模块化多功能抗肿瘤纳米载药体系的设计合成

Nanoparticles used as drug delivery system are generally spherieal particles which have the size between 10-500nm in diameter，and consist of different biodegradable materials such as natural or synthetic polymers. The drugs or biological molecules are dissolved，entrapped，encapsulated or attached to the matrix of the polymer. The drug delivery systems have significant advantages over free drugs，such as prolonged circulation in the blood stream，solubilization of hydrophobic drugs and enhanced cellular adhesion. Drug delivery therapeutics could enhance the concentration for enhanced diffusion to the diseased cells and minimize the side effects of drugs.. Polymer micelles，based on amphiphilic block/graft copolymer's self-assembly， have been widely used as antitumor drug carriers. Supramolecular nanocarries formed by host-gust interactions between beta-cyclodextrin and intelligent polymeric guest molecules which can actively respond to external stimuli such as temperature, pH and reductive environment have shown great potentials. . A major goal of this proposal is to construct a kind of multifunctional intelligent drug carriers such as targeting ability, intrcullular rapid release and imaging ability.. Firstly, dextran-b-polycaprolactone, a simple amphiphilic block copolymer, is synthesized by click reaction to investigate the correlation between antitumor effect and the size of polymeric micelles.. Secondly, a smart pH-triggered suparmolecular polymeric micelle is prepared by the host-guest interactions between cyclodextrin linked on dextrin and polymeric guest molecules. At pH of 7.4, drug is loaded in the micelle by suparmolecular self-assembly; while at pH of 6.0, the intracellular environment of tumors, loaded-drug can release out because of suparmolecular disassembly..Lastly, novel kind of modular multifunctional nano delivery systems are constructed using host-guest recognition as the driving force for macromolecular self-assembly, just like a personal computer. Cyclodextrin linked on dextrin acts as main case, while pre-synthesized multifunctional polymers with guest groups act as changeable modules. For different tumor therapeutic applications, different modules are chosen and inserted in the main case to achive a multifunctional delivery system.

本项目以天然多糖葡聚糖替代PEG作为亲水材料，针对抗肿瘤纳米载体靶向性、细胞内智能释放及多功能集成的需求，开展三方面的工作：一，采用高活性click反应合成葡聚糖-b-聚己内酯嵌段共聚物，研究不同粒径及键合不同靶向基团时，载体在体内不同组织及器官的富集情况。二，通过超分子主客体自组装作用得到智能性的基于葡聚糖与聚己内酯的超分子自组装体，中性水溶液中该组装体可自组装为超分子胶束而包载药物；而在pH较低的肿瘤细胞内，超分子胶束会解组装快速释放药物。三，基于对载体多功能化的要求，利用主客体超分子自组装作用，将侧基修饰有β-环糊精的葡聚糖作为骨架，预先合成的连有客体基团的多功能聚合物作为可被选择替换的功能模块，根据治疗需要，选择适合的模块在骨架上插接出多功能载药体系。通过该项目的深入研究，最终得到一类制备方法简单、结构可调控、具有智能性的可组装可拆卸的多功能抗肿瘤药物载体。

目前，肿瘤已经成为威胁人类健康的最大杀手之一，如何最大限度降低药物的毒副作用，提高病人用药舒适度，实现肿瘤治疗疗效最大化是癌症治疗的重点。具有良好生物相容性的粒径10-500纳米的聚合物纳米粒子在作为载体基质材料时显现出较大的优越性。高分子纳米抗癌药物载体也是最有希望应用于临床的纳米载体。包裹或吸附药物的纳米粒子具有增强治疗效果延长药物半衰期的特征，可以达到更好的治疗效果。在化疗过程中，降低化疗药物的毒副作用的同时提高药效是治疗癌症迫切要求。因此，设计在到达肿瘤细胞之前不释放或少释放，在进入达肿瘤细胞之后快速释放的载体十分重要。针对肿瘤细胞不同于人体其它正常细胞组织的特性，设计具有不同环境响应性（pH、温度、氧化还原）的药物载体，可以在肿瘤细胞环境的刺激下短时间内大量释放药物，使肿瘤细胞来不及外排药物，以使细胞内的药物浓度维持较高的水平，达到高效杀死肿瘤细胞的目的。. 本项目以天然多糖葡聚糖替代PEG作为亲水材料，针对抗肿瘤纳米载体靶向性、细胞内智能释放及多功能集成的需求，利用简便的超分子作用构建了模块化多功能抗肿瘤纳米载药体系，主要完成了三方面的工作：. 一，采用高活性click反应合成葡聚糖-b-聚己内酯嵌段共聚物，研究不同粒径及键合不同靶向基团时，载体在体内不同组织及器官的富集情况。二，通过超分子主客体自组装作用得到智能性的基于葡聚糖与聚己内酯的超分子自组装体，中性水溶液中该组装体可自组装为超分子胶束而包载药物；而在pH较低的肿瘤细胞内，超分子胶束会解组装快速释放药物。三，基于对载体多功能化的要求，利用主客体超分子自组装作用，将侧基修饰有β-环糊精的葡聚糖作为骨架，预先合成的连有客体基团的多功能聚合物作为可被选择替换的功能模块，根据治疗需要，选择适合的模块在骨架上插接出多功能载药体系。. 研究结果表明含有5%支化结构的葡聚糖作为亲水链段，更易于功能化；基于环糊精的主客体超分子作用具有酸敏感性，可以实现肿瘤细胞内酸触发释放；同时，将侧基修饰有环糊精主体的葡聚糖作为骨架主板，可将预先合成的带有客体功能团的多功能聚合物作为模块，通过超分子主客体自组装作用，根据不同的肿瘤治疗方案，采用更换模块的方式就可以设计有针对性的治疗。