基于肿瘤微环境调控的靶向给药系统的设计与作用机制研究

Tumor microenvironment plays a critical role during the tumor initiation, angiogenesis, progression and metastasis and also influences the curative effect of tumour. Cancer-associated fibroblasts (CAFs) are one of the most abundant stromal cells. CAFs have cross-talk with cancer cells and support tumor proliferation, invasion by secreting plenty of cytokines and growth factors on one hand, on the other hand, they provide physical barrier to decrease the chemotherapeutic drug penetration into tumors via mechanical support and secreting collagen, which ultimately results in inefficient of cancer therapy. Based on the importance and biological property of CAFs, we will construct a FH peptide-modified liposome targeting CAFs (FH-SSL-Nav). Navitoclax (Nav), which can specifically induce apoptosis in CAFs, is choosen for therapeutics. The FH peptide can specifically bind to tenascin C (TNC), a protein mainly expressed by CAFs and is used to delivery the Nav liposomes to tumor environment and CAFs. Through the advanced scientific research methods, this project will evaluate the CAFs targeting and specifically eradicating effect of FH-SSL-Nav in vitro and in vivo. Moreover, the project will investigate the targeted lipomes how to regulate the tumor microenvironment and clarify the laws and molecular mechanism. Finally, we will study whether the targeted liposomes can improve delivery of drugs or nanomedicines into tumor and therapeutic efficacy. The research ideas, the choice of drug and targeting peptide and research methods of the project are innovative. The project is hopeful to provide one of strategies to targeted tumor therapy based on tumor environment and have very important scientific significance. The project has good scientific research group, excellent research condition and prelimilary work, which insure the feasibility.

肿瘤微环境不仅在肿瘤生长转移过程中发挥关键作用，也影响肿瘤治疗效果。肿瘤相关成纤维细胞（CAFs）是肿瘤间质中最重要的细胞成份，其可通过分泌细胞因子和生长因子与癌细胞交互对话，促进肿瘤的演进；另外，其对肿瘤的机械性支持及分泌的胶原蛋白等，会阻碍药物向肿瘤内部渗透。基于CAFs的功能与特性，本项目以CAFs选择性凋亡诱导剂Navitoclax作为药物，构建多肽修饰的、靶向CAFs分泌蛋白Tenascin C的靶向脂质体，通过多学科的研究手段，评价其对CAFs的靶向性和对肿瘤微环境的调控作用，探索其用于肿瘤治疗、增加化疗药物及制剂肿瘤渗透性和疗效的可行性，揭示相关分子作用机制。本项目在研究思路、药物选择、靶向系统构建和研究方法上具有一定创新性，有望为基于肿瘤微环境的靶向治疗提供新的策略，具有一定的研究意义。项目前期工作基础较好，研究力量较强，研究单位的工作条件完善，完成项目的可行性较强。

本项目以肿瘤相关成纤维细胞（CAFs）为靶标，构建新型主动靶向载药脂质体，考察该脂质体对肿瘤微环境的调控作用及其用于促进脂质体肿瘤穿透和增强化疗药物抗肿瘤疗效的可行性。. 以CAFs选择性凋亡诱导剂Navitoclax(Nav)为药物，基于CAFs高表达Tenascin C（TNC），构建了高亲和力的FH多肽修饰的药物主动靶向脂质体 (FH-SSL-Nav)，以肝星型细胞LX-2细胞作为体外CAFs细胞模型，验证了靶向脂质体对CAFs的靶向性。. 以裸鼠皮下移植Hep G2瘤为肿瘤模型，研究了Nav制剂对肿瘤微环境的影响。结果表明Nav制剂能够显著降低肿瘤组织中CAFs的比例，减少胶原蛋白的含量，疏松肿瘤组织，达到降低肿瘤间质压，增强肿瘤组织血液灌流的作用。. 分别以肿瘤细胞-成纤维细胞共培养肿瘤球和荷瘤裸鼠为体内外模型，利用共聚焦、免疫荧光和活体成像等手段，证实了Nav制剂能够显著增加普通脂质体的瘤内渗透和蓄积。. 与阿霉素脂质体联用后，抗肿瘤效果优于单药组，主动靶向的Nav制剂与主动靶向的阿霉素脂质体联用后得到最佳的抑瘤效果。. 本研究为增加肿瘤药物纳米制剂的肿瘤渗透和瘤内分布提供了新的思路，有望解决现有药物治疗疗效差、肿瘤复发等难题。