针对肿瘤细胞周期的时相靶向制剂的研究

项目名称： 针对肿瘤细胞周期的时相靶向制剂的研究

项目编号： No.81503004

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 汤继辉

作者单位： 安徽医科大学

项目金额： 17.9万元

中文摘要： 鉴于很多化疗药物为细胞周期特异性药物，将其高效、靶向导入目标时相的肿瘤细胞是增效减毒的关键。本课题首次提出针对肿瘤细胞周期的时相靶向载体设计思路，该载体以磷脂酰乙醇胺（PE）探针Duramycin为靶向配体修饰PEG化聚乳酸（PEG-PDLLA）, 并与pH敏感的PEG化聚组氨酸（PEG-P(His)）组成混合胶束，构建以肿瘤细胞M时相外化PE及其pH偏酸性的肿瘤组织为标的的细胞周期特异性靶向载体。该载体借助EPR效应聚集于肿瘤组织后，pH敏感的PEG-P(His)胶束发生解聚合，暴露出Dur-PEG-PDLLA，利用Duramycin特异性结合至M期肿瘤细胞膜外化的PE，携带胶束聚集于M期肿瘤细胞而实现化疗药的增效减毒。本项目重点围绕混合胶束形成机制，载药和释药特性，肿瘤细胞周期特异性等展开系统性研究，为研究高效、低毒、肿瘤细胞靶向新型载体及技术提供新思路和新方法。

中文关键词： 药物输送；细胞周期；靶向制剂；纳米胶束

英文摘要： Nowdays, the majority of conventional chemotherapeutic agents are cell-cycle specific, acting preferentially on specific phase of the cell cycle. Deliverying these drugs to the desired phase of the tumor cells has been the key to enhance efficacy and/or reduced toxicity for cell cycle-specific anticancer drugs. However, previous drug delivery system was not designed based on the cell cycle. In this project, the duramycin (was coupled with PEG-PDLLA to form Dur-PEG-PDLLA) was used as a targeting ligand to design a cell cycle-specific drug delivery system. Duramycin was usually as a probe for studying the phosphatidylethanolamine (PE), while that PE localized in the cell’s inner membrane leaflet and exposed on the cell surface of the cleavage furrow during late cytokinesis. At the same time, the pH-responsive polymeric micelles of PEG-P(His) was used with Dur-PEG-PDLLA to form mixed micelles. With this novel drug delivery system, the micelles were gathered in the tumor tissue based on the Enhanced Permeation and Retention effect, then the PEG-P(His) disassembled in the acidic environment and, the Dur-PEG-PDLLA were exposed. Under the binding of duramycin and PE, the miclles gathered in the M phased tumor cell. This project will focus on the study of formation mechanism of the mixed micelles, the characteristics of drug loading, drug release and the cell cycle-specific behavior of this novel drug delivey system. This project will provide a novel method and idea for building highly efficient, low toxicity and cell cycle-specific tumor-targeting drug delivery system. This drug delivery system has great potential for applications in clinical practice.

英文关键词： drug delivery;cell cycle;targeting preparation;nano-micelles