarbonyl‐L‐lysine)/linear PEO block copolymers: Synthesis,physical characterization,self‐assembly,and drug‐release behavior

Dendron‐like poly(ε‐benzyloxycarbonyl‐L ‐lysine)/linear poly(ethylene oxide) block copolymers (i.e., Dm‐PZLys‐b‐PEO, m = 0 and 3; Dm are the propargyl focal point poly(amido amine) dendrons having 2^m primary amine groups) were for the first time synthesized by combining ring‐opening polymerization (ROP) of ε‐benzyloxycarbonyl‐L ‐lysine N‐carboxyanhydride (Z‐Lys‐NCA) and click chemistry, where Dm‐PZLys homopolypeptides were click conjugated with azide‐terminated PEO. Their molecular structures and physical properties were characterized in detail by FTIR, ¹H NMR, gel permeation chromatography, differential scanning calorimetry, polarized optical microscopy, and wide angle X‐ray diffraction. Both homopolypeptides and copolymers presented a liquid crystalline phase transition for PZLys block, and the transition was irreversible. Moreover, the degree of crystallinity of PEO block within linear copolymers decreased from 96.2% to 20.4% with increasing PZLys composition, whereas that within dendritic copolymers decreased to zero. The secondary conformation of PZLys progressively changed from β‐sheet to α‐helix with increasing the chain length. These copolymers self‐assembled into spherical nanoparticles in aqueous solution, and the anticancer drug doxorubicin‐loaded nanoparticles gave a similar morphology compared with their blank counterparts. The drug‐loaded nanoparticles showed a triphasic drug‐release profile at aqueous pH 7.4 or 5.5 and 37 °C and sustained a longer drug‐release period for about 2 months. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Synthesis,self‐assembly,drug‐release behavior,and cytotoxicity of triblock and pentablock copolymers composed of poly(ε‐caprolactone), poly(L‐lactide), and poly(ethylene glycol)

Biocompatible and biodegradable ABC and ABCBA triblock and pentablock copolymers composed of poly(ε‐caprolactone) (PCL), poly(L ‐lactide) (PLA), and poly(ethylene glycol) (PEO) with controlled molecular weights and low polydispersities were synthesized by a click conjugation between alkyne‐terminated PCL‐b‐PLA and azide‐terminated PEO. Their molecular structures, physicochemical and self‐assembly properties were thoroughly characterized by means of FT‐IR, ¹H‐NMR, gel permeation chromatography, differential scanning calorimetry, wide‐angle X‐ray diffraction, dynamic light scattering, and transmission electron microscopy. These copolymers formed microphase‐separated crystalline materials in solid state, where the crystallization of PCL block was greatly restricted by both PEO and PLA blocks. These copolymers self‐assembled into starlike and flowerlike micelles with a spherical morphology, and the micelles were stable over 27 days in aqueous solution at 37 °C. The doxorubicin (DOX) drug‐loaded nanoparticles showed a bigger size with a similar spherical morphology compared to blank nanoparticles, demonstrating a biphasic drug‐release profile in buffer solution and at 37 °C. Moreover, the DOX‐loaded nanoparticles fabricated from the pentablock copolymer sustained a longer drug‐release period (25 days) at pH 7.4 than those of the triblock copolymer. The blank nanoparticles showed good cell viability, whereas the DOX‐loaded nanoparticles killed fewer cells than free DOX, suggesting a controlled drug‐release effect. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010     

Poly(ϵ‐caprolactone)‐b‐poly(ethylene glycol)‐b‐poly(ϵ‐caprolactone) triblock copolymers: Synthesis and self‐assembly in aqueous solutions

Nontoxic and biodegradable poly(?‐caprolactone)‐b‐poly(ethylene glycol)‐b‐poly(?‐caprolactone) triblock copolymers were synthesized by the solution polymerization of ?‐caprolactone in the presence of poly(ethylene glycol). The chemical structure of the resulting triblock copolymer was characterized with ¹H NMR and gel permeation chromatography. In aqueous solutions of the triblock copolymers, the micellization and sol–gel‐transition behaviors were investigated. The experimental results showed that the unimer‐to‐micelle transition did occur. In a sol–gel‐transition phase diagram obtained by the vial‐tilting method, the boundary curve shifted to the left, and the gel regions expanded with the increasing molecular weight of the poly(?‐caprolactone) block. In addition, the hydrodynamic diameters of the micelles were almost independent of the investigated temperature (25–55 °C). The atomic force microscopy results showed that spherical micelles formed at the copolymer concentration of 2.5 × 10^?4 g/mL, whereas necklace‐like and worm‐like shapes were adopted when the concentration was 0.25 g/mL, which was high enough to form a gel. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 605–613, 2007     

Hyperbranched poly (amine‐ester)‐poly (lactide‐co‐glycolide) copolymer and their nanoparticles as paclitaxel delivery system

A new hyperbranched poly (amine‐ester)‐poly (lactide‐co‐glycolide) copolymer (HPAE‐co‐PLGA) was synthesized by ring‐opening polymerization of D , L ‐lactide (DLLA) glycolid and branched poly (amine‐ester) (HPAE‐OHs) with Sn(Oct)₂ as catalyst. The chemical structures of copolymers were determined by FT‐IR, ¹H‐NMR(¹³C NMR), TGA and their molecular weights were determined by gel permeation chromatography (GPC). Paclitaxel‐loaded copolymer nanoparticles were prepared by the nanoprecipitation method. Their physicochemical characteristics, e.g. morphology and nanoparticles size distribution were then evaluated by means of fluorescence spectroscopy, environmental scanning electron microscopy (ESEM), and dynamic light scattering (DLS). Paclitaxel‐loaded nanoparticles assumed a spherical shape and have unimodal size distribution. It was found that the chemical composition of the nanoparticles was a key factor in controlling nanoparticles size, drug‐loading content, and drug release behavior. As the molar ratio of DL ‐lactide/glycolide to HPAE increased, the nanoparticles size and drug‐loading content increased, and the drug release rate decreased. The antitumor activity of the paclitaxel‐loaded HPAE‐co‐PLGA nanoparticles against human liver cancer H7402 cells was evaluated by 3‐(4, 5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide (MTT) method. The paclitaxel‐loaded HPAE‐co‐PLGA nanoparticles showed comparable anticancer efficacy with the free drug. Copyright © 2010 John Wiley & Sons, Ltd.     

Well‐defined thermoresponsive dendritic polyamide/poly(N‐vinylcaprolactam) block copolymers

The first‐ and second‐generation well‐defined thermoresponsive amphiphilic linear–dendritic diblock copolymers based on hydrophilic linear poly(N‐vinylcaprolactam) and hydrophobic dendritic aromatic polyamide have been synthesized via reversible addition fragmentation chain transfer polymerization of N‐vinylcaprolactam by employing dendritic chain‐transfer agents possessing a single dithiocarbamate moiety at the focal point. These linear–dendritic copolymers exhibit reversible temperature‐dependent phase transition behaviors in aqueous solution as characterized by turbidity measurements using UV–vis spectroscopy. Their lower critical solution temperatures depend on the generation of the dendritic aromatic polyamides and the concentrations of the copolymer solutions. These amphiphilic copolymers are able to form nanospherical micelles in the aqueous solution as revealed by fluorescent spectroscopy, dynamic light scattering, and transmission electron microscope (TEM). The core–shell structure of micelles has been proved by ¹H NMR analyses of the micelles in D2O. The micelles loaded with indomethacin as a model drug showed high‐drug loading capacity and thermoresponsive drug release behavior. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3240–3250     

Disulfide‐centered star‐shaped polypeptide‐PEO block copolymers for reduction‐triggered drug release

Disulfide‐centered star‐shaped poly(ε‐benzyloxycarbonyl‐l ‐lysine)‐b‐poly(ethylene oxide) block copolymers (i.e., A₂B₄ type Cy‐PZlys‐b‐PEO) were synthesized by the combination of ring‐opening polymerization and thiol‐yne chemistry. Their molecular structures and physical properties were characterized in detail by FTIR, ¹H NMR, gel permeation chromatography, differential scanning calorimetry, wide‐angle X‐ray diffraction, and polarized optical microscope. Despite mainly exhibiting an α‐helix conformation, the inner PZlys blocks within copolymers greatly prohibited the crystallinity of the outer PEO blocks and presented a liquid crystal phase transition behavior in solid state. These block copolymers Cy‐PZlys‐b‐PEO self‐assembled into nearly spherical micelles in aqueous solution, which had a hydrophobic disulfide‐centered PZlys core surrounded by a hydrophilic PEO corona. As monitored by means of DLS and TEM, these micelles were progressively reduced to smaller micelles in 10 mM 1,4‐dithiothreitol at 37 °C and finally became ones with a half size, demonstrating a reduction‐sensitivity. Despite a good drug‐loading property, the DOX‐loaded micelles of Cy‐PZlys‐b‐PEO exhibited a reduction‐triggered drug release profile with an improved burst‐release behavior compared with the linear counterpart. Importantly, this work provides a versatile strategy for the synthesis of the disulfide‐centered star‐shaped polypeptide block copolymers potential for intracellular glutathione‐triggered drug delivery systems. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 2000–2010     

Synthesis and self‐assembly of novel amphiphilic copolymers poly(lactic acid)‐block‐poly(ascorbyl acrylate)

In this study, a novel type of amphiphilic block copolymers poly(lactic acid)‐block‐poly(ascorbyl acrylate) (PLA‐block‐PAAA) with biodegradable poly(lactic acid) as hydrophobic block and poly(ascorbyl acrylate) (PAAA) as hydrophilic block was successfully developed by a combination of ring‐opening polymerization and atom transfer radical polymerization, followed by hydrogenation under normal pressure. The chemical structures of the desired copolymers were characterized by ¹H NMR and gel permeation chromatography. The thermal physical properties and crystallinity were investigated by thermogravimetric analysis, differential scanning calorimetry, and wide angle X‐ray diffraction, respectively. Their self‐assembly behavior was monitored by fluorescence‐probe technique and turbidity change using UV–vis spectrometer, and the morphology and size of the nanocarriers via self‐assembly were detected by cryo‐transmission electron microscopy and dynamic light scattering. These polymeric micelles with PAAA shell extending into the aqueous solution have potential abilities to act as promising nanovehicles for targeting drug delivery. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Synthesis and supramolecular self‐assembly of thermosensitive amphiphilic star copolymers based on a hyperbranched polyether core

A novel amphiphilic thermosensitive star copolymer with a hydrophobic hyperbranched poly (3‐ethyl‐3‐(hydroxymethyl)oxetane) (HBPO) core and many hydrophilic poly(2‐(dimethylamino) ethyl methacrylate) (PDMAEMA) arms was synthesized and used as the precursor for the aqueous solution self‐assembly. All the copolymers directly aggregated into core–shell unimolecular micelles (around 10 nm) and size‐controllable large multimolecular micelles (around 100 nm) in water at room temperature, according to pyrene probe fluorescence spectrometry and ¹H NMR, TEM, and DLS measurements. The star copolymers also underwent sharp, thermosensitive phase transitions at a lower critical solution temperature (LCST), which were proved to be originated from the secondary aggregation of the large micelles driven by increasing hydrophobic interaction due to the dehydration of PDMAEMA shells on heating. A quantitative variable temperature NMR analysis method was designed by using potassium hydrogen phthalate as an external standard and displayed great potential to evaluate the LCST transition at the molecular level. The drug loading and temperature‐dependent release properties of HBPO‐star‐PDMAEMA micelles were also investigated by using indomethacin as a model drug. The indomethacin‐loaded micelles displayed a rapid drug release at a temperature around LCST. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 668–681, 2008     

Synthesis and self‐association behavior of poly[bis(2‐(2‐methoxyethoxy)ethoxy)phosphazene]‐b‐poly(propyleneglycol) triblock copolymers

Amphilic triblock copolymers with varying ratios of hydrophilic poly[bis (methoxyethoxyethoxy)phosphazene] (MEEP) and relatively hydrophobic poly(propylene glycol) (PPG) blocks were synthesized via the controlled cationic‐induced living polymerization of a phosphoranimine (Cl₃P?NSiMe₃) at ambient temperature. A PPG block can function as either a classical hydrophobic block or a less hydrophobic component by varying the nature of a phosphazene block. The aqueous phase behavior of MEEP‐PPG‐MEEP block copolymers was investigated using fluorescence techniques, TEM, and dynamic light scattering (DLS). The critical micelle concentrations (cmcs) of MEEP‐PPG‐MEEP block copolymers were determined to be in the range of 3.7–16.8 mg/L. The mean diameters of MEEP‐PPG‐MEEP polymeric micelles, measured by DLS, were between 31 and 44 nm. The equilibrium constants of pyrene in these micelles ranged from 4.7 × 10⁴ to 9.6 × 10⁴. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 692–699, 2009     

Synthesis and micellization of amphiphilic poly(sebacic anhydride)–poly(ethylene glycol)–poly(sebacic anhydride) block copolymers

Amphiphilic biodegradable block copolymers [poly(sebacic anhydride)–poly(ethylene glycol)–poly(sebacic anhydride)] were synthesized by the melt polycondensation of poly(ethylene glycol) and sebacic anhydride prepolymers. The chemical structure, crystalline nature, and phase behavior of the resulting copolymers were characterized with ¹H NMR, Fourier transform infrared, gel permeation chromatography, and differential scanning calorimetry. Microphase separation of the copolymers occurred, and the crystallinity of the poly(sebacic anhydride) (PSA) blocks diminished when the sebacic anhydride unit content in the copolymer was only 21.6%. ¹H NMR spectra carried out in CDCl₃ and D₂O were used to demonstrate the existence of hydrophobic PSA domains as the core of the micelle. In aqueous media, the copolymers formed micelles after precipitation from water‐miscible solvents. The effects on the micelle sizes due to the micelle preparation conditions, such as the organic phase, dropping rate of the polymer organic solution into the aqueous phase, and copolymer concentrations in the organic phase, were studied. There was an increase in the micelle size as the molecular weight of the PSA block was increased. The diameters of the copolymer micelles were also found to increase as the concentration of the copolymer dissolved in the organic phase was increased, and the dependence of the micelle diameters on the concentration of the copolymer varied with the copolymer composition. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 1271–1278, 2006     

Synthesis and characterization of a biodegradable amphiphilic copolymer based on branched poly(ϵ‐caprolactone) and poly(ethylene glycol)

A novel biodegradable amphiphilic copolymer with hydrophobic poly(ε‐caprolactone) branches containing cholic acid moiety and a hydrophilic poly(ethylene glycol) chain was synthesized. The copolymer was characterized by FTIR, ¹H NMR, gel permeation chromatography (GPC), differential scanning calorimetry (DSC), polarizing light microscopy (PLM), and wide‐angle X‐ray diffraction (WAXD) analysis. The amphiphilic copolymer could self‐assemble into micelles in an aqueous solution. The critical micelle concentration of the amphiphilic copolymer was determined by fluorescence spectroscopy. A nanoparticle drug delivery system with a regularly spherical shape was prepared with high encapsulation efficiency. The in vitro drug release from the drug‐loaded polymeric nanoparticles was investigated. Because of the branched structure of the hydrophobic part of the copolymer and the relatively fast degradation rate of the copolymer, an improved release behavior was observed. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 5256–5265, 2007     

Synthesis of end‐functionalized AB copolymers. II. Synthesis and characterization of carboxyl‐terminated poly(ethylene glycol)–poly(amino acid) block copolymers

AB block copolymers composed of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic poly(amino acid) with a carboxyl group at the end of PEG were synthesized with α‐carboxylic sodium‐ω‐amino‐PEG as a macroinitiator for the ring‐opening polymerization of N‐carboxy anhydride. Characterizations by ¹H NMR, IR, and gel permeation chromatography were carried out to confirm that the diblock copolymers were formed. In aqueous media this copolymer formed self‐associated polymer micelles that have a carboxyl group on the surface. The carboxyl groups located at the outer shell of the polymeric micelle were expected to combine with ligands to target specific cell populations. The diameter of the polymer micelles was in the range of 30–80 nm. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 3527–3536, 2004     

Synthesis,self‐assembly and recognition properties of biomimetic star‐shaped poly(ε‐caprolactone)‐b‐glycopolymer block copolymers

Biomimetic star‐shaped poly(ε‐caprolactone)‐b‐poly(gluconamidoethyl methacrylate) block copolymers (SPCL‐PGAMA) were synthesized from the atom transfer radical polymerization (ATRP) of unprotected GAMA glycomonomer using a tetra(2‐bromo‐2‐methylpropionyl)‐terminated star‐shaped poly(ε‐caprolactone) (SPCL‐Br) as a macroinitiator in NMP solution at room temperature. The block length of PGAMA glycopolymer within as‐synthesized SPCL‐PGAMA copolymers could be adjusted linearly by controlling the molar ratio of GAMA glycomonomer to SPCL‐Br macroinitiator, and the molecular weight distribution was reasonably narrow. The degree of crystallization of PCL block within copolymers decreased with the increasing block length ratio of outer PGAMA to inner PCL. Moreover, the self‐assembly properties of the SPCL‐PGAMA copolymers were investigated by NMR, UV‐vis, DLS, and TEM, respectively. The self‐assembled glucose‐installed aggregates changed from spherical micelles to worm‐like aggregates, then to vesicles with the decreasing weight fraction of hydrophilic PGAMA block. Furthermore, the biomolecular binding of SPCL‐PGAMA with Concanavalin A (Con A) was studied by means of UV‐vis, fluorescence spectroscopy, and DLS, which demonstrated that these SPCL‐PGAMA copolymers had specific recognition with Con A. Consequently, this will not only provide biomimetic star‐shaped SPCL‐PGAMA block copolymers for targeted drug delivery, but also improve the compatibility and drug release properties of PCL‐based biomaterials for hydrophilic peptide drugs. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 817–829, 2008     

Syntheses and characterizations of poly[2‐(dimethylamino)ethyl methacrylate]–poly(propylene oxide)–poly[2‐(dimethylamino)ethyl methacrylate] ABA triblock copolymers

A novel, near‐monodisperse, well‐defined ABA triblock copolymer, poly[2‐(dimethylamino)ethyl methacrylate]‐b‐poly(propylene oxide)‐b‐poly[2‐(dimethylamino)ethyl methacrylate], was synthesized via oxyanion‐initiated polymerization. The initiator was a telechelic‐type potassium alcoholate prepared from poly(propylene glycol) and KH in dry tetrahydrofuran. The copolymers produced were characterized by Fourier transform infrared, ¹H NMR, and gel permeation chromatography (GPC). GPC and ¹H NMR analyses showed that the products obtained were the desired copolymers, with narrow molecular weight distributions (ca. 1.09–1.11) very close to that of the original poly(propylene glycol). ¹H NMR, surface tension measurements, and dynamic light scattering all indicated that the triblock copolymer led to interesting aqueous solution behaviors, including temperature‐induced micellization and very high surface activity. © 2002 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 40: 624–631, 2002; DOI 10.1002/pola.10144     

Well‐defined poly[(dimethylamimo)ethyl methacrylate]‐b‐poly(fluoroalkyl methacrylate) diblock copolymers: Effects of different fluoroalkyl groups on the solution properties

A series of well‐defined, fluorinated diblock copolymers, poly[2‐(dimethylamino)ethyl methacrylate]‐b‐poly(2,2,2‐trifluoroethyl methacrylate) (PDMA‐b‐PTFMA), poly[2‐(dimethylamino)ethyl methacrylate]‐b‐poly(2,2,3,4,4,4‐hexafluorobutyl methacrylate) (PDMA‐b‐PHFMA), and poly[2‐(dimethylamino)ethyl methacrylate]‐b‐poly(2,2,3,3,4,4,5,5‐octafluoropentyl methacrylate) (PDMA‐b‐POFMA), have been synthesized successfully via oxyanion‐initiated polymerization. Potassium benzyl alcoholate (BzO^?K⁺) was used to initiate DMA monomer to yield the first block PDMA. If not quenched, the first living chain could be subsequently used to initiate a feed F‐monomer (such as TFMA, HFMA, or OFMA) to produce diblock copolymers containing different poly(fluoroalkyl methacrylate) moieties. The composition and chemical structure of these fluorinated copolymers were confirmed by ¹H NMR, ¹⁹F NMR spectroscopy, and gel permeation chromatography (GPC) techniques. The solution behaviors of these copolymers containing (tri‐, hexa‐, or octa‐ F‐atom)FMA were investigated by the measurements of surface tension, dynamic light scattering (DLS), and UV spectrophotometer. The results indicate that these fluorinated copolymers possess relatively high surface activity, especially at neutral media. Moreover, the DLS and UV measurements showed that these fluorinated diblock copolymers possess distinct pH/temperature‐responsive properties, depending not only on the PDMA segment but also on the fluoroalkyl structure of the FMA units. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2702–2712, 2009     

Lactic acid‐ and carbonate‐based crosslinked polymeric micelles for drug delivery

Our objective was to synthesize and evaluate lactic acid‐ and carbonate‐based biodegradable core‐ and core‐corona crosslinkable copolymers for anticancer drug delivery. Methoxy poly(ethylene glycol)‐b‐poly(carbonate‐co‐lactide‐co‐5‐methyl‐5‐allyloxycarbonyl‐1,3‐dioxane‐2‐one) [mPEG‐b‐P(CB‐co‐LA‐co‐MAC)] and methoxy poly(ethylene glycol)‐b‐poly(acryloyl carbonate)‐b‐poly(carbonate‐co‐lactide) [mPEG‐b‐PMAC‐b‐P(CB‐co‐LA)] copolymers were synthesized by ring‐opening polymerization of LA, CB, and MAC using mPEG as an macroinitiator and 1,8‐diazabicycloundec‐7‐ene as a catalyst. These amphiphilic copolymers which exhibited low polydispersity and critical micelle concentration values (0.8–1 mg/L) were used to prepare micelles with or without drug and stabilized by crosslinking via radical polymerization of double bonds introduced in the core and interface to improve stability. mPEG₁₁₄‐b‐P(CB₈‐co‐LA₃₅‐co‐MAC_2.5) had a higher drug encapsulation efficiency (78.72% ± 0.15%) compared to mPEG₁₁₄‐b‐PMAC_2.5‐b‐P(CB₉‐co‐LA₃₉) (20.29% ± 0.11%).¹H NMR and IR spectroscopy confirmed successful crosslinking (～70%) while light scattering and transmission electron microscopy were used to determine micelle size and morphology. Crosslinked micelles demonstrated enhanced stability against extensive dilution with aqueous solvents and in the presence of physiological simulating serum concentration. Furthermore, bicalutamide‐loaded crosslinked micelles were more potent compared to non‐crosslinked micelles in inhibiting LNCaP cell proliferation irrespective of polymer type. Finally, these results suggest crosslinked micelles to be promising drug delivery vehicles for chemotherapy. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

A novel optically active diblock copolymer composed of poly(ethylene glycol) and poly[N‐{o‐(4‐phenyl‐4,5‐dihydro‐1,3‐oxazol‐2‐yl)phenyl}maleimide]: Synthesis,micellization behavior,and chiroptical property

A series of optically active amphiphilic block copolymers were synthesizedby using potassium alkoxide of poly(ethylene glycol) monomethyl ether (MeOPEGO^?K⁺) to initiate the anionic polymerization of N‐{o‐(4‐phenyl‐4,5‐dihydro‐1,3‐oxazol‐2‐yl)phenyl}maleimide [(R)‐PhOPMI]. The PEG‐macroinitiators generated in situ in the reaction between MeOPEGOH and potassium naphthylide in tetrahydrofuran. The synthetic procedure may provide the PEG‐b‐PPhOPMI copolymers with well‐defined structure, as evidenced by gel permeation chromatography, ¹H NMR, FTIR, and elemental analysis. In particular, the preparation of block copolymers having a laevorotation or dextrorotation activity was accomplished by changing the feed composition. The micellization was examined for the amphiphilic block copolymers in aqueous milieu by fluorescence spectroscopy, dynamic light scattering, and circular dichroism. The results indicate that the copolymers could form regular spherical micelles with core‐shell structure when the hydrophilic component was long enough; in contrast, the copolymers containing shorter PEG segments formed aggregates in large dimension due to the considerable interaction between hydrophobic PPhOPMI components. Also, it was found that the aggregated structure of the polymeric micelles is strongly dependent on the medium nature and the polymer concentration. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 1025–1033, 2008