功能化BODIPY共轭聚合物纳米粒的构建及在肿瘤协同治疗中的应用

How to achieve efficient and targeted therapy is a compelling problem in cancer therapy. The construction of nanodrugs with synergistic anticancer efficacy is regarded as a most attractive research field. In this proposal, we intend to synthesize BODIPY conjugated polymers with photodynamic/photothermal activities as a novel drug delivery vehicle. And then cisplatin precursors are crosslinked with carboxylic groups in the side-chain of BODIPY conjugated polymers. Finally, they were self-assembled into nanoparticles with chemotherapy/photodynamic/photothermal synergistic effect. The physicochemical properties of nanoparticles are optimized to achieve effective cancer targeting effect and enhance cellular uptake. Under near infrared light irradiation, BODIPY conjugated polymer nanoparticles directly produce abundant intracellular ROS and hyperthermia. Meanwhile, cisplatin drugs are released by ligand exchange with Cl ions in the tumor cells. The intracellular ROS produced by BODIPY conjugated polymer nanoparticles can induce the disruption of lysosomal membrane, and thus trigger cytoplasmic transport of cisplatin. In addition, the hyperthermia can inhibit the expression of drug-resistant proteins in tumor cells, thereby reducing the efflux of cisplatin and enhancing its chemotherapeutic efficacy. This leads to realize chemotherapy/photodynamic/photothermal synergistic therapy. This project is highly valuable in the field of exploring antitumor nanodrugs with high efficiency and low toxicity, as well as developing synergistic therapy strategies.

如何实现高效精准治疗是肿瘤治疗领域的难点。构建具有肿瘤协同治疗效应的纳米药物是该领域的新研究方向。本项目拟合成具有光动力/光热活性的BODIPY共轭聚合物作为药物载体，利用其侧链的羧酸基团与顺铂前体化合物发生交联，自组装构建出具有化疗/光动力/光热协同治疗效应的纳米药物。通过调节纳米粒的理化性质，增强其肿瘤靶向和细胞摄取。在近红外光激发下，BODIPY共轭聚合物纳米粒产生ROS和光热效应。同时，纳米粒中顺铂前药与肿瘤细胞内氯离子发生配体交换反应释放出顺铂药物。通过BODIPY共轭聚合物纳米粒产生的胞内ROS破坏溶酶体膜，促进顺铂的胞浆转运。此外，利用光热效应有效抑制肿瘤细胞中耐药蛋白的表达，从而降低顺铂的外排，增强其化疗效果。最终实现化疗/光动力/光热协同治疗作用。本项目对探索高效、低毒的抗肿瘤纳米药物以及发展新的协同治疗策略具有重要的理论意义和实用价值。

如何进行肿瘤精确治疗是当前肿瘤治疗领域的关键问题。光治疗因其创伤小、治疗周期短、毒副作用小、选择性好和无抗药性等优势，在肿瘤精准治疗领域备受关注。然而目前临床可用的光敏药物非常有限，且光稳定性差，光转换效率低，严重限制了光治疗在临床上的使用。本项目着重围绕近红外光敏剂的设计、调控和输送而展开，并考察了其在肿瘤光治疗方面的潜力。代表性的研究成果主要包括以下方面：（１）采用聚合物载体构建有序聚集的光敏纳米胶束，探索近红外光诱导的肿瘤光动力/光热协同治疗。此工作为多功能纳米胶束的构建及肿瘤光动力/光热协同治疗奠定了良好的理论基础；（２）利用自聚集策略设计合成一类非重原子修饰的高性能光敏剂，实现了近红外光诱导的光动力/光热协同抑瘤效应。此工作为开发具有临床转化潜力的高性能光敏剂奠定了良好的前期基础。（３）利用多碘化策略优化光敏纳米胶束的单线态氧量子产率和光热转换效率，有效调控光动力/光热协同治疗效应。同时，利用光治疗效应重塑M2型肿瘤相关巨噬细胞为M1型细胞，改变肿瘤免疫微环境，最终实现了三阴性乳腺癌高效治疗。此工作对于发展光诱导肿瘤免疫治疗具有重要意义；上述研究工作已发表于Adv. Mater.、Adv. Healthc. Mater.、J. Mater. Chem. B等学术期刊，并申请国家发明专利5项（已有２项获授权）。