利用RAFT聚合方法合成药物载体的研究
摘要
利用高分子两亲性嵌段共聚物自组装形成的“核-壳”结构胶束，在药物/基因载体的研究领域得到了广泛地关注。相关实验表明，通过自组装行为形成的胶束稳定性通常不佳，容易受到外界环境的影响而导致体系的“崩溃”，以致失去对药物的有效输运及可控释放能力。为了增强此类载体的抗干扰能力，得到稳定、结构高度有序的高分子聚集体，研究工作者提出了交联胶束的概念，即通过化学键将胶束链接起来，以实现结构的固定和新功能的开发。
本论文拟利用可逆断裂-链转移聚合技术(RAFT)得到对药物阿苯哒唑(ABZ)和肝素(HP)进行传递的聚合物药物载体。为了实现体内药物的高效传递，利用RAFT聚合技术合成一系列基于两亲性嵌段共聚物的聚合物胶束体系。对于ABZ的传输，设计两个药物载体体系。第一，聚(乙二醇)甲基醚甲基丙烯酸酯被选作亲水性单体在水溶液中形成外壳，对硝基苯酚丙烯酸酯链段作为疏水链段形成内核，通过化学反应的交联作用，形成一种全核交联的核交联胶束。第二，将RAFT聚合技术与开环技术相结合，得到以聚己内酯作为疏水性片断的嵌段间面交联胶束。药物包载实验结果证明，聚己内酯形成的自组装胶束对于ABZ有良好的药物包载性能。
利用RAFT聚合方法合成含有(2-(甲基丙烯酰氧基)乙基)三甲基氯化铵的嵌段聚合物，其中(2-(甲基丙烯酰氧基)乙基)三甲基氯化铵片段呈正电性，可通过离子键直接与负电性肝素结合。细胞毒理实验证明，聚合物/肝素复合物无细胞毒性，随着聚合物中正电荷性的增强，细胞吸收能力也会随之提高。聚合物/肝素复合物能够有效抑制纤维素瘤的细胞增殖。
“Core-Shell” micelle as drug/gene delivery systems have gained more and moreattention in research area. With crosslinking method, it is easy to overcome theshortcoming of the self-assembled micelles and get stable cross-linked micelles. Theaim of this thesis is to investigate the applicability of polymeric nano-particlessynthesized via reversible addition fragmentation chain transfer (RAFT)polymerization that can be used for the drug delivery of albendazole (ABZ) andHeparin(HP).
To achieve this aim, a wide range of polymeric micelle systems based onamphiphilic block copolymers has been synthesized and investigated. Thebiocompatible poly(ethylene glycol) methyl ether methacrylate was chosen to formthe hydrophilic block. Based on the crosslinking techniques, p-nitrophenyl acrylatewas chosen to build the hydropobic block and the functional part. Poly(-caprolactone) was chosen to build another hydrophobic block as it demonstrated toachieve the highest compatibility with the ABZ. To stabilize the structure of micelles,nexus-crosslinking were employed.
To further study the efficiency of the drug delivery system, polymer/heparincomplexes have been made and showed enhanced cell uptake ability with theincreasing positive block part. The cytotoxicity assay showed the polymer/heparincomplexes presented little effect on cell viability. In-vitro studies revealed thepromising results of those polymer/heparin complex to be used as drugdelivey systemfor lymphoma treatment.
本论文拟利用可逆断裂-链转移聚合技术(RAFT)得到对药物阿苯哒唑(ABZ)和肝素(HP)进行传递的聚合物药物载体。为了实现体内药物的高效传递，利用RAFT聚合技术合成一系列基于两亲性嵌段共聚物的聚合物胶束体系。对于ABZ的传输，设计两个药物载体体系。第一，聚(乙二醇)甲基醚甲基丙烯酸酯被选作亲水性单体在水溶液中形成外壳，对硝基苯酚丙烯酸酯链段作为疏水链段形成内核，通过化学反应的交联作用，形成一种全核交联的核交联胶束。第二，将RAFT聚合技术与开环技术相结合，得到以聚己内酯作为疏水性片断的嵌段间面交联胶束。药物包载实验结果证明，聚己内酯形成的自组装胶束对于ABZ有良好的药物包载性能。
利用RAFT聚合方法合成含有(2-(甲基丙烯酰氧基)乙基)三甲基氯化铵的嵌段聚合物，其中(2-(甲基丙烯酰氧基)乙基)三甲基氯化铵片段呈正电性，可通过离子键直接与负电性肝素结合。细胞毒理实验证明，聚合物/肝素复合物无细胞毒性，随着聚合物中正电荷性的增强，细胞吸收能力也会随之提高。聚合物/肝素复合物能够有效抑制纤维素瘤的细胞增殖。
“Core-Shell” micelle as drug/gene delivery systems have gained more and moreattention in research area. With crosslinking method, it is easy to overcome theshortcoming of the self-assembled micelles and get stable cross-linked micelles. Theaim of this thesis is to investigate the applicability of polymeric nano-particlessynthesized via reversible addition fragmentation chain transfer (RAFT)polymerization that can be used for the drug delivery of albendazole (ABZ) andHeparin(HP).
To achieve this aim, a wide range of polymeric micelle systems based onamphiphilic block copolymers has been synthesized and investigated. Thebiocompatible poly(ethylene glycol) methyl ether methacrylate was chosen to formthe hydrophilic block. Based on the crosslinking techniques, p-nitrophenyl acrylatewas chosen to build the hydropobic block and the functional part. Poly(-caprolactone) was chosen to build another hydrophobic block as it demonstrated toachieve the highest compatibility with the ABZ. To stabilize the structure of micelles,nexus-crosslinking were employed.
To further study the efficiency of the drug delivery system, polymer/heparincomplexes have been made and showed enhanced cell uptake ability with theincreasing positive block part. The cytotoxicity assay showed the polymer/heparincomplexes presented little effect on cell viability. In-vitro studies revealed thepromising results of those polymer/heparin complex to be used as drugdelivey systemfor lymphoma treatment.
引文
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