基于逆脂肪摄取通路-光动力疗法联合治疗策略的雷公藤仿生给药系统抗转移性黑色素瘤作用研究

转移性黑色素瘤（MM）侵袭性高，治疗难度大，目前化疗、生物和免疫治疗均存在诸多不足。课题组前期研究发现，中药雷公藤主要有效成分雷公藤甲素（TP）可抑制MM增殖，但如何解决TP毒性大、半衰期短等问题，是充分发挥其药效作用的关键。本项目采用逆向思维，将脂肪酸天然靶向和光动力疗法联合治疗策略引入中药靶向抗MM研究中。以棕榈酸（PA）作为天然靶向黑色素瘤细胞的靶头，与TP偶联，制备TP-ss-PA。采用脂肪细胞作为包载TP-ss-PA和光敏剂Pc的仿生载体，利用肿瘤组织对脂肪细胞的募集、降解及对脂肪酸大量摄取的特性，实现药物的靶向递送和释放；联合光动力疗法，发挥多通路协同增效抗MM作用。并从离体、在体多层面阐明TP与光动力疗法协同调控MM侵袭迁移作用机理、体内分布特征、代谢机制及抑瘤效果。本项目的研究，有望突破瓶颈，为TP治疗MM的制剂学研究开辟新途径，为中药抗恶性肿瘤研究提供新的策略和方法。

Metastatic melanoma (MM) is highly invasive and difficult to treat. There are many shortcomings in chemotherapy, biological and immunotherapy in treating MM. We found that Triptolide (TP), the main active ingredient of Chinese herbal medicine Tripterygium wilfordii, could inhibit the proliferation of MM. However, how to overcome the TP shortcomings of high toxicity and short half-life is the key to fully exert its medicinal effect. This project uses reverse thinking to introduce a combination therapy strategy of natural targeting of fatty acids and photodynamic therapy (PDT) into the targeted anti-MM researches of traditional Chinese medicine. TP-ss-PA was prepared by coupling TP with palmitic acid (PA) that was used as a natural target for melanoma cells. The adipocytes as biomimetic carriers was applied to encapsulate TP-ss-PA and photosensitizer (Pc). And, the biomimetic system was targeted delivered to tumor tissue and the TP-ss-PA/Pc was released from adipocytes through the tumor cells recruiting and degrading the adipocytes. TP-ss-PA combined PDT will achieve multi-channel synergistic anti-MM effect. The mechanisms of regulating the invasion and migration of MM, the characteristics of the body distribution, the metabolic mechanisms and the anti-tumor effect of the combination therapy strategy of TP and PDT will be investigated by in vitro and in vivo evaluations. .This project is expected to break through the bottleneck with developing new approaches for the pharmaceutical research of TP in treating MM and providing innovative strategies and research methods for anti-malignant tumors of traditional Chinese medicine.