近红外光吸收与刺激响应性高分子前药的纳米医学体系及其化疗或鸡尾酒疗法—光热治疗的联合治疗新模式

Complex physiological microenvironment in tumor tissue and multidrug resistance are the bottleneck points that hinder the antitumor efficacy of chemotherapy drugs, thus developing the combination treatment based on synergistic effect provides a novel and practicable tool for enhancing the chemotherapeutic efficacy and complete tumor ablation. To integrate chemotherapy of single drug or cocktail chemotherapy of two or three drugs with photothermal therapy in one biocompatible polymeric nanomedicine, this project combines the three concepts of stimuli-responsive polymeric prodrug, nanomedicine, and photothermal therapy, prepares the trifunctional nanoparticles of polydopamine-based prodrugs and the combination prodrugs, develops novel aniticancer combination modalities of polymeric prodrug-based “chemotherapy or cocktail chemotherapy with photothermal therapy”, which holds great scientific importance and promising application. The main contents include: the design and synthesis of dopamine-based prodrugs with dynamic covalent bonds, their oxidative copolymerizations, and the preparation and characterization of NIR-absorbent and stimuli-responsive (pH, reduction, their dual stimuli-responsive) nanoparticles of the polydopamine-based prodrugs and combination prodrugs; the relationships between the composition structure, size, and surface physicochemical characteristics of these nanoparticles with the photothermal properties, the targeting ability, the drug release properties, and the tumor accumulation and penetration; the antitumor activity, the synergistic effect, and the biological assay of both combination treatments of “chemotherapy or cocktail chemotherapy with photothermal therapy”.

肿瘤组织复杂的生理微环境和多药耐药性是制约化疗药物发挥抗肿瘤功效的瓶颈，因此，基于协同效应原理而发展的联合疗法为增强化疗疗效和根除肿瘤提供了一种切实可行的新途径。为实现化疗或鸡尾酒疗法与光热治疗在同一种生物相容性高分子纳米医学体系的功能集成，本项目把刺激响应性高分子前药、纳米药物与光热治疗三者相结合，制备兼具三重功能的聚多巴类前药及其复合前药的纳米粒子，发展基于聚合物前药的“化疗或鸡尾酒疗法—光热治疗”联用的癌症治疗新模式，具有重要的科学价值与应用前景。研究包括：含动态共价键的多巴类抗癌药前药单体的设计合成、氧化性共聚合、近红外光吸收与刺激响应性（pH、还原、双重响应性）聚多巴类前药及其复合前药的纳米粒子的制备与表征；纳米粒子的组成结构、尺寸、表面物化特性与光热性能、靶向性、药物释放、及其在肿瘤部位的富集和渗透的关系规律；“化疗或鸡尾酒疗法—光热治疗”的抗肿瘤活性、协同效应、生物学评价。

肿瘤组织复杂的生理微环境和多药耐药性是制约化疗药物发挥抗肿瘤功效的瓶颈，因此，基于协同效应原理而发展的联合疗法为增强化疗疗效和根除肿瘤提供了一种切实可行的新途径。为实现化疗或鸡尾酒疗法与光热疗在同种生物相容性高分子纳米医学体系的功能集成，本项目把刺激响应性高分子前药、纳米药物与光热疗三者相结合，设计并构建了兼具三重功能的聚多巴类前药及其复合前药纳米粒子，发展了基于温和光热疗—化疗或鸡尾酒疗法的肿瘤联合治疗新模式，开拓了基于光热疗-一氧化氮气体-化疗的肿瘤三重疗法，不仅克服了常规的高温光热疗及其联合疗法的缺陷及其临床转化难题，而且实现了实体瘤和耐药性实体瘤的无痕消融，为根治多药耐药性实体瘤提供新的思路和方案，具有重要的科学意义和临床转化前景。主要进展与成果包括：设计合成了含有酰腙键的多巴胺-阿霉素前药和含有双硫键的多巴胺-苯丁酸氮芥前药，基于氧化性沉淀聚合和配位化学原理构建了近红外光吸收与刺激响应性（pH、还原、双重响应性）聚多巴类前药及其复合前药纳米粒子，揭示了药物含量与粒子尺寸、形貌、近红外吸收与光热性能的关系；在细胞和动物水平上详细评价了该前药及其复合纳米粒子的胞内响应性药物释放、细胞摄取与亚细胞器内转运、药代动力学与组织分布、多模式成像（荧光、光热、光声）及抗肿瘤的联合疗法，揭示并阐明了温和光热疗-化疗或鸡尾酒疗法、光热疗-一氧化氮气体-化疗三重疗法的协同抗肿瘤效应及其逆转多药耐药性的作用机制；经两次静脉注射聚多巴胺前药复合纳米粒子和两次温和近红外光照，实现了四种大肿瘤裸鼠模型（乳腺癌、耐阿霉素的乳腺癌、卵巢癌、耐顺铂的卵巢癌）中实体瘤与耐药性实体瘤的完全无痕消融，表现出优异的体内抗耐药性肿瘤的疗效和逆转肿瘤多药耐药性的效果。已发表SCI论文17篇，其中IF>5的论文16篇；在Elsevier出版壹英文章节；获授权国家发明专利2项。