编码α-毒素的非病毒基因药物靶向治疗恶性黑色素瘤的实验研究

金黄色葡萄球菌感染肿瘤引起部分肿瘤抑制或消退的现象为肿瘤治疗研究提供了新线索，其分泌的α-毒素是一种强烈的成孔素，可高效裂解肿瘤细胞，但损伤正常细胞及免疫排斥的问题限制了临床应用。基因治疗为肿瘤治疗提供了新手段，可通过在靶细胞表达目的蛋白质发挥治疗作用，为改善蛋白质药物的功效及成药性提供了新方案。本课题提出利用靶向基因药物在肿瘤细胞表达外源性α-毒素治疗恶性黑色素瘤的新策略，自主研发了可静脉注射的新型iDPP靶向纳米基因递送系统，结合TERT启动子调控的肿瘤特异性表达载体，设计、构建了一种编码α-毒素的新型非病毒基因药物，初步发现经静脉注射后可靶向杀伤肿瘤细胞及激发抗肿瘤免疫，疗效非常显著，且未引起明显毒副作用，在恶性黑色素瘤治疗中有巨大的潜力。下一步，将系统、深入地研究其治疗恶性黑色素瘤的作用与机制及进一步提高疗效的方法，为肿瘤基因治疗研究提供新思路，为恶性黑色素瘤治疗提供潜在新选择。

Staphylococcus aureus infection of the tumor caused some tumor inhibition or regression, which provided a new clue for cancer research. The α-hemolysin secreted by Staphylococcus aureus is a strong pore-forming cytotoxin that can efficiently lyse tumor cells. However, the damage to normal cells and immune rejection limit its clinical application. Gene therapy provides a new method for tumor treatment and genetic drugs can express the encoded protein in targeted cells for treatment, providing a new method to modify the functions and enhance the efficacy and druggability of protein drug. In this project, we propose a new strategy of using targeted gene drugs to express exogenous α-hemolysin in tumor cells for cancer treatment. We have created a novel targeted gene delivery system，called iDPP, which is suitable for intravenous administration. Combined the targeted gene delivery system and TERT promoter regulated tumor specific expression vector, we designed and constructed a new non-viral gene formulation that encodes α-hemolysin. It was initially found that this formulation could kill tumor cells and stimulate anti-tumor immunity after intravenous injection, without obvious toxicity and side effects. The anticancer efficacy was very obvious, implying the great potential in treating malignant melanoma. In the next step, we will systematically and deeply study the effect and mechanism in the treatment of malignant melanoma and new methods to improve the efficacy. This work would provide new ideas for cancer gene therapy research and potential options for melanoma therapy.