2025-08-13 作者：ZJ 来源：文献：Co -delivery of doxorubicin and epacadostat via heparin coated pH -sensitive to the metastasis of melanoma 文献链接：https://xueshu.baidu.com/usercenter/paper/show?paperid=1w190a201e120v80kh7q00m0ps520552&site=xueshu_se 作者：Yi Chen, Qianming Du, Ying Zou, Qianqian Guo, Jing Huang, Ling Tao,Xiangchun Shen, Jianqing Peng 原文摘要：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 migration in vitro. After systemic administration, HP/LDE provided the optimum anti-metastasis effect on the melanoma. The results of evaluation on DC maturation, CD8+ cytotoxic Tlymphocytes (CTLs) activation and T cell mediated cytotoxicity were consistent in vitro and in vivo. Taken together, our study established a functional liposomal dual-delivery system with ideal anti-metastasis efficacy on melanoma.
DSPE-PEG2000 可溶于水、氯仿、二氯甲烷等有机溶剂，具有良好的生物相容性和热稳定性，能减少对生物体的免疫反应和有害性作用. 作为一种功能化聚乙二醇制剂，是形成磷脂聚乙二醇脂质体的优质材料，可用于化合物输送、基因转染等，还可通过修饰与目标表面配体结合，实现化合物靶向。基于此该文献研究开发了一种pH敏感的脂质体双递送系统的阿霉素（DOX）和表皮细胞抑制素（EPA）与HP涂层（HP/LDE）。制备过程如下：
图:HP/LDE的假设结构
DOX和EPA负载脂质体的制备
用薄脂膜分散法制备含有EPA的脂质体，随后用远程加载法加载DOX。将DOTAP、DOPE、Chol和DSPE-PEG2000以一定的质量比溶解在氯仿中。将溶解在甲醇中的EPA以化合物与总磷脂（DOTAP和DOPE）的质量比为加入。然后，用旋转蒸发器蒸发混合物，得到薄脂质薄膜。然后，加入硫酸铵溶液，水浴中孵育。水化后，脂质体超声并过滤。脂质体在蔗糖溶液中透析后，在脂质双分子层上形成硫酸铵梯度。然后，将脂质体与DOX溶液以DOX/EPA质量比孵育。通过透析去除未卸载的DOX，得到了LDE。
载药脂质体上的涂层
将HP溶解于PBS中，将HP原液滴加入等体积脂质体溶液中，磁搅拌，过滤。通过超滤分离以去除游离HP。
图:LDE和HP/LDE的代表性TEM图像
结论：DSPE-PEG2000参与制备的DOX和EPA负载脂质体与HP涂层（HP/LDE）可以增强细胞poison性和细胞Apoptosis ，逆转被激活的上皮间充质转化（EMT），并防止体外侵袭和迁移。在全身给药后，HP/LDE对黑色素tumor提供了抗转移效果。对DC成熟、CD8+CTLs活化和T细胞介导的细胞poison性的评价结果在体内外都是一致的。
