基于光热免疫治疗构建响应型层释递药系统用于抑制黑色素瘤增殖和转移的研究

黑色素瘤在临床治疗中转移性强且治愈率低，因而亟需开发针对其增殖快和转移性强的治疗方案。光热免疫疗法既能够利用热效应抑制肿瘤增殖，还可通过热疗后产生的肿瘤抗原特异性诱导免疫应答，清除转移病灶。由于肿瘤细胞可过量表达吲哚胺-2，3双加氧酶（IDO）实现免疫逃逸，因而通过联用光敏剂和IDO抑制剂，在光热治疗的同时抑制肿瘤分泌的IDO活性，有望增强抗肿瘤免疫应答，提高治疗效果。基于此，本项目拟在申请者前期开发的抗肿瘤转移纳米粒的基础上，构建肝素化响应型层释递药系统，共包载光敏剂-Cypate和IDO抑制剂-epacadostat，使载药纳米粒在肿瘤部位响应性“脱去”肝素发挥抗转移作用，进而暴露配体基团，促进靶细胞摄取，入胞后利用微环境响应性触发载体解聚和药物组合快速释放，增强光热免疫治疗效果，抑制黑色素瘤的增殖和转移。本研究为开发全新、高效、安全的抗黑色素瘤制剂提供了新思路。

In the clinical treatment of melanoma, due to the high metastasis capability and low cure rate, the development of effective therapies aiming at the fast growth and high metastasis is in need. Photothermal immunotherapy have shown inhibition effects not only on the growth of tumor via heat effect, but also on the metastasis by the specific tumor antigen induced immune response. Because the overexpression of indoleamine-2,3 dioxygenase (IDO) by the tumor cells could lead to the immune escape of tumor cells, the combination of photosensitizer and IDO inhibitor can inhibit the activity of IDO enzyme in the photothermal treatment, which is expected to enhance the tumor immune response and improve the therapeutic effect. On the basis of anti-metastasis nanoparticles developed by the applicant in the previous study, a heparin modified stimuli-responsive stepwise delivery system with both photosensitizer-Cypate and IDO inhibitor-epacadostat encapsulated were prepared in this project. In the tumor region of melanoma, the heparin could be "taken off" and inhibit the potential metastasis of melanoma cells. The exposed targeting ligand on the nanoparticles further improves the cellular uptake. In the intracellular environment, the stimuli-responsive components will induce decomposition of nanoparticles and realize the fast release of drug combination, enhance the photothermal immunotherapy effect and inhibit tumor proliferation and metastasis. This study will provide a new method for the development of novel, effective and safe preparations for melanoma treatments.