聚(醚-酐)凝胶性能的优化及用于包载难溶性药物的研究

在制备聚醚酐凝胶的基础上, 用两种不同的可光交联疏水性单体与聚醚酐大分子单体在紫外光引发下制备三维交联凝胶, 使得凝胶的溶胀性能和亲-疏水性能发生变化, 从而影响凝胶与难溶性药物的相容性; 选用吲哚美辛为模型药物, 通过后包合法将其包载于凝胶网络中, X射线衍射(XRD)检测结果表明, 药物能以分子或无定形态分散于其中, 优化后的凝胶可得到更高的载药量和包封率, 能有效地提高疏水性药物的溶出度, 且药物体外释放速率与单纯聚醚酐凝胶相比, 被有效延缓, 更适于临床应用.     

可降解光交联聚(醚-酐)凝胶用于难溶性药物增溶的研究

将水难溶性药物吲哚美辛包埋于可降解聚(醚-酐)三维光交联网络凝胶中, 使该凝胶具有较好的溶胀性能. X射线衍射测定结果表明, 药物能以分子或无定形态分布, 贮存2个月后药物仍无形态改变, 溶出实验结果表明, 包载在凝胶中的药物比原料药物具有更快的溶出速率和累积溶出量. 采用该法能提高制剂中药物的物理稳定性, 阻延药物析晶, 有效地用于药物增溶.     

Transition metal-catalyzed one-pot synthesis of water-soluble dendritic molecular nanocarriers

Here, we report the first example of transition metal-catalyzed one-pot synthesis of water-soluble dendritic molecular nanocarriers behaving like unimolecular micelles. Using the palladium-alpha-diimine chain walking catalyst, copolymerization of ethylene and comonomer 3 afforded, in one step, amphiphilic copolymer 1 having a hydrophobic core and a hydrophilic shell. A much larger amphiphilic core-shell copolymer 2 was synthesized by a two-step approach: a copolymer having many free hydroxyl groups was first prepared, which was subsequently coupled to poly(ethylene glycol) (PEG) to afford the copolymer 2. Light-scattering, fluorescence, and UV/vis spectroscopic studies with Nile Red in aqueous solution showed unimolecular micellar properties for both copolymers 1 and 2. The dye encapsulation capacity for the core-shell copolymers is nearly proportional to the molecular weight of the hydrophobic core. The unimolecular micellar properties coupled with the good water solubility and biocompatibility of the PEG moieties make these molecular nanocarriers promising candidates for many applications including drug delivery and controlled drug release.     

Preparation and characterization of biodegradable nanoparticles based on amphiphilic poly(3-hydroxybutyrate)-poly(ethylene glycol)-poly(3-hydroxybutyrate) triblock copolymer

Amphiphilic triblock copolymers of poly(3-hydroxybutyrate)-poly(ethylene glycol)-poly(3-hydroxybutyrate) (PHB-PEG-PHB) were directly synthesized by the ring-opening copolymerization of β-butyrolactone monomer using PEG as macroinitiator. Their structure, thermal properties and crystallization were investigated by ¹H NMR, differential scanning calorimetry (DSC) and X-ray diffraction. It was found that both PHB and PEG blocks were miscible. With the increase in the PHB block length, the triblock copolymers became amorphous because amorphous PHB block remarkably depressed the crystallization of the PEG block. Biodegradable nanoparticles with core-shell structure were prepared in aqueous solution from the amphiphilic triblock copolymers, and characterized by ¹H NMR, SEM and fluorescence. The hydrophobic PHB segments formed the central solid-like core, and stabilized by the hydrophilic PEG block. The nanoparticle size was close related to the initial concentrations of the nanoparticle dispersions and the compositions of the triblock copolymers. Moreover, the PHB-PEG-PHB nanoparticles also showed good drug loading properties, which suggested that they were very suitable as delivery vehicles for hydrophobic drugs.     

Crosslinked poly(ethylene oxide) for drug release systems

Three types of poly(ethylene oxide) (PEO)- based hydrogels have been synthesized and studied for drug release applications: γ-irradiated high molecular weight PEO, biodegradable polyether-polyester networks with malic acid as crosslinker of poly(ethylene glycol)s and amphiphilic PEO-based polyureas crosslinked with multifunctional isocyanates. Varying the length of the PEO chain and the type of the crosslinker, hydrogels with different swelling properties, loading capacities and release characteristics were obtained. A large number of pharmaceuticals (acebutolol. HCl, diclofenac. Na, procaine. HCl, phenobarbital.a, propranolol, etc.) were tested for a sustained release in different media (pH=1.2, 6.5, 7.4). Most of them # gave reasonable retarded release profiles for 8 hours when incorporated before the γ-irradiation crosslinking of PEO. While amphiphilic hydrogels were found to be suitable for hydrophobic solutes, the biodegradable PEO-based polyester ones affected predominantly the release of water-soluble drugs. No pH effect was found for the γ-irradiated PEO as a carrier in contrast to the strong pH dependence for the degradable polyester networks.     

Direct synthesis of amphiphilic block copolymers from glycidyl methacrylate and poly(ethylene glycol) by cationic ring‐opening polymerization and supramolecular self‐assembly thereof

Amphiphilic block copolymers composed of a hydrophilic poly(ethylene glycol) (PEG) block and a hydrophobic poly(glycidyl methacrylate) (PGMA) block were synthesized through cationic ring‐opening polymerization with PEG as the precursor. The model reactions indicated that the reactivity of the epoxy groups was higher than that of the double bonds in the bifunctional monomer glycidyl methacrylate (GMA) under the cationic polymerization conditions. Through the control of the reaction time in the synthesis of block copolymer PEG‐b‐PGMA, a linear GMA block was obtained through the ring‐opening polymerization of epoxy groups, whereas the double bond in GMA remained unreacted. The results showed that the molecular weight of the PEG precursor had little influence on the grafting of GMA, and the PGMA blocks almost kept the same length, despite the difference of the PEG blocks. In addition, the PGMA blocks only consisted of several GMA units. The obtained amphiphilic PEG‐b‐PGMA block copolymers could form polymeric core–shell micelles by direct molecular self‐assembly in water. The crosslinking of the PGMA core of the PEG‐b‐PGMA micelles, induced by ultraviolet radiation and heat instead of crosslinking agents, greatly increased the stability of the micelles. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 2038–2047, 2005     

Synthesis strategies and properties of smart amphiphilic networks

This paper briefly surveys recent developments in the field of amphiphilic networks (APN) which are a new class of crosslinked polymer systems consisting of covalently bonded hydrophobic and hydrophilic chain segments. The covalent bonds between immiscible hydrophobic and hydrophilic polymer chains prevent demixing and yield polymer networks with unique structure and properties. Telechelic macromonomers provide the basis for the first generation of APNs obtained by copolymerization of the macromonomer with selected low molecular weight monomers. Synthesis of a variety of APNs using methacrylate-telechelic polyisobutylene (PIB) macromonomers prepared by living carbocationic polymerization (LCCP) and quantitative chain end derivatization is reviewed. The second generation of PIB-based amphiphilic networks is prepared by crosslinking of well-defined hydroxy-telechelic PIB and partially deprotected silylated poly(2-hydroxyethyl methacrylate) (PHEMA) precursor chains. Other opportunities providing better structural control of APNs by crosslinking of functional amphiphilic block copolymers (or precursors) obtained by combining living carbocationic and anionic polymerizations are outlined as well. Properties of APNs, such as control of swellability by composition, pH-response of swelling, fast surface structure reorganization by contacting with solvent, morphology, sustained release of drugs and bio- and blood compatibility, are also summarized.     

Construction of temperature responsive hybrid crosslinked self‐assemblies based on PEG‐b‐P(MMA‐co‐MPMA)‐b‐PNIPAAm triblock copolymer: ATRP synthesis and thermoinduced association behavior

A novel amphiphilic thermosensitive poly(ethylene glycol)₄₅‐b‐poly(methyl methacrylate₄₆‐co‐3‐(trimethoxysilyl)propyl methacrylate)₂‐b‐poly(N‐isopropylacrylamide)₄₂₉ (PEG₄₅‐b‐P(MMA₄₆‐co‐MPMA₂)‐b‐PNIPAAm₄₂₉) triblock copolymer was synthesized via consecutive atom transfer radical polymerization techniques. The thermoinduced association behavior of the resulting triblock copolymers in aqueous medium was further investigated in detail by ¹H NMR, transmission electron microscopy, and dynamic light scattering. The results showed that at the temperature (25 °C) below the LCST, PEG₄₅‐b‐P(MMA₄₆‐co‐MPMA₂)‐b‐PNIPAAm₄₂₉ triblock copolymers self‐assembled into the core crosslinked micelles with the hydrophobic P(MMA‐co‐MPMA) block constructing a dense core, protected by the mixed soluble PEG and PNIPAAm chains acting as a hydrophilic shell simultaneously. With an increase in temperature, the resulting core‐shell micelles converted into a new type of micelles with the hydrophilic PEG chains stretching out from the hydrophobic core through the collapsed PNIPAAm shell. On the other hand, at the temperature (40 °C) above the LCST, such triblock copolymers formed the crosslinked vesicles with the hydrophobic PNIPAAm and P(MMA‐co‐MPMA) blocks constructing a membrane core and the soluble PEG chains building the hydrophilic lumen and the shell. On further decreasing the temperature, the resulting vesicles underwent transformation from the shrunken to the expanded status, leading to the formation of swollen vesicles with enlarged size. This study is believed to present the first formation of two types of hybrid crosslinked self‐assemblies by thermoinduced regulation. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Synthesis and characterization of novel degradable photocrosslinked poly(ether‐anhydride) networks

New degradable poly(ether‐anhydride) networks were synthesized by UV photopolymerization. Dicarboxylated poly(ethylene glycol) (PEG) or poly(tetramethylene glycol) (PTMG) was reacted with an excess of methacrylic anhydride to form dimethacrylated macromers containing anhydride linkages. The percent of conversion for the macromer formation was more than 80% at 60 °C after 24 h. ¹H NMR and IR spectroscopies show the presence of anhydride linkages in the macromer. In vitro degradation studies were carried out at 37 °C in PBS with crosslinked polymer networks formed by UV irradiation. All PEG‐based polymers degraded within 2 days, while PTMG‐based polymers degraded by 50% of the initial weight after 14 days. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 1277–1282, 2000     

基于光聚合星型PEG-b-PCL大分子单体可生物降解水凝胶的合成及表征

以辛酸亚锡为催化剂 ,通过星型聚乙二醇 (PEG)引发ε 己内酯 (CL)开环聚合 ,制备了PEG b PCL嵌段共聚物 ,进一步以丙烯酸酯封端 ,合成了 3种水溶性大分子单体 .以 2 ,2 二甲氧基 2 苯基苯乙酮为引发剂 ,在紫外光作用下 ,大分子单体在水中由于胶束的形成能够迅速聚合形成水凝胶 .利用1 H NMR、FTIR、DSC、TGA、ESEM、凝胶含量、溶胀比等分析测试手段对大分子单体及其形成的水凝胶进行了表征 .结果表明 ,干胶迅速吸水而达到溶胀平衡 ,水凝胶具有较大的溶胀比和高的水含量 ;随着PEG臂数的增加 ,干胶的熔融峰顶温度下降 ,凝胶的溶胀比减小 ;ESEM图片上清晰地表明水凝胶的网络结构     

Drug release and biocompatibility of self‐assembled micelles prepared from poly (ɛ‐caprolactone/glycolide)‐poly (ethylene glycol) block copolymers

A series of poly(?‐caprolactone/glycolide)‐poly(ethylene glycol) (P(CL/GA)‐PEG) diblock copolymers were prepared by ring opening polymerization of a mixture of ?‐caprolactone and glycolide using mPEG as macro‐initiator and stannous octoate as catalyst. Self‐assembled micelles were prepared from the copolymers using nanoprecipitation method. The micelles were spherical in shape. The micelle size was larger for copolymers with longer PEG blocks. In contrast, the critical micelle concentration of copolymers increased with decreasing the overall hydrophobic block length. Drug loading and drug release studies were performed under in vitro conditions, using paclitaxel as a hydrophobic model drug. Higher drug loading was obtained for micelles with longer poly(ε‐caprolactone) blocks. Faster drug release was obtained for micelles of mPEG2000 initiated copolymers than those of mPEG5000 initiated ones. Higher GA content in the copolymers led to faster drug release. Moreover, drug release rate was enhanced in the presence of lipase from Pseudomonas sp., indicating that drug release is facilitated by copolymer degradation. The biocompatibility of copolymers was evaluated from hemolysis, dynamic clotting time, and plasma recalcification time tests, as well as MTT assay and agar diffusion test. Data showed that copolymer micelles present outstanding hemocompatibility and cytocompatibility, thus suggesting that P(CL/GA)‐PEG micelles are promising for prolonged release of hydrophobic drugs.     

Preparation of Magnetite Nanoparticles Coated with an Amphiphilic Block Copolymer: A Potential Drug Carrier with a Core‐Shell‐Corona Structure for Hydrophobic Drug Delivery

Summary: The synthesis of magnetic magnetite nanoparticles coated with amphiphilic block copolymers of poly(ethyl methacrylate)‐block‐poly(2‐hydroxyethyl methacrylate) for use as new potential carriers for hydrophobic drug delivery is reported. The results show that a new core‐shell‐corona structural material is obtained with a very narrow molecular weight distribution of the hydrophobic segment (PDI = 1.10). UV‐Vis results show that 37% of progesterone is released from the nanoparticles after 22 h, much slower than free release (99% after 14 h), which demonstrates that the presence of the hydrophobic segment can effectively control the release of hydrophobic drugs.

Synthesis of an amphiphilic block polymer poly(ethyl methacrylate)‐block‐poly(2‐hydroxyethyl methacrylate) on magnetite nanoparticles and their use as potential drug carriers     

Core Crosslinking of Biodegradable Block Copolymer Micelles Based on Poly(ester carbonate)

A biodegradable amphiphilic block copolymer, PEG‐b‐P(LA‐co‐MAC), was used to prepare spherical micelles consisting of a hydrophobic P(LA‐co‐MAC) core and a hydrophilic PEG shell. To improve their stability, the micelles were crosslinked by radical polymerization of the double bonds in the hydrophobic blocks. The crosslinked micelles had similar sizes and a narrow size distribution compared to their uncrosslinked precursor. The improved stability of the crosslinked micelles was confirmed by measurements of the CMC and a thermodynamic investigation. These micelles can internalize into Hela cells in vitro as demonstrated by inverted fluorescence microscopy and CLSM. These stabilized nanoscale micelles have potential use in biomedical applications such as drug delivery and disease diagnosis.

     

Poly(ethylene glycol)‐based amphiphilic model conetworks: Synthesis by RAFT polymerization and characterization

Poly(ethylene glycol) (PEG)‐containing quasi‐model amphiphilic polymer conetworks (APCNs) were prepared by reversible addition fragmentation chain transfer (RAFT) polymerization using α,ω‐bis(2‐cyanoprop‐2‐yl dithiobenzoate)‐PEG as a bifunctional RAFT macrochain transfer agent (macro‐CTA) and stepwise additions of a hydrophobic monomer and a crosslinker (crosslinker: macro‐CTA = 10:1, reaction time 24 h). Three different types of monomers, methyl methacrylate (MMA), n‐butyl acrylate and styrene, were employed as the hydrophobic monomers, whereas ethylene glycol dimethacrylate, ethylene glycol diacrylate and 1,4‐divinylbenzene served as the respective crosslinkers. PEG homopolymer hydrophilic quasi‐model networks were also prepared by RAFT‐polymerizing the three crosslinkers directly onto the two active ends of the PEG‐based macro‐CTA. From the three ABA triblock copolymers prepared, the MMA‐containing one was obtained at the highest polymerization yields. The crosslinking yields of the three ABA triblock copolymers with the corresponding crosslinkers were higher than those of the PEG‐based macro‐CTA with the same crosslinkers. The degrees of swelling (DSs) of all conetworks were measured in water and in tetrahydrofuran (THF). The DSs of the APCNs in THF were higher than those in water, whereas the reverse was true for the DSs of the hydrophilic homopolymer networks. Finally, the aqueous DSs of the APCNs were lower than those of the corresponding hydrophilic homopolymer networks. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 7556–7565, 2008     

Soft nanoparticles assembled from linear poly(ethylene glycol) and linear brush polydimethylsiloxane diblock copolymers

A series of novel amphiphilic diblock copolymers composed of hydrophilic linear poly(ethylene glycol) (PEG) and linear brush hydrophobic polydimethylsiloxane (PDMS) were synthesized. Three different molecular weights of monomethyl ether PEG were initially functionalized with 2‐bromoisobutyryl bromide to afford macroinitiators suitable for atom‐transfer radical polymerization. The macroinitiators were characterized by gel permeation chromatography, ¹H and ¹³C nuclear magnetic resonance spectroscopic analysis and matrix‐assisted laser desorption ionization time‐of‐flight mass spectroscopy. The three different molecular weight macroinitiators were then chain extended with monomethacryloxypropyl‐terminated PDMS and photoactive 2‐(methylacyloyloxy)ethyl anthracene‐9‐carboxylate in different molar ratios to afford a series of photoresponsive amphiphilic diblock copolymers with high conversions. Self‐assembly of these linear–linear brush diblock copolymers in N,N‐dimethylformamide afforded nanoparticles with hydrodynamic diameters (d_H) ranging from 41 to 268 nm, as determined by dynamic light scattering analysis. Crosslinking and stabilization of the nanoparticles was achieved via [4+4] photodimerization of the anthracene moieties upon exposure to UV radiation at 365 nm with the reverse reaction studied at a wavelength of 254 nm. Transmission electron microscopy revealed that the self‐assembled nanoparticles and their crosslinked derivatives had spherical morphologies. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 1251–1262     

Y‐shaped poly(ethylene glycol) and poly(trimethylene carbonate) amphiphilic copolymer: Synthesis and for drug delivery

New Y‐shaped (AB₂‐type) amphiphilic copolymers of poly(ethylene glycol) (PEG) with poly(trimethylene carbonate) (PTMC), PEG‐b‐(PTMC)₂, were successfully synthesized by the ring‐opening polymerization (ROP) of TMC with bishydroxy‐modified monomethoxy‐PEG (mPEG). First, a bishydroxy functional ROP initiator was synthesized by esterification of acryloyl bromide with mPEG, followed by Michael addition using excess diethanolamine. A series of Y‐shaped amphiphilic PEG‐(PTMC)₂ block copolymers were obtained via ROP of TMC using this PEG with bishydroxyl end groups as macroinitiator and ZnEt₂ as catalyst. The amphiphilic block copolymers with different compositions were characterized by gel permeation chromatography (GPC) and ¹H NMR, and their molecular weight was measured by GPC. The results showed that the molecular weight of Y‐shaped copolymers increased with the increase of the molar ratio of TMC to mPEG‐(OH)₂ initiator in feed while the PEG chain length was kept constant. The Y‐shaped copolymer mPEG‐(PTMC)₂ could self‐assemble into micelles in aqueous medium and the critical micelle concentration values of the micelles decrease with increase in hydrophobic PTMC block length of mPEG‐(PTMC)₂. The in vitro cytotoxicity and controlled drug release properties of the Y‐shaped amphiphilic block copolymers were also investigated. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 8131–8140, 2008     

ABA-type amphiphilic triblock copolymers containing p-ethoxy azobenzene via atom transfer radical polymerization: Synthesis,characterization, and properties

ABA-type amphiphilic triblock copolymers composed of poly(ethylene glycol)s (PEGs) with different number-average molecular weights as the hydrophilic blocks (B) and poly{6-[4-(4-ethoxyphenylazo)phenoxy]hexyl methacrylate} (PA6C) as the hydrophobic blocks (A) were prepared via atom transfer radical polymerization. These copolymers were prepared from bromo-terminated macroinitiators based on PEG6000, PEG2000, and PEG600, with CuBr/N,N,N′,N″,N″-pentamethyldiethylenetriamine as the catalytic system, at 85 °C in anisole. The block copolymers were characterized with ¹H NMR spectroscopy and gel permeation chromatography. Differential scanning calorimetry measurements were performed to reveal the phase segregation. In contrast to those polymers with similar compositions and structures in previous reports, these amphiphilic copolymers exhibited unusual liquid-crystalline properties over a wide temperature range, being stable even at room temperature. These copolymers showed photoresponsive isomerization under the irradiation of UV–vis light both in THF solutions and in solid films. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 2225–2234, 2007     

聚乙二醇在新型药物制剂中的应用

聚乙二醇具有良好的生物相容性和两亲性 ,在生物医药领域中有着广泛的应用 ,本文就聚乙二醇在新型药物制剂中的应用进行综述 ,主要包括纳米给药系统、蛋白质药物修饰和疏水性药物的前药等。     

Thermoregulated phase‐transfer catalysis via PEG‐armed Ru(II)‐bearing microgel core star polymers: Efficient and reusable Ru(II) catalysts for aqueous transfer hydrogenation of ketones

Thermoregulated phase‐transfer catalysis for the transfer hydrogenation of 2‐octanone in 2‐propanol/H₂O biphasic media was achieved with ruthenium‐bearing microgel‐core star polymers with amphiphilic, thermosensitive poly(ethylene glycol) (PEG) arms [Ru(II)‐PEG star], which were directly prepared by the ruthenium‐catalyzed living radical polymerization in conjunction with a phosphine ligand‐carrying styrene derivative. The star polymers were first placed in the aqueous (lower) layer at room temperature and immediately moved into the organic (upper) layer at 100 °C, and once again, moved down to the aqueous layer (lower) upon cooling the solution to room temperature. The Ru(II)‐PEG star catalyst was clearly superior to the original Ru(II) catalyst and related non‐microgel catalysts [Ru(II)‐PEG block] in terms of activity and recovery/recycle, due to the unique designer structure of the microgel‐core star polymers. Other substrates (less hydrophobic alkyl ketones and aromatic ketone) were also efficiently hydrogenated into the corresponding sec‐alcohols with the star catalyst in aqueous media. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 373–379, 2010     

聚乙二醇-聚谷氨酸-聚丙氨酸三嵌段共聚物的合成及其胶束的pH-响应性药物控制释放

通过大分子引发剂ω-胺基-α-甲氧基聚乙二醇引发N-羧基-α-氨基环内酸酐开环聚合和酸性水解制备了一种具有pH-响应性的三嵌段共聚物聚乙二醇-聚谷氨酸-聚丙氨酸(mPEG-PLGA-PLAA).通过核磁共振、ζ-电势、动态光散射、电子显微镜等手段表征了此类三嵌段共聚物的自组装过程及所形成胶束的pH-响应性.使用圆二色谱和红外光谱,分析了胶束结构随环境pH值转变过程中聚氨基酸链段二级结构的变化.以阿霉素作为模型药物,研究了三嵌段共聚物的载药能力和在不同pH条件下的药物释放能力.在碱性条件下,PLGA链段去质子化,链段从疏水性变为亲水性,胶束中间层由于水合作用变得松散,药物释放速率增加;在酸性条件下,PLGA链段质子化,不带电荷,与阿霉素药物分子间的静电相互作用消失.同时,PLGA链段α-螺旋含量增加,形成由链内氢键维持的刚性棒状结构,将链段周围包埋的药物分子"挤出",加速了药物的释放.