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首页> 外文学位 >Development of novel polymeric materials for gene therapy and pH-sensitive drug delivery: Modeling, synthesis, characterization, and analysis.
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Development of novel polymeric materials for gene therapy and pH-sensitive drug delivery: Modeling, synthesis, characterization, and analysis.

机译：用于基因治疗和pH敏感药物递送的新型聚合物材料的开发：建模，合成，表征和分析。

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The aim of this work was to obtain a fundamental understanding of drug release mechanisms from polymers that undergo thermoreversible gelation and to synthesize new polymers based on these that exhibit both pH and temperature sensitivity. Novel block and random copolymers with cationic character have been developed for drug delivery and gene therapy applications. The development of these materials began with a study of the mechanism of drug release from poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) block copolymers. This study revealed the release rates of drugs from water-soluble hydrogels composed of the PEO-PPO-PEO block copolymer PluronicRTM F127 was dictated almost solely by the rate of interfacial dissolution at the water/gel interface. A setup was designed to measure drug release from such soluble systems in order to avoid confounding hydrodynamic effects as a result of shear on the delicate polymer/gel interface. This study was followed by a complementary analysis of the effect ionic salts play in the phase transitions and drug release profiles in aqueous F127 solutions.; In an attempt to incorporate pH sensitivity into such drug release systems, several block copolymers of poly(N,N-diethylaminoethyl methacrylate) (PDEAEM), PEO and PPO were synthesized via anionic polymerization. Diblock materials (PEO-b-PDEAEM), either with or without a carboxylic acid endcap, were synthesized and characterized. Tablet dissolution experiments demonstrated pH-sensitivity in their drug release profiles relative to PEO tablets. Pentablock materials (PDEAEM-b-PEO-b-PPO- b-PEO-b-PDEAEM) were synthesized that maintain the thermoreversible gelation and micellization properties of F127 while introducing pH-dependent release from aqueous gels of the copolymer. This is the first example of non-crosslinked materials that exhibit both pH- and temperature-sensitive behavior. Using a similar synthesis route, random copolymers of PDEAEM and poly(poly(ethylene glycol) methyl ether methacrylate)) (PEGME) were synthesized which are water soluble and non-cytotoxic, whereas homopolymers of PDEAEM are neither. These materials have potential as gene therapy vectors.
机译：这项工作的目的是对经历热可逆凝胶化作用的聚合物的药物释放机理有一个基本的了解，并基于具有pH和温度敏感性的聚合物合成新的聚合物。具有阳离子特性的新型嵌段和无规共聚物已经被开发用于药物递送和基因治疗应用。这些材料的开发始于对药物从聚环氧乙烷（PEO）和聚环氧丙烷（PPO）嵌段共聚物释放的机理的研究。这项研究表明，药物从由PEO-PPO-PEO嵌段共聚物PluronicRTM F127组成的水溶性水凝胶中释放的速率几乎完全由水/凝胶界面的界面溶解速率决定。设计一种装置来测量药物从此类可溶系统中的释放，以避免由于剪切作用在易碎的聚合物/凝胶界面上而造成混淆的流体动力学效应。这项研究之后，对F127水溶液中离子盐在相变和药物释放曲线中的作用进行了补充分析。为了将pH敏感性结合到这种药物释放系统中，通过阴离子聚合合成了聚（N，N-甲基丙烯酸二乙氨基乙酯）（PDEAEM），PEO和PPO的几种嵌段共聚物。合成和表征了具有或不具有羧酸端帽的二嵌段材料（PEO-b-PDEAEM）。片剂溶解实验表明，其药物释放曲线相对于PEO片剂具有pH敏感性。合成了五嵌段材料（PDEAEM-b-PEO-b-PPO-b-PEO-b-PDEAEM），该材料保持F127的热可逆凝胶化和胶束化特性，同时从共聚物的水凝胶中引入pH依赖性释放。这是非交联材料的第一个实例，它既显示pH值，又显示温度敏感性。使用相似的合成途径，合成了PDEAEM和聚（聚（乙二醇）甲基醚甲基丙烯酸甲酯）（PEGME）的无规共聚物，它们是水溶性且无细胞毒性的，而PDEAEM的均聚物则不是。这些材料具有作为基因治疗载体的潜力。

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