肿瘤微环境触发增强Lyp-1靶向呈递的纳米载药体系在抑制乳腺癌生长及转移中的应用基础研究

Malignant tumor seriously threatens to human health, and its distant metastasis is especially the leading cause to the failure of anti-tumor program. Ideal anti-cancer treatment should focus on precise targeting to the tumor sites, which combined effectively enhancing the inhibitory effect on the primary tumor with chemotherapy drugs, and achieving dual suppression for the primary and distant metastatic tumors by enhancing the body's immune response. This project intends to construct a composite polypeptide-modified nanomicelles which with the multifunction of both tumor-microenvironment responsive targeting and specifically block the PD-1 / PD-L1 signal pathways. MMPs with high expression around tumor tissues can responsively recognize the MMP-sensitive peptide sequences, which furtherly enhance the Lyp-1 target presentation effect to p32 receptor on breast cancer cellmembrane, contributing to improve the delivery of chemotherapy drugs into the breast tumor cells. Simultaneously, the controlled-released anti-PD-1 polypeptide sequences have the specific function to block the PD-1/PD-L1 signal pathways, activating the immunological activity of cytotoxic T lymphocytes and enhancing the immune response of body’s immune system to eventually achieve the dual suppression for both the primary tumors and its distant metastasis. According to the in vitro cell experiments and in vivo studies of the animal models of bilateral tumor or tumor metastasis, we will demonstrate that the MMPs intelligent response performance of the nanosystem, and the precised combination inhibition of chemotherapy/immunotherapy for the tumor growth and metastasis effect. Overall, these excellent properties make the composite micelles a ideal tool with high efficient delivery, controlled tumor microenvironment response, and low toxicity. The successful implementation of this project is expected to provide new ideas and new strategies for the anticancer treatment strategy with potential for clinical application.

恶性肿瘤严重威胁人类健康，其远端转移是导致抗肿瘤方案失败重要原因。理想的肿瘤治疗方案应以精准靶向肿瘤为前提，有效提高化疗药物对原发肿瘤抑制效果的同时，通过增强机体免疫应答实现对原发肿瘤与远端转移肿瘤的双重抑制。本项目拟构筑兼具肿瘤微环境响应性靶向与特异性阻断PD-1/PD-L1信号通路功能的复合多肽修饰纳米胶束：基于MMPs触发的可增强Lyp-1靶向呈递效果的多肽序列修饰，提高纳米药物对乳腺癌化疗药物的递送；同时局部释放免疫阻断抑制多肽序列，阻断PD-1/PD-L1信号通路，激活细胞毒性T细胞的免疫活性、增强机体免疫应答水平，以期最终实现对原发肿瘤与远端转移肿瘤的双重抑制。通过细胞实验和动物双侧肿瘤或肿瘤转移模型，论证该体系的MMPs智能响应性效能、精准化疗/免疫治疗联合抑制肿瘤生长及转移的作用效果。本项目的顺利实施，有望为抗肿瘤治疗策略提供具有临床应用潜力的新思路与新策略。

以安全低毒、粒径理想的可修饰纳米胶束 PEG-PCL 为基底载体，通过绿色温和的修饰手段构建出具有可控性的智能药物释放体系，实现基于免疫增强的联合抗肿瘤治疗模式是理想的肿瘤治疗方案。肿瘤微环境中免疫应答效率是纳米体系能否实现预期免疫联合治疗效果的前提。在本项目前期研究中，原构建的纳米体系的免疫应答效率仍不够理想，需开发基于微环境调控的新型纳米体系。通过前期研究表明，纳米氧化铁不仅具有磁共振成像剂的作用，能够实现实时诊断与监测，同时还能够调控巨噬细胞极化行为，诱导TAMs向促炎性M1亚型极化，提高ROS产率，激活T细胞免疫效应，在构建微环境响应性纳米体系中具有优良的开发潜力。项目申请人在原有对有机嵌段共聚物纳米材料的研究基础上，进一步开发新型纳米凝胶体系，成功将纳米氧化铁MNPs与10-羟基喜树碱CPT共载于纳米凝胶的网状结构中，实现了MRI成像介导的化疗-光热协同治疗，显著提高了对原发瘤与远端转移瘤的双重抑制效果。同时，还开发了MNPs/AIPH复合纳米体系，MNPs的光热转换触发AIPH分解生成非氧依赖型自由基，有效诱导肿瘤细胞死亡，释放的MNPs可进一步募集并诱导TAMs极化，提高ROS产率，成功构建了一种具有非氧依赖性与级联效应的PTT/TDT联合治疗肿瘤方案。在本项目的资助下以第一作者或通讯作者发表SCI论文1篇，另有部分相关性研究工作已完成，目前投稿中，此后续工作成果发表后将继续对该项目进行基金资助标注。本项目已基本完成项目计划内容，研究成果已基本达到项目的预期目标。