基于热海绵效应和肿瘤微酸环境响应特性的聚合物纳米粒用于化学免疫联合治疗肿瘤的研究

Cancer chemotherapy regimens, together with surgery and radiotherapy, are currently the main methods of tumor mass ebulking. Unfortunately these means of intervention are often insufficient to cure cancer patients and relapse commonly follows due to clinically undetectable micrometastases. A large amount of pre-clinical researches and clinical trials have proven that a combination of cancer chemotherapy, to deplete tumor cells, combined with immunotherapy, to prevent relapses, can enhance the efficacy of anticancer. In this program, we select interleukin-2(IL-2) and paclitaxel(PTX) as model drugs and develop a tumor-acidity-responsive core-shell polymer nanoparticles based on thermal sponge effect. The formulated polymeric nanoparticles will be conditioned to entrap hydrophobic drug for chemotherapy and hydrophilic cytokine for immunotherapy and decorate by a tumor targeting cyclic peptide. Furthermore, the nanoparticles realize the pH-responsive releasing of encapsulated payloads on tumor tissue. This rationally designed multi-drug delivery system will exert a synergistic antitumor effect and improve therapeutic outcomes. To sum up, this program will not only obtain a novel drug delivery system for co-delivery of multi-drugs, but also provide a novel strategy and referential experiences for multimodality treatment of tumor.

目前癌症的治疗手段依旧是以化疗为主，结合手术和放疗。由于肿瘤细胞易发生难以检测的微小转移，因此这些干预方法并不足以治愈癌症病人并导致其易复发。大量基础和临床研究表明将杀死肿瘤细胞的化学疗法和阻止复发的免疫治疗联合使用，能增强肿瘤治疗的效果。在此背景下，本项目拟以IL-2与PTX作为联用模型药物，构建一种具有微酸响应特性和热海绵效应的“核-壳”结构聚合物纳米颗粒载体。通过载体设计，将具有不同理化性质的药物分子装载于载体的特定区域，实现对不同理化性质药物的共包载和共输送；并在表面偶联具有肿瘤靶向作用的环肽，以增强肿瘤细胞对药物的摄取；通过对聚合物官能基团的调节，可使纳米颗粒对肿瘤组织间的低pH值产生响应，实现在肿瘤组织的敏感释放，发挥各药物协同抗肿瘤作用，达到提高疗效的目的。本项目不仅能够获得全新的多药共载递送系统，还将为肿瘤的综合治疗提供新的策略和实验依据。

在恶性肿瘤的治疗中，将直接杀死肿瘤细胞的化疗与激活机体免疫系统、调节肿瘤微环境的免疫治疗相结合，是目前较为有效的肿瘤治疗方法之一。然而，如何将不同理化性质的药物联合应用于免疫化疗仍然是当前面临的一大挑战。在此背景下，本研究通过酸敏感材料mPEG-Dlinkm-PDLLA和Pluronic F127的低温膨胀效应，开发了用于同时递送疏水化疗药物紫杉醇(PTX)和生物大分子白介素-12 (IL-12)的纳米颗粒。此纳米颗粒实现了肿瘤部位的富集，显著抑制了乳腺癌细胞4T1的生长和转移，延长了荷瘤小鼠的整体生存期。我们进一步探讨其潜在的免疫机制。PTX和IL-12联用可以激活T淋巴细胞及NK细胞，释放细胞因子IFN-γ,选择性地抑制调节性T细胞和诱导M1型肿瘤分化的巨噬细胞，从而提高肿瘤免疫抑制微环境。本项目不仅能够获得全新的多药共载递送系统，还将为肿瘤的综合治疗提供新的策略和实验依据。