用于肿瘤协同治疗的近红外光响应性硅纳米粒的研究

It is a major challenge to achieve highly efficient efficacy for cancer treatment. The nanoparticles with synergistic therapeutic efficacy are considered as a new promising focus in this field. In this proposal, Cypate modified with an alkynyl group is used to conjugate doxorubicin (DOX) modified with a diselenide-containing linker ending with a azide group and silane with an amino group. The obtained conjugate is then used to prepare mesoporous silica nanoparticles (MSNP) loaded with Cypate and DOX, finally resulting in near-infrared (NIR) light-responsive silica nanoparticles for cancer thermo-chemotherapy. Under excitation of NIR (785 nm), the Cypate/DOX-loaded MSNP in the targeted cells can produce heat for hyperthermia therapy and reactive oxygen species (ROS) for inducing DOX release by breaking the diselenide bond. Furthermore, the produced ROS can disrupt the lysosomal membrane to accelerate the transport of DOX into the cytoplasm, resulting in enhanced chemotherapy. Therefore, the Cypate/DOX-loaded silica nanoparticles can achieve NIR-responsive synergistic photothermal-chemotherapy of cancer. This work is highly valuable to explore efficient anticancer nanoparticles for synergistic strategy of cancer therapy.

肿瘤的高效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载体是该领域的新方向。本项目将Cypate与氨基硅烷化学偶联，并通过氧化敏感的双硒键与阿霉素连接，合成Cypate与阿霉素的硅烷偶联物，然后制备载Cypate和阿霉素的硅纳米粒，构建出可用于肿瘤化疗与光热协同治疗的近红外光响应性硅纳米药物载体。在近红外光激发下，靶细胞内硅纳米粒通过Cypate产生光热效应和活性氧自由基 (ROS)：一方面光热效应可诱导肿瘤细胞急性坏死，产生光热治疗作用；另一方面，ROS可以迅速诱导连接阿霉素的双硒键氧化断裂而响应释放药物，ROS可同时诱导溶酶体膜破裂，促进阿霉素胞浆转运，增强其化疗作用。硅纳米粒在近红外光诱导下产生化疗与光热治疗协同作用，实现高效的肿瘤治疗。本项目对探索新型高效抗肿瘤纳米药物以及协同治疗策略具有重要理论意义和实用价值。

近年来，纳米药物载体在肿瘤联合治疗中的应用受到关注，通过多种药物的共传输可以有效提高肿瘤的治疗作用。探索高效、低毒的纳米药物，实现肿瘤多模式协同治疗，对提高肿瘤疗效具有重要意义。本课题构建了具有近红外光响应性快速释药、可用于肿瘤化疗或分子靶向治疗与光热协同治疗的纳米粒，研究了其协同治疗机制和体内外抑瘤效果。主要研究成果包括：1）通过光照产生的光热效应降低药物与载体间π-π相互作用而促进药物释放，阐明了光响应性释药诱导的热化疗协同增效机制；2）通过光照产生单线态氧诱导胶束解离而促进药物快速释放，实现了药物高效胞浆转运和细胞核分布，阐明了光响应性快速释药诱导的肿瘤协同治疗机制；3）提出了热疗分子靶向双向协同肿瘤治疗机制，有效提升肿瘤协同治疗效果。在本项目的资助下，课题负责人作为第一或共同第一在Small、Adv Funct Mater、ACS Nano等高水平国际期刊发表SCI论文4篇，获授权专利2项，培养硕士研究生4名。