近红外光控多功能稀土上转换纳米药物载体的构筑及免疫化疗研究

Chemotherapy is one of the most effective treatment option in clinic. However, small molecules based chemotherapy resulted in great side effects as well as occurrence of drug resistance. Moreover, immune tolerance is also a key factor that causes the failure of chemotherapy, which brings the immune supersession and its negative feedback regulatory mechanism throughout the development and the treatment of cancer. Blocking this specific negative feedback regulatory mechanism could be an effective way of cancer immune therapy. This project aims to construct 808 nm near infrared light (NIR) responsive core-shell upconversion nanoparticles (UCNPs) loaded with both photosensitive platinum (IV) agents and immunosuppressant IDO agents (NLG919). Upon NIR irradiation, platinum (IV) drugs can be reduced to highly toxic Pt (II) species, which attach the cell nucleus for DNA crosslinking, inhibition of DNA replication and eventual apoptosis; NLG919 which is loaded in the core of UCNP can be triggered to release through the pore of the nanoparticles that can be triggered to be opened via host-guest chemistry. The released NLG9191 can stimulate T cells, which combines with chemotherapy to work in a concerted way for cancer therapy.

化学治疗是目前临床上肿瘤治疗最有效的手段之一，但小分子化疗药物毒副作用大，易产生多药耐药性；此外肿瘤的免疫耐受是导致化疗失败的关键因素,产生的免疫抑制和负反馈调节机制贯穿肿瘤的发展和治疗的全过程，通过阻断该负反馈调节机制被认为是活化肿瘤免疫治疗有效的策略。本项目拟基于核壳结构的稀土上转换纳米复合材料，构筑一类近红外光（808 nm）刺激响应型无机纳米药物载体，同时实现化疗药物（光敏铂前药）及免疫药物（IDO抑制剂-NLG919）的担载。其创新性是在近红外光激发下产生紫外光迅速将光敏铂前药分子还原为高毒性的二价铂分子，直接杀死肿瘤细胞；同时，主-客体分子作用的堵孔分子脱落，介孔二氧化硅孔腔内的NLG919释放出来，促进T细胞免疫应答，联合化学治疗实现肿瘤的免疫化疗，系统研究药物的光靶向可控释放及肿瘤的协同治疗效果。

该项目，以“近红外光控多功能稀土上转换纳米药物载体的构筑及免疫化疗研究”为主题，围绕稀土上转换纳米复合材料的设计制备、功能化修饰、生物医学应用为研究主线，开展相关研究工作。① 构筑稀土基纳米孔结构材料用于高效负载抗原分子或者光敏剂分子等, 探索其作为免疫佐剂，实现了近红外光响应的光动力免疫协同治疗等；② 发展了稀土上转换纳米材料共价负载大配体四价铂前药用于药物靶向传递及双模式生物医学成像研究；③ 构建仿生复杂病毒Fe3O4@Bi2S3的纳米催化剂(F-BS NCs)的策略，通过连接典型的过氧化物酶Fe3O4 (MNPs)和窄带隙半导体Bi2S3 (BS)，依靠有限的瘤内过氧化物和有效的外部光热刺激来提高酶活性。④ 合成了超大介孔二氧化硅均匀包覆的上转换纳米材料（UCS），通过共价连接顺铂前药（DSP）和物理吸附治疗性蛋白RNase A，得到双治疗剂负载的纳米药物（UCSPtR）。项目完成了既定的发表论文、申请专利、参加会议、研究生培养等多项指标：发表SCI论文11篇（完成既定的5-8篇的研究目标），培养毕业研究生8名，其中博士研究生6名，硕士研究生2名。