GSH/pH响应型星形聚合物前药的设计、构建及靶向抗肿瘤研究

Cancer is the biggest threat to human health. The ideal therapeutic strategy for cancer therapy in not to improve the therapeutic efficacy but to avoid the strong drug side effects. Nanotechnology-based drug controlled release system shows unique superiorities during the treatment of cancer, when compared to traditional medical techniques. Meanwhile, high efficient and safe drug controlled release system is essential to the therapeutic efficacy. Based on the applicant’s research experience in the synthesis of linear and star-like block polymer, we propose to prepare a kind of drug controlled release system based on glutathione/pH star-like polymeric prodrugs. A systematic investigation will be conducted by exploring the underlying mechanism and inherent relationship of drug loading, targeted delivery, controllable drug release and micellar stability with the preparation condition of polymeric prodrug. Several star-like polymeric prodrugs will be prepared and evaluated via structure and property characterizations, in vitro and in vivo assays of their therapeutic effect. We believe this study has important scientific significance and broad application prospects, and its success can elucidate the theoretical basis of the construction of stimuli-responsive star-like polymeric prodrugs, develop a new strategy for preparing star-like polymeric prodrugs with high drug loading and strong micellar stability, and thus promote the applications of other biological stimuli-responsive drug controlled release system for cancer therapy.

癌症是威胁人类健康的头号疾病，理想的治疗策略不仅要提高治疗效果，还要避免毒副作用。纳米药物控释系统在癌症的靶向治疗中表现出了超越传统医疗手段的独特优势，而安全、高效的药物控释系统是影响其最终治疗效果的关键。本项目结合申请人在线形和星形嵌段聚合物合成方面的研究基础，拟构建一类基于GSH/pH响应型星形聚合物前药的控释系统，通过研究星形聚合物前药制备条件与载药率、靶向性、释放可控性和胶束稳定性等之间的关系，揭示星形聚合物前药的相关科学问题，进一步通过体外和体内生物实验评估控释体系的靶向抗肿瘤性能，阐明星形聚合物前药在靶向抗肿瘤过程中的效应与作用机制。该项目不仅可为刺激响应型星形聚合物前药的构建提供理论基础，发展一种合成兼具高载药量和高稳定性的星形聚合物前药的新策略，而且为研究其它刺激响应型聚合物前药控释系统提供借鉴性思路，具有重要的科学价值和实际应用前景。

肿瘤治疗是当今医学研究领域的热点与难点。纳米药物控释系统可结合纳米材料和小药物分子的双重优势，在改变药代动力学模式，降低非靶向毒副作用以及提高肿瘤治疗效果等方面表现突出，但面临抗肿瘤活性低、血液循环稳定性差及不易产业化等局限。本项目围绕“如何兼顾高载药率与高胶束稳定性”和“如何降低治疗过程中毒副作用”两个关键科学问题，通过整合线形聚合物前药高载药率和非线形聚合物高胶束稳定性的优势，构建一系列肿瘤微环境响应性（例如：pH响应、还原响应和ROS响应等）的非线形聚合物前药，系统研究所得聚合物药物递送系统的结构、性质与抗肿瘤性能之间的联系与机制，取得了以下研究成果：创新性以环糊精、葡聚糖等多糖为基础，设计并合成了一系列非线形聚合物前药，用于多种化疗药物（例如阿霉素、喜树碱、伊立替康等）的选择性递送与可控释放，实现肿瘤的增强型化疗；此外，通过引入光疗和声动力试剂，深入研究了基于非线形聚合物前药的化疗与光疗、化疗与声动力等联合治疗模式，为肿瘤治疗提供新的策略。为了更好地实现项目目标，我们还研究了集高灵敏诊断、与选择性释放等优点于一体的分子前药和聚合物纳米凝胶递送系统，为肿瘤的高灵敏诊疗和肿瘤免疫应答率的提高提供了新载体策略，并取得了一些有意义的研究成果。在项目完成期间，在国内和国际专业SCI期刊上发表学术论文23篇，相关成果授权国家发明专利6项，撰写书章节1次，培养硕士研究生7名，目前在读硕士研究生9名，参加国内学术会议10余人次，圆满完成项目目标。