K-Ras(G12C)抑制剂/药物共载的还原敏感性多肽纳米粒子及其抗肿瘤效应的协同作用研究

基因突变是造成人类肿瘤发生的重要原因之一。Ras癌基因能调控细胞生长和分化，与多种肿瘤的形成有密切联系。因此，有效的抑制突变的Ras蛋白，可大幅度降低突变的肿瘤细胞系的活性并增加其凋亡，这已经成为了肿瘤靶向治疗的研究热点。本项目利用纳米药物传递系统，结合在癌基因突变位点抑制方面最新发现的特异性分子抑制剂，拟构建一种可将K-Ras突变抑制剂递送至肿瘤细胞内部，并共装载抗肿瘤药物，在胞内快速释放的还原敏感型纳米药物传递系统。该载体采用具有优良穿膜性能的寡聚精氨酸(R9)作为亲水性外壳，多聚谷氨酸酯亲水肽段以及用于连接抑制剂的半胱氨酸肽段作为主链，利用巯基反应构建二硫键偶联的PArg-PGlu-PCys-K-Ras(G12C) inhibitor 6纳米粒子，并装载不同类型化疗药物构建共载系统，研究K-Ras抑制剂与化疗药物的协同治疗作用及其机制，以期强化分子水平药物在肿瘤治疗中的作用。

Gene mutation is one of the important reasons for human cancer. The Ras onco-gene can regulate cell growth and differentiation, closely linked with the formation of a variety of tumors. Therefore, effective suppression of the mutant Ras protein, which can greatly decrease the activity of tumor cells and increase the apoptosis, has become a research hotspot of tumor targeting therapy. The project, using nano drug delivery system, along with the latest finding specific molecular inhibitors in cancer gene mutation, aims to construct a bioreducible polypeptide nanoparticular delivery system for intracellular co-delivery and fast intracellular release of K-Ras(G12C) inhibitor and anticancer drugs. The carrier system uses poly-arginine (R9) with excellent cellular peptrating properties as the hydrophilic shell; poly glutamic acid ester (Glu (OCH2CH2O) 2CH3) as hydrophilic peptide; and cysteine (Cys) as the peptide for connecting the inhibitor. K-Ras(G12C) inhibitor 6 is connected to the carrier molecule through disulfide bond that formed by sulfhydryl reaction to construct the amphiphilic PArg-PGlu-PCys-K-Ras(G12C) inhibitor 6 nanoparticles. Different types of anticancer drugs are loaded to form co-encapsulating system. The synergistic therapeutic effect of the inhibitor and anticancer drugs will be investigated based on the different mechanism of inhibitor and these drugs.