逆转肿瘤顺铂耐药的两亲性嵌段配位高分子纳米胶束

The clinical dosage and effectiveness of platinum(II)-based anticancer drugs are limited by their drawbacks of severe side effects and intrinsic or acquired drug resistance. There is correspondingly a clear incentive to develop new strategy for safer and more effective cancer therapy to overcome cisplatin resistance using platinum. A novel amphiphilic block coordinate copolymer micelle system is proposed by uniting platinum (IV) pro-drug, combination chemotherapy and polymeric controlled drug delivery system. This is the first time to combat cisplatin resistance all aimed in once at the multiple cisplatin resistance mechanisms including reduced intracellular drug uptake, enhanced DNA repair and drug deactivation. Two anti-cancer drugs, platinum and demethylcantharidin, are creatively used as monomers for condensation polymerization and introduced to the polymer backbone to prepare the block coordinate copolymer micelle, which is not only a drug carrier but also a polymeric combination chemotherapy system itself. With this block coordinate copolymer micelle design, responsive fast degradation and active drugs release can be achieved under the intracellular reductive and acidic micro-environments of tumour cells, resulting in enhanced efficacy and cisplatin resistance reversal. Taking advantages of specific-simple structure, definitive ratio of each drug, controlled drug exposure, low toxicity of this system, the effectiveness and mechanisms to overcome cisplatin resistance are in-depth studied, providing theoretical guidance and experimental basis for the design of other high-level polymeric combination chemotherapy systems to combat drug resistance.

二价铂药的严重毒副作用及先天和后天肿瘤耐药性极大地限制了其在临床上的剂量效果和化疗效用，开发更安全、高效尤其能够克服肿瘤顺铂耐药性的抗癌新策略将产生巨大的社会和经济效益。本项目首次同时针对肿瘤顺铂耐药的细胞内铂药摄取蓄积减少、增强的DNA修复和解毒等多重耐药机制，设计结合有四价铂前药、联合化疗以及高分子纳米控制释放系统的高分子纳米联合化疗体系。该体系创新性的将铂药和去甲基斑蝥素作为聚合单体参与缩聚反应引入到高分子主链中，形成了既是载体又是高分子联合化疗体系的新型两亲性嵌段配位高分子纳米胶束，在肿瘤细胞微环境刺激下实现响应性胶束主链崩解和活性药物释放，有望提高抗癌效果，甚至逆转肿瘤顺铂耐药性。充分利用该体系结构简单明确、药物间比例确定且释放可控、毒副作用低的优势，深入研究其逆转顺铂耐药性的效果和机理，为更高水平的克服肿瘤顺铂耐药性的高分子纳米联合药物输送体系设计提供理论指导和试验依据。

二价铂类药物的严重毒副作用及先天和后天肿瘤耐药性极大地限制了其在临床上的剂量效果和化疗效用，开发更安全、高效尤其能够克服肿瘤顺铂耐药性的抗癌新策略将产生巨大的社会和经济效益。本项目首次同时针对肿瘤顺铂耐药的细胞内铂药摄取蓄积减少、增强的DNA修复和解毒等多重耐药机制，设计了结合有四价铂前药、联合化疗以及高分子纳米控制释放系统的高分子纳米联合化疗体系。该体系创新性的将铂药和去甲基斑蝥素作为聚合单体参与缩聚反应引入到高分子主链中，形成了既是载体又是高分子联合化疗体系的新型两亲性嵌段配位高分子纳米胶束，在肿瘤细胞特有微环境刺激下响应性的胶束主链崩解和活性药物释放。在具有较高肿瘤异质性和分子多样性的人源化的PDX肺腺癌模型中，此纳米药物表现出很好的抑瘤效果，给药治疗51天后的肿瘤体积仅是生理盐水组的六分之一，顺铂组的二分之一。充分利用该体系结构简单明确、药物间比例确定且释放可控、毒副作用低的优势，我们通过免疫荧光、HE染色、TUNEL染色、定量分析肿瘤细胞内的铂蓄积、Pt-DNA加和物的产生等手段深入地研究了其逆转顺铂耐药性的效果和机理。该纳米药物因铂药作为聚合单体在聚合物的主链上，铂含量可高达10%，我们利用铂的重金属性，通过CT成像直接对药物和胶束的体内分布进行了时间和空间上的有效追踪，实现了诊疗一体化。本项目为更高水平的克服肿瘤顺铂耐药性的高分子纳米联合药物输送体系设计提供理论指导和试验依据。