主客体组装构建肿瘤光热与免疫协同治疗纳米制剂

Tumor photothermal therapy has a significant effect on superficial tumors, while causes tumor-specific immune response and releases related antigens. This is beneficial to combine with immunotherapy to enhance anti-tumor synergy and improve prognosis. In this funding proposal, we intend to construct multifunctional nanotherapeutics via a simple host-guest assembly strategy. By this way, various therapeutic agents in different domains of the assemblies can be loaded effectively, transported efficiently and released controllably. Firstly, mannose-targeting decorated β-cyclodextrin and double-alkyl chain modified adamantane will be synthesized to construct tumor acidic microenvironment responsive nanosystems based on host-guest self-assembly. Then we employ the nanosystems to efficiently encapsulate indocyanine green with near-infrared fluorescence absorption and photothermal effect for tumor imaging and photothermal therapy. Meanwhile, CpG oligodeoxynucleotide as the vaccine adjuvant can also be loaded and delivered together with the model antigen ovalbumin to specifically stimulate the immune response at the tumor site and improve the vaccine effect. Finally the synergistic effect of photothermal therapy and immunotherapy can be achieved. Furthermore, we attempt to explore the characteristics of the nanotherapeutics to clarify the structure-function relationship between the chemical compositions and multistage assembly, to adjust the multi-site loading and control the release behavior of the therapeutic agents. This paradigm involved with the host-guest interactions represents one promising nanoplatform as a versatile strategy for synergistic tumor therapy.

肿瘤光热治疗对浅表肿瘤效果显著，同时会引起肿瘤特异性免疫反应并释放相关抗原，在此基础上结合免疫治疗能够实现协同增效并改善预后。本项目拟通过简单易行的主客体组装构建多功能纳米制剂，实现各组分在组装体不同区域的有效负载、高效运输及可控释放。首先制备甘露糖靶向的氨基修饰β-环糊精与双链烷基化金刚烷，通过主客体组装构建肿瘤微酸性响应的纳米体系；然后利用该纳米体系高效包载吲哚菁绿实现肿瘤成像与光热治疗，同时负载CpG作为疫苗佐剂，并与模型抗原卵清蛋白共同输送，靶向性地刺激肿瘤部位的免疫应答，提高肿瘤疫苗的有效性，最终达到光热与免疫协同治疗的目的；进一步挖掘该纳米制剂的特性，研究其化学构成与更高层次组装行为，明确不同区域负载和控制释放之间的关系，有望构筑主客体纳米载体系统在肿瘤协同治疗领域较为通用的策略。

肿瘤光热治疗对浅表肿瘤效果显著，同时会引起肿瘤特异性免疫反应并释放相关抗原，在此基础上结合免疫治疗能够实现协同增效并改善预后。本项目通过简单易行的组装模式构建肿瘤免疫协同治疗纳米制剂，实现各组分在组装体不同区域的有效负载、高效运输及可控释放。通过多种手段调节肿瘤免疫抑制微环境，包括肿瘤相关巨噬细胞，肿瘤相关脂代谢，肿瘤相关铁死亡等，最终实现肿瘤免疫治疗的协同增效。（1）制备主客体纳米系统高效包载吲哚菁绿实现肿瘤成像与光热治疗，同时负载CpG作为疫苗佐剂，并与模型抗原卵清蛋白共同输送，靶向性地刺激肿瘤部位的免疫应答，提高肿瘤疫苗的有效性，最终达到光热与免疫协同治疗的目的；（2）主客体纳米系统通过共载R848免疫佐剂和CD47siRNA调控肿瘤相关巨噬细胞，使其从促进肿瘤生长的M2亚型极化为抑制肿瘤生长的M1亚型，CD47siRNA则能下调癌细胞的“Don’t eat me”信号，增强巨噬细胞对癌细胞的吞噬作用。通过对巨噬细胞的双重调控作用，改善肿瘤微环境，实现高效抗肿瘤免疫治疗；（3）主客体纳米系统通过共载IDO1抑制剂NLG919和MGLLsiRNA，实现对肿瘤免疫抑制微环境的调控，MGLLsiRNA则能引起肿瘤脂代谢相关2-AG的上调，促进CD8+T细胞的迁移从而协同作用增强肿瘤免疫治疗；（4）构建金属-多酚配位的纳米药物组装体，实现对模型蛋白OVA和铁死亡抑制剂BSO的共同负载，通过近红外光照产生光热治疗效果，BSO进一步下调GSH并抑制GPX4，实现铁死亡介导的肿瘤免疫级联反应。挖掘自组装纳米制剂的特性，研究其化学构成与更高层次组装行为，明确不同区域负载和控制释放之间的关系，有望构筑自组装纳米载体系统在肿瘤协同治疗领域较为通用的策略。