【作者】 陈伟东；

【导师】 计剑；

【作者基本信息】 浙江大学 ， 材料学， 2005， 硕士

【摘要】 目前,临床上对于癌症的治疗普遍采用化学疗法,即大剂量的抗肿瘤药物的应用,抗肿瘤药物对于肿瘤有着极强的细胞毒性,然而由于这些小分子抗癌药物能够自由而快速地穿过细胞膜,渗透分散于全身各处,在有效杀伤肿瘤细胞的同时也会大量破坏正常的组织细胞。为了提高药物的靶向性和降低药物的毒性,聚合物胶束作为药物载体引起了人们广泛的兴趣,聚合物胶束载药范围广、结构稳定、具有优良的组织渗透性、体内滞留时间长,能使药物有效地到达靶点,而且粒径较小,不超过100nm,具有纳米材料的特性,是一种很有潜力的药物载体。本文从细胞膜仿生角度出发,研究设计了一种由细胞膜重要成分磷酸胆碱、胆固醇分子组成的两亲聚合物Chol-b-pMPC,该聚合物有着高度的亲水性和生物相容性,在水溶液中可自发形成仿细胞膜的核壳胶束结构,并以此作为药物储存释放的载体。本文采用原子转移自由基活性聚合(ATRP)的方法,制备了两亲聚合物Chol-b-pMPC分子,利用其在水溶液中自发形成胶束的性质,制备了空白胶束,通过H-NMR和芘荧光光度计法证实了水溶液中仿细胞膜胶束核壳结构的形成,其外层是磷酸胆碱亲水性外壳,内层由疏水性胆固醇组成,并由AFM和TEM测得空白胶束的粒径在16nm左右。本文以抗癌药物ADR为模型药物,采用水包油乳化法制备了聚合物载药胶束,TEM、AFM测定载药胶束的粒径在30-70nm左右,并研究了胶束的载药量及其在体外的药物释放行为,发现CMPC载药胶束缓释效果显著,在体外释放7天之后只有20%左右的ADR释放。通过体外成骨细胞的培养,显示出Chol-b-pMPC分子有着很好的生物相容性,毒性很小。在体外肿瘤细胞的培养实验中,自由ADR在短时间内即表现出极强的药效,毒性很大;而CMPC-ADR载药胶束在初期对细胞毒性很小,随着负载药物的缓慢释药而逐步杀死细胞,在8天之后达到了相同浓度自由ADR的药效。更多还原

【Abstract】 Current cancer therapy involves chemotherapy to shrink any cancer by using anticancer drugs. Unfortunately, these drugs lack specificity to cancer cells and hence lead to severe side effects. In order to improve the specific delivery of drugs with low cytotoxicity, polymeric micelles have been the object of growing attention. This paper designs a new biomimic amphiphilic copolymer as durg delivery systems.Novel amphiphilic copolymers Chol-b-pMPC was synthesized via atom transfer radical polymerization (ATRP). The association behavior of Chol-b-pMPC in aqueous solution was studied by ~1H-NMR, fluorescence probe technique and atom force microscope (AFM).A commercial obtained polymeric amphiphiles, Chol-b-PEO which had a similar structure with Chol-b-pMPC, was used as a control in the cytotoxicity test. The results showed that Chol-b-PEO has obvious cytotoxicity while Chol-b-pMPC has good biocompatibility by osteoblast cell culture.Anti-cancer drug adriamycin (ADR) was chosen as a hydrophobic drug to be incorporated into the inner core of the micelles by the oil-in-water method, In vitro release experiments showed that the drug loading micelles present a sustained release behavior without any burst effect while free ADR release very quickly.The K562 tumor cell was chosen as the model to investigate the anti-cancer activity of the ADR-loaded micelles. The MTT assay showed that these drug-loaded micelles (CMPC-ADR) have the sustained release behavior. By loaded in polymeric micelles, ADR show less cytotoxicity than unloaded ADR at begin, and after 7 days culture the killing effect reach the same effect as unloaded ADR.These experimental results suggested that the micelles prepared from CMPC block copolymers could be a good candidate for anti-cancer drug delivery carrier.更多还原