级联放大释放的纳米给药系统及其肿瘤多药耐药研究

Multi-drug resistance of tumors is the main cause to the failure of chemotherapy. This project is aimed to develop a class of nano-drug delivery systems, which is the integration of targeting groups, oligomethylene glycols, multi-drug resistance inhibitors, two synergistic chemotherapeutic drugs and near-infrared fluorescent molecules, for the efficient reversion of tumor multi-drug resistance. Via the self-assembly of the amphiphilic polymers, the nano-drug delivery systems were constructed, showing some specific features, such as active targeting, stimulus respondence and cascade amplification drug release. With the stimulation of reactive oxygen species (ROS) in the tumor cell, the thioketal bond intercalated in Lapa could be cleaved, resulting in Lapa and drugs releasing partially. Then, the released Lapa can boost the ROS levels in tumor cells and further lead more Lapa and drug release. In this interaction process, the P-glycoprotein expression was downregulated simultaneously, enhancing the drug accumulation in tumor. Moreover, near-infrared fluorophore introduced in the nano-drug delivery system could self-report the ROS level in tumor microenvironment via its "off-on" fluorescencent property, thus the emerging fluorescence signal from the fluorophore could be used to evaluate the special effect of Lapa and the drug release efficiency. With the combination of drug/drug/resistance inhibitor co-delivery and cascade amplification drug release property, this project is expected to efficiently reverse tumor multi-drug resistance, advancing the development of novel nano-drug delivery system for tumor therapy.

肿瘤多药耐药是导致化疗失败的主要原因。针对肿瘤多药耐药的复杂性和多样性问题，本项目拟开发一类两亲性聚合物，其中整合了靶向基团、寡聚乙二醇、耐药抑制剂、两种协同化疗药物和近红外荧光分子，通过自组装技术构建刺激响应级联放大释放的“三位一体”纳米给药系统，用于高效逆转肿瘤多药耐药。此纳米给药系统可主动靶向肿瘤细胞，在胞内ROS刺激下，硫缩酮键断裂使部分β-拉帕醌（Lapa）和药物先释放，释放出的Lapa在胞内既可以提升ROS水平，促使Lapa和药物进一步释放，又可下调P-糖蛋白表达，抑制多药耐药，改善治疗效果。纳米给药系统中引入的近红外荧光团，具有ROS响应荧光自报告能力，可监测胞内ROS水平，通过其荧光信号可对Lapa的作用效果及释药情况进行评估。此纳米给药系统结合了药/药/耐药抑制剂协同联用的给药方式和级联放大式地释放优势，有望高效逆转肿瘤多药耐药，为发展新型耐药抑制型纳米给药系统奠定基础。

抑制肿瘤的多药耐药已成为当前恶性肿瘤治疗必须克服的重要难题，具有重大的科学研究意义和社会价值。本项目设计构建了药/药/小分子抑制剂联用的具有肿瘤微环境刺激响应性的级联放大释放纳米给药系统，探究了药/药/小分子抑制剂协同联用逆转肿瘤多药耐药效果，在一定程度上揭示药/药/小分子抑制剂级联放大方式释放与肿瘤多药耐药逆转的内在联系，为高效逆转MDR纳米给药系统的构建奠定基础。通过材料结构的设计优化，赋予了纳米给药系统肿瘤靶向能力、肿瘤微环境特异性级联放大释放能力、刺激响应性荧光自报告能力，揭示了影响该给药系统抗耐药肿瘤效果的因素、规律和作用机制等；提出了可用于耐药肿瘤治疗的智能型多功能纳米给药系统的设计原理、构建技术与方法，获得了具有我国自主知识产权的聚合物纳米给药系统，为具有临床应用价值的抗耐药肿瘤给药系统的研究和应用奠定基础；同时，在国际知名期刊上发表高水平论文3篇，申请中国发明专利1项，合作培养了3名硕、博士研究生。