Co -delivery of doxorubicin and epacadostat via heparin coated pH -sensitive to the metastasis of melanoma
Co -delivery of doxorubicin and epacadostat via heparin coated pH -sensitive to the metastasis of melanoma
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DOI：
10.1016/j.ijpharm.2020.119446
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发表时间：
2020-06-30
影响因子：
5.8
通讯作者：
Peng, Jianqing
中科院分区：
文献类型：
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作者：
Chen, Yi;Du, Qianming;Peng, Jianqing
高转移是黑色素瘤治疗失败的原因。化学免疫治疗不仅对肿瘤的原位生长有明显的抑制作用，而且对远处器官转移也有明显的抑制作用。鉴于肿瘤微环境中吲哚胺-2，3双加氧酶（IDO）的过度表达导致免疫逃逸，化疗药物和IDO抑制剂的联合应用可能是一种有前途的化学免疫治疗方法。血小板介导的血行转移可能被肝素（HP）阻断。因此，具有所有这些元素的药物递送系统可能是黑色素瘤的潜在治疗方法。在这里，我们开发了一种pH敏感的脂质体双传递系统的阿霉素（DOX）和epacadostat（EPA）与HP涂层（HP/LDE）。体外实验证实，它能增强细胞毒作用，促进细胞凋亡，逆转血小板激活的上皮间质转化（EMT），阻止细胞的侵袭和迁移。全身给药后，HP/LDE对黑色素瘤具有最佳的抗转移作用。体外和体内DC成熟、CD 8+细胞毒性T淋巴细胞（CTL）活化和T细胞介导的细胞毒作用评价结果一致。综上所述，我们的研究建立了一个功能性的脂质体双传递系统，具有理想的抗转移疗效的黑色素瘤。
High metastasis is responsible for the failure in the treatment of melanoma. Chemoimmunotherapy has shown conspicuous inhibition effects not only on the growth of tumor in situ, but also on the metastasis to distant organs. Given that the indoleamine-2,3 dioxygenase (IDO) overexpressed in the microenvironment of tumor leads to the immune escape, the combination of chemotherapeutic drug and IDO inhibitor might be a promising chemoimmunotherapy. Besides, the hematogenous metastasis mediated by platelets was supposed to be blocked by the heparin (HP). Therefore, a drug delivery system with all these elements involved might be a potential treatment for melanoma. Here, we developed a pH-sensitive liposomal dual-delivery system for doxorubicin (DOX) and epacadostat (EPA) with HP coated (HP/LDE). It was confirmed to enhance cytotoxicity and apoptosis, reverse the platelets-activated epithelial mesenchymal transformation (EMT) and prevent the invasion and migrationin vitro. After systemic administration, HP/LDE provided the optimum anti-metastasis effect on the melanoma. The results of evaluation on DC maturation, CD8+cytotoxic T lymphocytes (CTLs) activation and T cell mediated cytotoxicity were consistentin vitroandin vivo. Taken together, our study established a functional liposomal dual-delivery system with ideal anti-metastasis efficacy on melanoma.