靶向前药与脂质体杂化体系介导的化疗-免疫治疗与机理研究

Chemo-immunotherapy that combines a chemotherapeutic agent with an immunomodulator is a promising strategy for tumor treatment, which certain development has been obtained in clinic. Nevertheless, spatially targeted delivery of these two active agents is extremely difficult due to their completely different physicochemical properties. Our previous work demonstrated a “synergistic assembly and delivery” phenomenon between a targeted prodrug and liposomes—that the hydrophobic regions in the prodrug insert into the lipid bilayers and, whereas, the hydrophilic regions coat the liposomes, forming a new drug delivery system which is potent for combined treatment. Here, we will design a hybrid nanoplatform assembled from prodrug hyaluronic acid- oridonin and temperature-sensitive liposomes loading a chemokines, CXCL 10, aiming to spatially target the tumor microenvironment (TME) and cancer cells and achieve chemo-immunotherapy. In detail, upon HT treatment, the prodrug and chemokines could be released in the TME and, subsequently, the prodrug targets the CD44 receptors highly expressed on cancer cells and kill the cancer cells while the chemokines in the TME would recruit effective immune cells to kill the drug-resistant cells. The designed platform has marked significance in promoting chemo-immunotherapy, as well as the efficiency of immunotherapy. The design of the work is original, and the base of relevant work for the plane is solid and the primary results indicate its feasibility.

化疗-免疫治疗是一种联用化疗药物与免疫调节剂协同治疗肿瘤的方法，在临床上取得了一定的进展。然而，由于化疗药物与免疫调节剂通常具有完全不同的理化性质，实现二者的空间靶向递送极富挑战性。根据前期发现：靶向前药与纳米载体之间存在“共组装与协同递送”的行为，即前药疏水端能插入脂质体膜内部，而亲水端包被于脂质体的表面，形成新的联合递药体系。本课题拟设计一种基于靶向前药透明质酸-冬凌草甲素与趋化因子CXCL 10-温敏脂质体的杂化系统，从空间上同时靶向肿瘤微环境与肿瘤细胞，实现化疗-免疫治疗：热疗后释放前药与CXCL 10，前药靶向肿瘤细胞的CD44受体，高效杀灭肿瘤细胞，而CXCL 10定位于微环境、招募免疫细胞，最后杀伤非敏感肿瘤细胞。拟开展的工作对于推动化疗-免疫治疗的进一步应用以及免疫治疗效率的提高，均具有重要科学意义。本设计思路新颖，基础扎实，已有工作结果表明本项目的可行性良好。

化疗-免疫联合治疗策略在多种肿瘤治疗中显示出良好的应用前景，但是药物联用对递送载体和联合机制的设计提出了更高的要求。本课题针对化疗-免疫联合治疗存在的药物共载困难、递送系统体内命运不明确、免疫系统激活不充分等难点，构建了靶向前药与脂质体杂化体系形成的“隐形”递送系统，并解决了以下问题：1）将化疗药物冬凌草甲素（oridonin, ORD）共价连接在高分子透明质酸（hyaluronic acid, HA）上合成前药HA-ORD，并通过氢键和范德华力包裹在负载免疫治疗药物C-X-C基序趋化因子10（C-X-C motif chemokine 10, CXCL10）的脂质体表面，形成杂化脂质体，解决了大分子免疫药物与高分子前药的共载与递送问题；2）利用CXCL10和HA-ORD在杂化体系表面形成的人工蛋白冠，实现了递送系统的“隐形”，降低了血液中白细胞对脂质体的捕获，延长了体内循环时间，并利用HA靶向肿瘤细胞表面高表达的CD44受体，有效提高了肿瘤部位的蓄积，解决了纳米递送系统的体内命运不明确的问题；3）对药物联用机制的进行合理设计，在ORD和CXCL10分别介导肿瘤细胞凋亡和免疫细胞招募的基础上，利用ORD对PI3K/AKT通路进行抑制，与先天免疫产生的IFN-γ等细胞因子共同促进巨噬细胞向M1型极化，重塑免疫抑制性微环境，进一步刺激树突细胞分泌CXCL10，实现肿瘤部位的炎症级联放大，解决了免疫系统激活不充分的问题。因此，本课题为肿瘤的化疗-免疫联合治疗提供了新的治疗策略和实验依据。受本基金标注的研究成果包括SCI论文14篇，中文文献7篇。上述研究成果为我们在后续课题中开展更加深入化疗-免疫联合治疗策略研究奠定了基础。