用于调控肿瘤微环境的光热/分子靶向型胶束的构建及其与免疫检查点抗体协同增效的研究

纳米药物载体在肿瘤部位的蓄积和渗透，以及T细胞的浸润是纳米肿瘤学及其联合免疫治疗的关键科学问题。调控肿瘤微环境来提高纳米药物载体的治疗效果是该领域的新方向。本项目拟合成生物相容、可降解的聚乙二醇-b-聚炔丙基甘氨酸-b-聚半胱氨酸三嵌段聚合物，在侧链偶连近红外二区光敏剂Flav和引入哌啶氮氧自由基化合物，与TOPK酶抑制剂OTS964通过自组装和表面修饰靶分子来构建出具有靶向性的高分子胶束。该高分子胶束可以响应一氧化氮合酶（NOS）在肿瘤定点释放一氧化氮（NO）来调控肿瘤微环境和改善肿瘤血管，来促进纳米药物的蓄积和渗透作用，从而增强纳米药物载体对肿瘤的靶向和疗效，并提高T淋巴细胞的浸润来增强联合免疫检查点抗体的免疫治疗效果，实现对乳腺癌及其肺转移的分子靶向化疗、光热治疗和免疫治疗的高效、协同治疗作用。

The accumulation and penetration of nanocarriers, as well as the infiltration of T cells into tumors are critically important for nano-oncology and combined immunotherapy. Modulating tumor microenvironment to improve the therapeutic efficacy is regarded as a new promising direction. This project proposes to synthesis biocompatible and biodegradable PEGx-P(propargylglycine) y-P(Cys)z block copolymers, and then conjugates the NIR-II dye Flav and nitroxide radical groups to the side chain of polymers, to self-assembly with TOPK enzyme inhibitor OTS964 for preparing tumor-targeting polymeric micelles by installing ligands on the surface. The polymeric micelles could release nitric oxide (NO) when responding to NO synthase (NOS) to modulating the tumor microenvironment and normalize tumor vasculatures, which could increase the accumulation and penetration of polymeric micelles for improved targeting and therapeutic effects. Meanwhile, it also could promote the infiltration of T cells for better immunotherapeutic effects with immune checkpoint antibody. All of those could be combined for treating breast cancer and its lung metastasis by the synergistic effects of molecularly targeted chemotherapy, photothermal therapy and immunotherapy.