主链含铂、花菁高分子纳米颗粒用于多模式成像指导下多模式协同治疗的研究

The polymeric nanocarriers mediated co-delivery of chemotherapeutic drug and imaging agent were limited by complicated synthesis procedure, low drug/imaging agent loading capacity, uncontrollable release fasion, and inconsistant pharmacokinetics. So it is vitally important to develop new polymeric nanotheranostic agents for simultaneous high loading capacity and controllable release of both drugs and imaging agents. Anticancer prodrug, platinum(Ⅳ) complex, are creatively incorporated into the hydrophobic backbone of amphiphilic copolymer as reduction-sensitive segment and CT contrast agent. At the same time, cyanines are used as NIR fluorescent agent, photoacoustic agent, photothermal agent, photodynamic agent, and are repeatedly arranged in the backbone with platinum(Ⅳ) complex . When the formed nanoparticles were internalized by tumor cells, NIR fluorescent, PA and CT imaging could be used to precisely detect tumor site. After NIR light irradiation, cyanines would generate cytotoxic reactive oxygen species(ROS) and photothermal effects for enhanced cancer cell killing effect, and simultaneously platinum(Ⅱ) anticancer drugs were released under the reductive microenvironment of endosomes/lysosomes, which would result in the fast degradation of the polymeric backbone. Then the synergistic effect of cisplatin and cyanines could be fully realized, resulting in enhanced antitumor efficacy and even reversing cisplatin resistance. Taking advantage of high loading capacity, controllable and consistant release behavior of both drugs and imaging agents, the multimodal imaging guided combination therapy efficacy and synergy mechanisms were in-depth and systematically investigated. The project provides significant theoretical guidance and experimental basis for the design of high-level polymeric nanocarrier system mediated co-delivery of drugs and imaging agents for cancer theranostics.

高分子药物和成像剂纳米共输送受到合成繁琐、药物/成像剂担载量低、释放不可控、药代动力学不同步等问题限制。开发新型高分子纳米诊疗剂同时实现药物和成像剂高效担载和可控释放具有至关重要的意义。本项目创新性的将四价铂药作为还原响应组分和CT造影剂引入到高分子疏水主链；同时，兼具近红外成像、光声成像、光热、光动力治疗等功能的花菁和四价铂药交替排布在高分子主链。该纳米颗粒内吞入癌细胞，近红外、光声、CT等成像技术可用于肿瘤精确定位。近红外光控下，花菁产生活性氧簇和光热效应有效杀伤癌细胞；同时，在内涵体/溶酶体中还原为抗癌活性二价铂药，聚合物主链结构崩解；充分发挥顺铂和花菁协同增效作用，甚至逆转顺铂耐药性。利用该体系药物和成像剂同时高效担载、可控且同步释放行为的优势，系统、深入研究其多模式成像指导下联合治疗效果与协同作用机制，为更高水平高分子化疗和成像剂纳米共输送体系的设计提供理论指导和试验依据。

一体化的高分子纳米诊疗剂的应用受到合成繁琐、药物/成像剂担载量低、释放不可控、药代动力学不同步、诊疗效果不理想等问题限制，开发新型的高分子纳米药物递送系统实现更高效、安全的癌症诊疗将产生巨大的社会和经济效益。本项目针对药物担载量低、精准诊疗、顺铂耐药性等问题，设计了结合有四价化铂药、化疗联合光学治疗以及高分子纳米控制释放系统的多功能高分子纳米诊疗剂。本项目创新性的将四价化铂药作为还原响应性组分和CT造影剂引入到高分子疏水主链上；同时，兼具近红外荧光成像、光热成像、光声成像、光热治疗、光动力治疗等功能的花菁也作为聚合单体和四价化铂药共同聚合，形成了既是载体又是前药的两亲性高分子，进而自组装形成纳米颗粒。该纳米颗粒内吞入癌细胞，近红外荧光成像、光热成像、光声成像、CT成像等成像技术可用于肿瘤精确定位。近红外光控下，花菁产生活性氧簇和光热效应能够有效杀伤癌细胞；同时，在内涵体/溶酶体中还原为具有抗癌活性的二价铂药，造成聚合物主链结构崩解；充分发挥顺铂和花菁协同增效作用，甚至逆转顺铂耐药性。项目取得的结果包括：（1）制备了三种高载药量的四价化铂药和花菁共输送的一体化高分子前药纳米药物体系；（2）从体外和动物水平上系统评价了三个体系的近红外荧光成像、光热成像、光声成像、CT成像效果，实现肿瘤的精准诊断，进而指导肿瘤的治疗；（3）在细胞和动物水平上探索了化疗联合光学治疗的效果，在逆转顺铂耐药性方面也取得了一些结果。本项目的研究使我们对药物作为聚合单体构建聚合型高分子前药有了较为全面的认识，为更高水平一体化高分子纳米诊疗剂的设计提供理论指导和实验依据。