靶向肿瘤相关Tie2+单核细胞（TEMs）的药物和基因载体研究

Myeloid Derived Suppressor Cells (MDSCs) were found to play important roles in tumor development and metastases. We propose to develop targeted drug and gene delivery system toward these cells and specifically the Tie2 expressing monocytes (TEMs). We had previously designed and selected a few peptide ligands that we shown bound to the Tie2 extracellular domain. Liposomes and lipid nanoparticles containing these peptide ligands could bind and deliver drugs and genes specifically to Tie2+ cells. In this study, we propose to address the unique properties of lymphocytes, and optimize the targeted delivery systems for Tie2+ monocytes. Based on these studies, we would then develop targeted liposome formulations contain the drug all trans retinoic acid (ATRA) and targeted lipoplex formulations containing plasmid encoding the cytokine Interferon-alpha. We plan to evaluate their activities in vivo by following the changes in TEMs number and phonotype in circulation, TEMs extravasation in tumor tissues and their proangiogenic properties. We believe the proposed studies would provide some valuable information for the development of new anticancer strategies focusing on MDSCs.

髓系来源的免疫抑制细胞在肿瘤发生发展以及转移过程中有重要的作用，本课题旨在针对其中一类具有特殊表型的细胞，即Tie2＋表达单核细胞（TEMs），研制主动靶向的药物和基因输送系统。我们在前期工作中，通过设计和筛选获得了多个与Tie2胞外区有特异性结合作用的配体多肽，并制备了配体修饰的脂质载体，显示对Tie2+细胞有较好的结合和药物输送能力。本课题希望针对Tie2+淋巴细胞的特点，进一步优化处方，实现针对TEMs的高效药物输送和基因转染。在此基础上，制备具有实际药效作用的靶向药物载体（ATRA脂质体）和靶向基因输送载体（IFN-alpha基因/脂质复合粒子），考察其体内输送效果，检测药物和基因导入前后TEMs数量和表型的变化，及TEMs被肿瘤组织招摹和参与肿瘤血管新生的情况，评价肿瘤治疗的效果。本课题的研究，将为发展针对肿瘤相关免疫抑制细胞的靶向药物治疗新思路提供依据。

通过本课题研究，我们探索了一系列针对肿瘤相关巨噬细胞（TAM）和髓系抑制细胞（MDSC）的药物和基因治疗的新策略，研制了全反式维甲酸(ATRA)脂质体制剂和IRF5和STAT3基因导入载体系统，作用于TAM和MDSC，能够有效地降低其免疫抑制活性，改变肿瘤免疫微环境，提高针对肿瘤的免疫抑制作用。相关制剂均具有自主知识产权，已进展到新药开发阶段。肿瘤免疫治疗正在成为肿瘤治疗中最重要且最被寄予厚望的治疗途径， 目前国内外进展大多集中在免疫应答中T细胞相关因素研究，如T细胞检查点抑制剂，CAR-T等，我们提出了针对肿瘤相关单核／巨噬细胞的新的免疫治疗策略，并通过动物实验初步证明了其有效性和作用机理，具有较好的科学意义和应用价值。已申请专利7项，其中3项已获得授权；发表论文6篇，另有2篇论文正在审稿中，1篇论文在撰写中。