Ocular Permeability of Pirenzepine Hydrochloride Enhanced by Methoxy poly(ethylene glycol)–poly(D,L-lactide) Block Copolymer

Methoxy poly(ethylene glycol)–poly(D,L-lactide) block copolymer was tested as an ocular permeation enhancer for pirenzepine hydrochloride. The block copolymers with the methoxy poly(ethylene glycol) to poly(D,L-lactide) weight ratio of 80/20, 50/50, 40/60 were synthesized by a ring-opening polymerization procedure. In vitro transcorneal experiments demonstrated that the block copolymer 80/20 significantly enhanced the transcorneal permeation of pirenzepine at the mass ratio of 1/1.4 (pirenzepine hydrochloride/copolymer). Interaction between pirenzepine and copolymer was identified by infrared spectroscopy analysis and dialysis experiments. Ocular pharmacokinetics of pirenzepine/copolymer preparation by in vivo instillation experiments confirmed that block copolymer could enhance the ocular penetration of pirenzepine. Ocular chronic toxicity experiments of block copolymer and pirenzepine/copolymer preparation were studied on rabbits, and no significant toxicity in both groups was observed within 9 months. It could conclude that pirenzepine/copolymer preparation is effective and safe in ocular delivery of pirenzepine.     

星形聚乙二醇-聚乳酸嵌段共聚物的合成与表征

以不同臂数和分子量的星型聚乙二醇(sPEG)和L-丙交酯为原料,采用开环聚合法合成了以星型聚乙二醇为内部嵌段、聚L-乳酸为外部嵌段的多臂星形聚乙二醇-聚乳酸嵌段共聚物(sPEG-b-PLLA)。研究了sPEG的臂数、分子量及L-丙交酯/sPEG投料比等参数对产物结构与性能的影响。并分别用红外光谱(FT-IR)、核磁共振(1H-NMR)、凝胶渗透色谱(GPC)、差示扫描量热(DSC)对产物进行了表征,证实所合成的嵌段共聚物具有预期的结构。结果表明,sPEG-b-PLLA为结晶性聚合物,且表现出与PLLA相似的晶型,随着PLLA链段的增加,产物的结晶度也呈增大的趋势;与PLLA相比,sPEG-b-PLLA的接触角随着PEG链段的增多而增大,表明其亲水性明显改善。     

端氨基聚乙二醇-聚乳酸嵌段共聚物的合成及表征

以聚乙二醇为原料,采用四步反应,合成了二碳酸二叔丁酯单保护的氨基聚乙二醇(BOC-PEG-NH2);并以DOe-PEG-NH2为引发剂,引发丙交酯开环聚合,得到了叔丁氧基酰胺基聚乙二醇-聚乳酸嵌段共聚物(BOC-PEG-PLA).在三氟乙酸二氯甲烷溶液中,脱去保护基团,得到了端氨基聚乙二醇-聚乳酸嵌段共聚物(NH2-PEG-PLA).采用核磁共振氢谱(1H-NMR)、紫外光度仪(UV)表征各聚合物的结构,由凝胶色谱仪(GPC)测定嵌段共聚物的分子量以及分子量分布.结果表明:合成的氨基引发在无催化剂条件下能够引发丙交酯开环聚合,制得分子量高、分子量分布窄的双亲性共聚物.通过三氟乙酸脱保护得到了端氨基聚乙二醇-一聚乳酸(NH2-PEG-PLA),且对分子量没有影响.     

Preparation of gold nanosheets using poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) block copolymers via photoreduction

Gold nanosheets having single crystalline structure were successfully synthesized using the bulk phase mixture of HAuCl₄ and poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) block copolymers through the irradiation of a glow lamp for 5 days. When the molar ratio of propylene oxide to ethylene oxide block units in the block copolymer is about 1.75, mostly gold nanosheets were obtained. Gold nanosheets with an average width of 8 and 5 μm were obtained from the when the molar ratio of gold salt to the ethylene oxide units in the block copolymer were 1/80 and 1/160, respectively.     

Engineering of poly(ethylene glycol) chain-tethered surfaces to obtain high-performance bionanoparticles

Abstract

A poly(ethylene glycol)-b-poly[2-(N,N-dimethylamino)ethyl methacrylate] block copolymer possessing a reactive acetal group at the end of the poly(ethylene glycol) (PEG) chain, that is, acetal-PEG-b-PAMA, was synthesized by a proprietary polymerization technique. Gold nanoparticles (GNPs) were prepared using the thus-synthesized acetal-PEG-b-PAMA block copolymer. The PEG-b-PAMA not only acted as a reducing agent of aurate ions but also attached to the nanoparticle surface. The GNPs obtained had controlled sizes and narrow size distributions. They also showed high dispersion stability owing to the presence of PEG tethering chains on the surface. The same strategy should also be applicable to the fabrication of semiconductor quantum dots and inorganic porous nanoparticles. The preparation of nanoparticles in situ, i.e. in the presence of acetal-PEG-b-PAMA, gave the most densely packed polymer layer on the nanoparticle surface; this was not observed when coating preformed nanoparticles. PEG/polyamine block copolymer was more functional on the metal surface than PEG/polyamine graft copolymer, as confirmed by angle-dependent x-ray photoelectron spectroscopy. We successfully solubilized the C₆₀ fullerene into aqueous media using acetal-PEG-b-PAMA. A C₆₀/acetal-PEG-b-PAMA complex with a size below 5 nm was obtained by dialysis. The preparation and characterization of these materials are described in this review.     

Preparation and characterization of fenofibrate-loaded PLA–PEG microspheres

A series of biodegradable block copolymer of poly(lactide)(PLA)/poly(ethylene glycol) (PEG) were prepared by Ring-Opening polymerization of D, L-lactide, using stannous octoate as a catalyst. By nanoprecipitation method, the PLA-PEG can be made into microspheres containing fenofibrate, which is a kind of important cholesterol-lowering drugs. The purpose of this study is to investigate the effect of the copolymer composition on the size, the entrapment and the release behavior of the fenofibrate loaded microspheres. The microspheres can be achieved with small size below 100 nm, better encapsulation efficiencies of more than 55.3% and slower release rates. The release of fenofibrate from microsphere would reach the balance first, when the microsphere prepared by high proportion of hydrophilic PEG block. And the release property of fenofibrate/PLA-PEG microsphere was better than Lipanthyl (a commercial capsule of fenofibrate). It was observed that the composition of PLA-PEG copolymer played a major role in encapsulation efficiency of microspheres and release rates.     

一种生物可降解材料PDLLA-(MAh-PEG)_n-PDLLA的合成与表征

丙交酯(LA)开环聚合时同时引入功能性单体合成含活性基团的可降解聚合物,是目前对聚乳酸(PLA)类材料进行改性的一个重要研究方向。文中首先以聚乙二醇(PEG)和马来酸酐(MAh)为原料,采用溶液缩聚法制得聚乙二醇与马来酸酐的交替预聚物(MAh-PEG)n;然后以辛酸亚锡为催化剂,(MAh-PEG)n为引发剂,引发D,L-丙交酯(D,L-LA)开环聚合,制得聚(D,L-乳酸)(PDLLA)与(MAh-PEG)n的共聚物PDLLA-(MAh-PEG)n-PDLLA。采用凝胶渗透色谱(GPC)、傅里叶红外(FT-IR)、核磁共振(NMR)等方法对共聚物的结构和性质进行研究。结果发现,随着(MAh-PEG)n用量的增加,共聚物的分子量有所下降。这种聚合物的主链含有不饱和双键和亲水性的链段,预计将成为一种新的生物可降解材料。     

Formation of PLLA-PEG-PLLA Microparticles by Supercritical Antisolvent Process

A biodegradable triblock copolymer of poly(L-lactide)–poly(ethylene glycol)–poly(L-lactide) (PLLA-b-PEG-b-PLLA) was synthesized via a new process by the ring-opening polymerization of L-lactide with PEG as macroinitiator and Sn(Oct)₂ as catalyst. The structure and molecular weight of the polymer were characterized by ¹H NMR spectra, Fourier transform infrared spectroscopy (FTIR), and gel permeation chromatography (GPC). Then the microparticles were prepared with the synthesized copolymer by supercritical antisolvent (SAS) process. The optimal operating conditions were explored using an orthogonal array design. The effects of the mixed organic solvent, the concentration of polymer solution and the flow rate of polymer solution on the morphology and thermal properties of the microparticles were investigated experimentally. The morphology, size and thermal properties of microparticles were characterized by scanning electron microscopy (SEM), laser particle size analyzer, x-ray diffractometer (XRD) and differential scanning calorimeter (DSC) respectively. The results indicated that the use of mixed solvent (dichloromethane/acetone) and the polymer concentration played important roles on particle morphology, size and size distribution. In addition the PLLA-PEG-PLLA particles prepared by supercritical antisolvent process have less crystalline.     

赖氨酸改性聚乳酸/聚乙二醇共聚物的制备及表征

在丙交酯与聚乙二醇开环共聚的基础上进行了二次聚合,利用具有生物相容性的赖氨酸对聚乳酸/聚乙二醇低聚物进行改性,制备出了赖氨酸改性聚乳酸/聚乙二醇共聚物。通过红外光谱、核磁共振谱、X射线衍射分析仪、差示扫描量热仪、凝胶渗透色谱和接触角测量仪分析比较了聚乳酸、聚乳酸/聚乙二醇和赖氨酸改性聚乳酸/聚乙二醇3种聚合物之间存在的差异。结果表明,实验成功合成了赖氨酸改性聚乳酸/聚乙二醇共聚物;赖氨酸(L-lys)的引入使得共聚物的热焓(ΔH)和熔点(T_m)分别由纯PLLA的81.57 J/g和177.34℃降到46.02 J/g和151.34℃,有效地改善了分子链的柔性和结晶度;聚合物的数均相对分子质量(M_n)也由纯PLLA的7.7×10~4降到了3.2×10~4,且相对分子质量分布变宽,但亲水性却得到大幅提高,有望适用于组织工程领域。     

聚乙二醇单甲醚/聚己内酯嵌段共聚物的微波合成及胶束制备

微波辅助下聚乙二醇单甲醚(MPEG)引发ε-己内酯(ε-CL)开环聚合合成了聚乙二醇单甲醚/聚己内酯(MPEG-b-PCL)嵌段共聚物,利用核磁共振(1H-NMR)和凝胶渗透色谱(GPC)方法对共聚物结构进行了表征。以芘作荧光探针,研究了共聚物胶束的形成及其临界胶束浓度(CMC)),利用动态光散射(DLS)和透射电镜(TEM)分别研究了胶束的粒径分布和形态。结果表明,在微波辅助下MPEG能够在较短时间内引发ε-CL开环聚合得到嵌段共聚物,当反应时间为5min,微波功率为700 W时能够得到理想的目标共聚物;嵌段共聚物在一定条件下能够形成球形的单分散纳米级胶束,CMC的数量级为10-3mg/mL。     

聚乙二醇对淀粉原位熔融接枝聚乳酸的影响

研究了在聚乙二醇(PEG)存在下,淀粉与丙交酯的原位熔融接枝反应。较系统地考察了PEG的加入量及分子量的变化对淀粉一聚乳酸原位熔融接枝反应的影响。结果表明,当有PEG存在时,丙交酯可以有效地接枝到淀粉链上,得到淀粉一聚乳酸接枝共聚物。PEG对淀粉的增塑效果是影响淀粉与丙交酯熔融接枝反应至关重要的因素。     

Block copolymers of L-lactide and poly(ethylene glycol) for biomedical applications

Poly (L-lactide)-poly (oxyethylene)-poly (L-lactide) block copolymers obtained in bulk, by a ring opening mechanism, from poly (ethylene glycol)s (PEG)s and L-lactide (LA), at 120–140°C, in the absence of added catalysts are described. By using PEGs with different molecular masses, 3000 and 35000, respectively, and varying the initial molar ratio LA to PEG, two series of copolymers with different molecular masses, relative length of blocks and hydrophilicity were obtained. Physico-chemical characterization of the copolymers had been previously performed. The morphological characteristics of the copolymers were investigated by means of X-ray diffractometry, optical and scanning electron microscopy. The biological properties of the materials were determined by evaluating their cytotoxicity, cytocompatibility, hemocompatibility and degradability using different standard tests. The results obtained indicate that the block copolymers synthesized may be useful for biomedical applications, in particular as resorbable drug vehicles. The materials are brittle and their mechanical properties are not appropriate for implant devices.     

Synthesis and characterization of cholesterol-poly(ethylene glycol)-poly(D,L-lactic acid) copolymers for promoting osteoblast attachment and proliferation

A novel cholesterol-poly(ethylene glycol)-poly(D,L-lactic acid) copolymer (CPEG-PLA) has been synthesized as a potential surface additive for promoting osteoblast attachment and proliferation. The gel permeation chromatography (GPC) and nuclear magnetic resonance spectroscopy (NMR) results indicated the product had expected structure with low polydispersities in the range of 1.1–1.5. By blending the poly(D,L-lactic acid) (PLA) with CPEG-PLA, the surface of modified PLA membrane was investigated by atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS) and contact angle. The results revealed the enrichment of PEG chain on the surface. Osteoblast cell line (MC3T3) was chosen to test the cell behavior on modified PLA membranes. The osteoblast test about cell attachment, proliferation, cell viability and cell morphology investigation on CPEG-PLA modified PLA substrates showed the CPEG-PLA with 15 and 5 ethylene glycol units promoted osteoblast attachment and growth, while the CPEG-PLA with 30 ethylene glycol units prevent osteoblast adhesion and proliferation. This simple surface treatment method may have potentials for tissue engineering and other biomedical applications.     

HECS-g-PDLLA共聚物的微波合成及与聚乳酸的相容性

在微波作用下,以辛酸亚锡为催化剂,羟乙基壳聚糖（HECS）为大分子引发剂引发D,L-丙交酯（D,L-LA）开环聚合制备羟乙基壳聚糖-g-聚乳酸（HECS-g-PDLLA）,通过红外（IR）、元素分析（EA）、氢核磁共振（1H-NMR）、X射线衍射（XRD）和差示扫描量热分析（DSC）对产物进行了表征。然后采用溶液共混法...     

熔融缩聚合成聚乳酸-聚乙二醇共聚物及其性能研究

采用羧基封端乳酸预聚物与聚乙二醇熔融缩聚合成了聚乳酸-聚乙二醇共聚物,并用GPC、FTIR、1H-NMR等方法表征了预聚物与共聚物,结果表明,预聚物的羧基封端率高于95%,预聚物的相对分子质量可由投料比(物质的量比)控制.热分析结果表明,共聚物中聚乳酸链段呈无规分布,而聚乙二醇链段能够形成结晶微区.力学性能测试结果表明,共聚物的断裂伸长率达371%,有望在聚乳酸韧性改性方面得到应用.     

The biodegradation of poly (ester-ether-ester) block copolymers in a cellular environmentin vitro

In this paper we report about the biodegradation of tri-block poly (ester-ether-ester) copolymers obtained by reaction of preformed poly (ethylene glycol) (PEG) with two different lactone monomers, i.e. -caprolactone (CL) and L-lactide (LA). The two series of copolymers will be indicated as PCL-POE-PCL and PLA-POE-PLA. We identified and measured by HPLC analysis the amount of degradation products of the poly (ester-ether-ester) copolymers; three copolymers were tested for each series during 3–8 week experiments. The experiments were carried out both in the presence and absence of fibroblast cell populations. We evaluated at the same time the decrease of copolymer molecular mass after degradation by means of intrinsic viscosity [] measurements. From the [] measurements we can conclude that the higher the hydrophilicity of the material, the faster the rate of decrease of its intrinsic viscosity with time. The HPLC results indicate that the amount of the degradation products, i.e., respectively, the monomers 6-hydroxyhexanoic acid and L-lactic acid, is a function of both hydrophilicity of the molecule and the lateral block length. When the fibroblast cell populations were present in the same wells together with the biodegradable copolymers, signs of cellular metabolism of the degraded monomers were detected.     

聚(甲基丙烯酸丁酯+(4-乙烯基)吡啶)共聚物膜的富氧性能研究

通过自由基共聚合反应，合成了一系列不同分子量、不同乙烯基吡啶基的聚（甲基丙烯酸丁酯 （4-乙烯基）吡啶）共聚物，并以低真空度法测试了其氧氮渗透性能。结果表明，随着共聚物膜中乙烯基吡啶含量的增加，共聚物的密度、玻璃化转变温度及氧氮选择性都随之增加，但氧氮渗透率和扩散系数、溶解度系数却相应下降。     

Biodegradable amphiphilic block-graft copolymers based on methoxy poly(ethylene glycol)-b-(polycarbonates-g-polycarbonates) for controlled release of doxorubicin

In this paper, novel biodegradable amphiphilic block-graft copolymers based on methoxy poly(ethylene glycol)-b-(polycarbonates-g-polycarbonates) (mPEG-b-(PATMC-g-PATMC)) were synthesized successfully for controlled release of doxorubicin (DOX). Backbone block copolymer, methoxy poly(ethylene glycol)-b-poly(5-allyloxy-1,3-dioxan-2-one) (mPEG-b-PATMC) was synthesized in bulk catalyzed by immobilized porcine pancreas lipase (IPPL). Then, mPEG-b-PATMC-O, the allyl epoxidation product of mPEG-b-PATMC, was further grafted by PATMC itself also using IPPL as the catalyst. The copolymers were characterized by ¹N HMR and gel permeation chromatography results showed narrow molecular weight distributions. Stable micelle solutions could be prepared by dialysis method, while a monomodal and narrow size distribution could be obtained. Transmission electron microscopy (TEM) observation showed the micelles dispersed in spherical shape with nano-size before and after DOX loading. Compared with the block copolymers, the grafted structure could enhance the interaction of polymer chains with drug molecules and improve the drug-loading capacity and entrapment efficiency. Furthermore, the amphiphilic block-graft copolymers mPEG-b-(PATMC-g-PATMC) had low cytotoxicity and more sustained drug release behavior.     

超临界CO2抗溶剂法制备紫杉醇缓释微球

采用超临界流体强制分散溶液技术,以D,L-聚乳酸和D,L-聚乳酸-聚乙二醇共聚物为载体材料,分别制备了紫杉醇缓释微球.通过扫描电镜、激光粒度仪检测微球外形及粒径分布;紫外吸光度法测量其载药量和包封率,恒温振荡透析法检测药物的体外释放性能;MTT法检测载药微球对Hela细胞的抑制作用.实验表明,两种载体的缓释微球球形度均较好,表面光滑,平均粒径较小,且粒径分布较窄.以聚乳酸和共聚物为载体的缓释微球载药量分别为5.4%±0.3%和5.3%±0.4%,包封率分别为51%±3%和45%±3%;药物释放呈缓释模式,共聚物载药微球药物释放速率较快.MTT法检测结果表明,载药微球对Hela细胞的增殖有明显抑制,共聚物载药微球对细胞增殖抑制更为明显.     

生物降解型嵌段共聚物P(VP-b-DLLA)的合成与自组装

以萘钠为引发剂,以聚乳酸(PDLLA)为疏水链段,聚N-乙烯基吡咯烷酮(PVP)为亲水链段,采用阴离子聚合方法合成了新型P(VP-b-DLLA)两亲型生物降解嵌段共聚物医用高分子材料。通过傅立叶红外光谱(FT-IR)、核磁共振谱(1H-NMR)、热重和元素分析等手段对合成的两亲型嵌段共聚物表征证明了嵌段共聚物的发生,并且得到性能良好的高分子材料。采用透射电镜(TEM)、动态激光光散射(DLS)和荧光分光光度计等技术研究了嵌段共聚物在选择性溶剂中的自组装行为,结果表明所形成胶束具有稳定的结构和适合的药物载体的流体力学直径。