基于肿瘤微环境原位自组装多肽纳米纤维的化疗联合免疫治疗研究

With the increasingly sophisticated development of biology and medical science, there is mounting evidence to support that the appropriate combination of chemotherapy and immunotherapy can achieve synergetic antitumor effect to eradicate tumor, inhibit metastasis and prevent recurrence, and the synergism is closely related to the tumor microenvironment. However, it is still a great challenge to fabricate the chemo-immunotherapeutic drug codelivery system with consideration on the properties of tumor microenvironment which can target tumor and immune cells respectively and then realize the real synergistic effect. Therefore, in this project, we take advantage of precise targeting drug system to design a novel peptide-based delivery platform which can in-situ self-assemble to nanofiber in tumor microenvironment and release drugs spatiotemporally for chemo-immunotherapy. The targeting effect of formyl peptide receptor agonist W peptide in the formulation will promote the accumulation of drugs in tumor microenvironment. The immunotherapeutic drug will be first released under enzyme-responsive tumor microenvironment to activate antitumor immune response. At the same time, the enzyme cleaved peptide with cisplatin and adjudin conjugation will self-assemble to nanofiber with the assembly-induced retention effect, which can promote the drug retention and uptake by tumor cells. Subsequently, the conjugated drugs are able to be dissociated under intracellular reductive and pH-responsive environment to develop their synergistic antitumor and multidrug resistance inhibition effects. The drug delivery platform will realize the effective tumor killing through combination chemo-immunotherapy with the properties of precise targeting, in-situ self-assembly and spatiotemporal drug release in tumor microenvironment. It may provide a novel strategy for cancer treatment and complete tumor removal.

化疗联合免疫治疗有望在肿瘤清除、抑制转移和预防复发方面发挥理想效果，但其协同抗肿瘤作用与肿瘤微环境息息相关。然而，如何针对肿瘤微环境特性而构建免疫和化疗药物共输送载体，分别靶向免疫和肿瘤细胞，实现真正意义上的协同增效仍面临极大挑战。本项目拟构建具有精确靶向递送特性、联合化疗免疫的肿瘤原位自组装药物多肽载体体系，利用甲酰肽受体激动剂多肽靶向肿瘤，并在肿瘤酶敏感环境下首先释放免疫药物，作用于肿瘤微环境中的免疫细胞；继而发生超分子自组装成纳米纤维产生聚集诱导停留效应，实现药物在肿瘤局部的富集和肿瘤细胞的高效摄取；载药纳米纤维进入肿瘤细胞后进一步通过还原和pH敏感特性释放化疗药物顺铂、抑制耐药和协同抗肿瘤作用的药物阿杜丁。相关研究将探索肿瘤微环境精确靶向性、肿瘤原位自组装特性、免疫和化疗药物逐级释放特性、化疗联合免疫途径全方位杀伤肿瘤的可行性和协同作用机制，为治疗甚至根除肿瘤提供创新性的研究思路。

三阴性乳腺癌是一种转移风险极高和预后极差的乳腺癌，免疫组化结果显示其雌激素受体（Estrogen Receptor, ER）、孕激素受体（Progesterone Receptor, PR）和人表皮生长因子受体-2（Humor Epidermal Growth Factor Receptor 2, Her-2）均为阴性。因此，目前还没有特定的标准治疗指南，其仍然按照常规的乳腺癌进行治疗，且主要以化疗为主。因此，本项目报道了一种以诱导凋亡和促进免疫原性细胞死亡反应为前提的三阴性乳腺癌协同免疫疗法，该疗法利用顺铂、阿杜丁和WKYMVm构建了一种结构可转变的纳米颗粒。该纳米颗粒可对基质金属蛋白酶-2、pH值和谷胱甘肽响应，实现结构转化，具有最佳尺寸变化、高效给药和可控释放等优点。顺铂和阿杜丁可协同放大活性氧(ROS)级联反应，最终增加过氧化氢和下游高毒性ROS•OH的形成，通过内质网应激、凋亡细胞死亡和自噬等机制引发免疫原性细胞死亡。WKYMVm通过激活甲酰肽受体1，在树突状细胞与濒死癌细胞之间建立稳定的相互作用，进一步促进抗三阴性乳腺癌免疫。因此，纳米颗粒实现了显著的原发肿瘤消退和肺转移抑制，以及显著的生存益处，增强了先天和适应性抗三阴性乳腺癌免疫。.总之，我们提出了一种可转化的纳米颗粒激活方法，协同诱导和促进ICD，最终实现有效的抗肿瘤和抗转移治疗TNBC。这一策略激发了强烈的肿瘤特异性免疫应答，其特征是在肿瘤中招募免疫效应细胞，并调节与肿瘤生长和转移相关的免疫抑制微环境。该策略可通过疫苗接种、局部治疗或全身给药等方式应用于临床实践，并可与PD-L1抑制剂等免疫检查点抑制剂治疗方法结合，也可应用于其他癌症的治疗。相关研究为探索结合原位自组装效应构筑肿瘤免疫联合药物递送系统提供了良好的理论依据与实践基础，研究成果已相继在国际学术期刊Advanced Functional Materials、Biomaterials和Nanoscale等发表该基金资助文章，并多次参加国际国内学术会议做口头报告。