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Aliphatic biodegradable polymers containing pendant carboxyl groups

By 关会立

Abstract

生物降解脂肪族聚酷如聚乙交醋(PGA)、聚丙交醋(PLA)、聚。一己内酷(PCL)以及它们的共聚物由于具有良好的生物相容性和生物降解性而在外科手术缝合线、组织工程、药物控制释放、骨固定等领域得到很多应用。但是,它们自身缺乏功能基团,亲水性差,因而在应用上受到很大限制。因此,含有功能侧基生物降解聚合物的制备在过去十年中受到大家极大的关注。功能基团的引入对于调节聚合物的性能如:亲水性、生物降解性和药物的渗透性等非常重要。需要特别指出的是,功能基团的引入为把药物和其它生物活性物质与聚合物结合进而扩大聚合物的应用范围提供了机会。本文合成了几个功能化单体并且通过共聚的方法制备了几种新型的两亲性功能化聚合物。这些改性后的聚合物可以通过化学键接上药物或者其它生物活性物质,有望作为靶向控释药物载体和智能化的组织工程支架材料。具体的研究结果如下:1.以2,2-二羟甲基丙酸节酷为功能单体,通过两步法成功合成了一系列新的带功能基团的聚酷酞胺,并通过1H NMR和FTIR对聚合物的化学结构进行了表征,DSC结果表明所合成的聚酯酰胺的Tm和Tg分别在150℃和0℃左右;2.合成了功能化的环状单体(35)-3-[(苄氧羰基)乙基」吗啉-2,5-二酮(BEMD),并以PEG作为引发剂,Sn(Oct)2作为催化剂,通过L一LA和BEMD的开环共聚合得到共聚物PLGBG-PEG-PLGBG;随后用10%铭碳催化氢化得到带有侧梭基的两亲性嵌段共聚物PLGG-PEG-PLGG和其它两亲性嵌段共聚物一样,PLGG-PEG-PLGG在水溶液中能够自组装成胶束,用花作为荧光探针,通过荧光光谱法研究了其形成胶束的过程并测定了它们的临界胶束浓度,发现在总的分子量大致相当的情况下,PLGG-PEG4600-PLGG比PLGG-PEG2000-PLGG有较高的临界胶束浓度;场发射电子显微镜表征结果显示胶束具有均一的球形特征,动态光散射结果表明该胶束具有较窄的单峰粒径分布;蛋白酶K溶液中的降解研究表明带有侧梭基的PLGG-PEG-PLGG比PLA具有更快的降解速率;人胚关节软骨细胞培养结果表明所合成的聚合物PLGG-PEG-PLGG显示出较好的细胞相容性。3.在缩合剂DCC和催化剂DMAP存在下,带有侧梭基的两亲性嵌段共聚物PLGOPEG-PLGG和紫杉醇发生缩合反应得到两亲性嵌段共聚物一紫杉醇键合药P(LGG-paclitaxel)-PEG-P(LGG-paclitaxel)。它具有两亲性嵌段共聚物的性质,能够自组装成胶束,场发射电子显微镜表征结果表明胶束具有均一的球形特征,动态光散射结果表明该胶束具有较窄的粒径分布,平均粒径为119.4nm。该胶束的药物释放具有pH敏感性,酸性环境中比生理环境中(pH=7.4)具有较快的释放速率。P(LGG-Paclitaxel)-PEG-P(LGG-paclitaxel)胶束的壳层由良好亲水性的PEG组成,避免了胶束纳米粒子在血液循环中被人体网状内皮系统吞噬,保证有充足的时间通过EPR效应在肿瘤部位聚集,进而通过细胞内吞进入细胞并在细胞内的酸性环境中释放药物,进一步的研究工作有待深入进行。4.合成了功能化的环状碳酸酷单体MBC,以MPEG作为引发剂,ZnEt2作为催化剂,LLA和MBC发生开环共聚合,以较高的转化率,得到高分子量共聚物MPEG-b-P(LA-co-MBC)。13C NMR表明LLA和确c发生了无规共聚合;DSC征结果表明MPEG-b-P(LA-co-MBC)为无定型态聚合物,Tg在20-50℃之间,随着MBc含量的增加而降低;MPEG-b-P(LA-co-MBC)脱保护后得到带侧梭基的MPEG-b-P(LA-co-MCC),它的Tg明显提高,可能是聚合物侧梭基之间强的氢键作用力以及梭基对水解反应的催化作用造成的;脱保护前后的共聚物在蛋白酶K溶液中的降解研究表明,MPEG-b-P(LA-co-MCC)的降解速率大于MPEG-b-P(LA-co-MBC)的降解速率;人胚关节软骨细胞培养结果表明,所合成的MPEG-b-P(LA-co-MCC)是一种具有良好生物相容性的新型生物降解材料。5.利用本实验室开发的一种新型有机氨锯引发剂Sr-PO在温和的条件下通过顺序加料聚合的方法合成了新的嵌段共聚物PCL-b-PMBC。WAXD结果表明 PCL-b-PMBc中PCL的衍射峰均可观察到,只是衍射峰的强度随着PMBC含量的增加而减弱。DSC结果表明PCL-b-PMBC中PCL的Tm在57到52℃之间,并且随着PMBC含量的增加而降低。PCL-b-PMBC的玻璃化转变在-41.6 到-23.3℃之间,随着PMBC含量的增加而增加,这表明PMBC和PCL之间 有着强的相互作用,尽管两段不是完全相容的。PCL-b-PMBC的侧节醋在10%把碳催化下氢化还原为带侧梭基的PCL-b-PMCC后,衍射峰和结晶焙大大降低,说明侧梭基的存在使得分子链间有着强的氢键相互作用而不利于结晶。由以上分析可知,PCL-b-PMCC侧梭基的存在将会使共聚物的降解速度大大提高,而且因为功能梭基的存在可以使共聚物通过化学键连接上药物、短肤、寡糖或者其它生物活性物质,从而扩大该聚合物在生物医学领域的应用范围。Biodegradable aliphatic polyesters such as poly(glycolide) (PGA), poly(L-lactide) (PLA), poly(s-caprolactone) (PCL) and their copolymers have found wide applications in sutures, tissue engineering, bone fixation, and controlled drug delivery due to their excellent biocompatible and biodegradable properties. But their shortage of functional pendant groups and low hydrophilicitiy limited their further applications. T hus the preparation of biodegradable aliphatic polymers containing pendant functional groups has been attracting considerable attention in the past decade. The availability of functional groups along the chains is highly desirable for fine tuning the polymer properties, such as hydrophilicity, biodegradability, permeability and so forth. Particularly, it provides an opportunity for covalently attaching drugs and other bioactive reagents onto the polymers, which is expected to facilitate a variety of potential biomedical applications, hi this paper, several functional monomers were synthesized, and several functional polymers were prepared by copolymerization of these functional monomers with other cyclic monomers. These functional polymers are expected to be used as the drug carriers in targetable and controlled delivery and intelligent scaffolds materials in tissue engineering, if drugs and other bioactive reagents were conjugated covalently to their functional groups. The main results were listed as follows: 1. New aliphatic poly(ester amide)s containing functional groups were successfully prepared by a two-step polycondenzation using benzyl 2, 2-bis(hydroxymethyl)-propionate as a functional monomer. The chemical structure of poly(ester amide)s was characterized by !H NMR and FTIR. Tm and Tg of the poly(ester amide)s are approximately 150°C and 0°C, respectively, as determined by DSC. 2.(3s)-3-[(Benzoxycarbonyl)ethyl]morpholine-2,5-dione (BEMD) was synthesized. Poly(ethylene glycol)-WocAr-dipoly{ (lactic acid)-co-[(glycolic acid)-afr-(y-benzyl- L-glutamic acid)]} (PLGBG-PEG-PLGBG) was successfully prepared by ring-opening polymerization (ROP) of LLA with BEMD in the presence of dihydroxyl PEG as a macroinitiator using SnOct2 as catalyst. Subsequent catalytic hydrogenation using 10% Pd/C as catalyst led to the formation of corresponding copolymer PLGG-PEG-PLGG with pendant carboxyl groups. Similar to other amphiphilic block copolymers, PLGG-PEG-PLGG could self-assemble into micelles in aqueous solution. The formation of micellar structure was confirmed and critical micelle concentrations (cmc) were estimated by a fluorescence technique using pyrene as a probe. The cmc of PLGG-PEG4600-PLGG7 is higher than that of PLGG-PEG2000-PLGG3 when their molecular weights are equivalent. EMES and DLS analysis of the micelles revealed homogeneous spherical morphology and a narrow unimodal size distribution. In vitro degradation investigation in the presence of proteinase K showed that the degradation rate of PLGG-PEG-PLGG with pendant carboxyl groups was faster than that of PLLA. The incubation of articular cartilage cell with PLGG-PEG-PLGG demonstrated in a low degree of cytotoxicity. 3.A novel polymer-drug conjugate P(LGG-paclitaxel)-PEG-P(LGG-paclitaxel) has been prepared by condensation reaction of the hydroxyl group of paclitaxel with the pendant carboxyl groups of PLGG-PEG-PLGG in the presence of DCC and DMAP in dichloromethane. B ecause paclitaxel is lipophilic, the resulting polymer-drug conjugate is amphiphilic, and can self-assemble into nanometer micelles, similar to conventional amphiphilic block copolymers. EMES and DLS analysis of the micelles revealed homogeneous spherical morphology, a unimodal size distribution and a mean particle size of 119 nm. The release rate of paclitaxel from the conjugate micelles is pH-sensitive, and faster in acid environment (pH=4~5) than in normal physiological conditions (pH=7.4). Because their shell consists of PEG that has high water-solubility, micelles from P(LGG-paclitaxel)-PEG-P(LGG-paclitaxel) have a prolonged circulation in the blood, thus avoiding the nonspecific uptake by reticuloendothelial systems (RES), and have enough time to accumulate in tumour site due to enhanced permeation and retention (EPR effect), and finally enter the cells by endocytosis, where the drug is released at lower pH value. Further investigation is in progress

Topics: 聚酷酞胺, 聚碳酸醋, 功能化聚合物, 两亲性嵌段共聚物, 聚合物键合药, 高分子化学与物理
Year: 2004
OAI identifier: oai:ir.ciac.jl.cn:322003/34653
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