多重刺激响应型核交联胶束载药系统的构建及靶向抗肿瘤研究

The key to improving the therapeutic effect of tumor chemotherapy is to construct a high efficient, safe and stable targeted drug delivery system. Multiple stimuli-responsive core-crosslinked polymeric micelles, as an intelligent drug delivery system, are of great value in the field of anti-cancer drug delivery. However, at present, it is still difficult for multiple stimulus-responsive micellar carriers to simultaneously achieve stable delivery of drugs in vivo and selectively act on the tumor site and precisely control release as needed. In this project, a series of pH, reactive oxygen species (ROS) and reduction triple stimulus-responsive core-crosslinked micellar carriers are to be constructed via green enzymatic polymerization and photocrosslinking reaction, which exhibits non-toxic degradation, high stability, targeting, tumor microenvironment responsiveness and controlled drug release properties. Paclitaxel will be used as a model drug to systematically study the stability of the core-crosslinked micelles for drug delivery system. The relationship between the molecular structure of the carrier and the nature of the stimuli response will be explored. The influence of multiple stimulus responsiveness on the drug controlled release behavior will also be revealed. Meanwhile, the targeting and anti-tumor mechanisms of drug delivery system in vivo and in vitro will be further clarified. Therefore, this project will provide effective information and means for the precise treatment of cancer.

构建高效、安全、稳定的靶向载药系统是改善肿瘤化疗疗效的关键。多重刺激响应型聚合物胶束作为一种智能化纳米药物载体，在抗癌药物传输领域具有重要的应用价值。然而，目前多重刺激响应型胶束载体还难以同时实现药物在体内稳定输送、选择性地作用于肿瘤部位并按需精确控释的目标。本项目，拟通过绿色的酶促聚合方法和光交联技术，构建一系列具有pH、活性氧簇（ROS）和还原三重刺激响应性的核交联胶束药物载体，其具有无毒可降解、高稳定、靶向、肿瘤微环境响应和可控释放等多种功能特性。以紫杉醇为模型药物，系统研究核交联胶束载药系统的稳定性，探讨载体分子结构与刺激响应性质的关系，揭示多重刺激响应性能对药物控释行为的影响规律，并阐明载药系统在体内外的靶向性和抗肿瘤作用机制，为癌症精准治疗提供有效的信息和手段。

构建安全的载药系统是改善肿瘤化疗效果、降低毒副作用的有效途径，其关键在于发展高效、低毒、稳定、靶向的药物载体。本项目，通过绿色的酶促聚合方法和光交联技术，构建了一系列刺激响应的聚合物药物载体，包括pH和活性氧簇（ROS）响应的超支化脂肪族聚（β-硫醚酯）材料、含酮脂肪族聚酯功能化材料、乙烯基功能化聚（β-硫醚酯）材料以及ROS响应型核交联胶束材料，系统研究了载体材料的物理化学性能，包括热稳定性、降解性等。以阿霉素为模型药物，系统研究核交联胶束载药系统的稳定性，探讨载体分子结构与刺激响应性质的关系，揭示刺激响应性能对药物控释行为的影响规律，为靶向的抗肿瘤药物递送提供有效的信息和手段。