文献：ROSResponsive Berberine Polymeric Micelles Efectively Suppressed the Infammation of Rheumatoid Arthritis by Targeting Mitochondria

文献链接：https://link.springer.com/article/10.1007/s40820-020-0410-x

作者：Xingxing Fan, Mengze Xu, Elaine LaiHan Leung, Cai Jun , Zhen Yuan, Liang Liu

相关产品：PLGA 聚乳酸-羟基乙酸共聚物

原文摘要：Rheumatoid arthritis (RA) is an autoimmune disease, which attacks human joint system and causes lifelong infammatory condition. To date, no cure is available for RA and even the ratio of achieving remission is very low. Hence, to enhance the efcacy of RA treatment, it is essential to develop novel approaches specifcally targeting pathological tissues. In this study, we discovered that RA synovialfbroblasts exhibited higher reactive oxygen species (ROS) and mito

chondrial superoxide level, which were adopted to develop ROS-respon sive nano-medicines in infammatory microenvironment for enhanced RA treatment. A selenocystamine-based polymer was synthesized as a ROS-responsive carrier nanoplatform, and berberine serves as a tool drug. By assembling, ROS-responsive berberine polymeric micelles were fabricated, which remarkably increased the uptake of berberine in RA fbroblast and improved in vitro and in vivo efcacy ten times higher. Mechanistically, the anti-RA efect of micelles was blocked by the co-treatment of AMPK inhibitor or palmitic acid, indicating that the mechanism of micelles was carried out through targeting mitochondrial, suppressing lipogenesis and fnally inhibiting cellular proliferation. Taken together, our ROS-responsive nano-medicines represent an efective way of preferentially releasing prodrug at the infammatory microenvironment and improving RA therapeutic efcacy.

PLGA是聚乳酸-羟基乙酸共聚物（polylactic-co-glycolic acid）的简称，是由乳酸和羟基乙酸两种单体聚合而成的生物可降解高分子材料。这种结构赋予了PLGA良好的生物相容性，在体内使用时不会引发强烈的免疫反应。而且，PLGA具有可调节的降解性能，其降解速度可以通过改变乳酸与羟基乙酸的比例来控制。可作为化合物载体，将化合物包裹在内部，以一定的速率在体内释放，延长化合物的作用时间。在组织工程方面，PLGA可作为支架材料，为细胞的生长和组织的修复提供支撑，同时随着组织的修复逐渐降解。小编引用的本篇文献发现RA滑膜纤维细胞表现出更高的活性氧（ROS）和线粒体超氧化物水平，用于在微环境中开发ROS再生纳米化合物，增强RA。合成了一种硒半胱胺基聚合物作为ROS响应载体纳米平台。过程如下：

图：BPseP胶束作用机制

VPsePCo聚合物的合成

在高温下，乳酸和甘醇酸的羧酸基和羟基发生酯化反应，生成 PLGA。当反应进行到一定程度时，加入羧化剂，将部分乳酸单元的羟基转化为羧基，制成 OH-PLGA-COOH。将DCC、DMAP和TEA溶解在二氯甲烷中激活VES的羧基，然后加入OH-PLGA-COOH逐滴取出VES-PLGA-COOH，随后与2,2‘-二黑色素二基二乙醇胺盐酸盐反应获得VES-PLGA-Se-Se-NH2，mPEG-COOH通过EDC/得到VES-PLGA-Se-Se-mPEG/nhs介导的酰胺反应，均通过乙醚共沉淀、透析和冻干纯化。除维生素E琥珀酸聚（乳酸（乙二醇）胺（mPEG-NH2）为反应物外，合成了琥珀酸-聚乙二醇-甲氧基聚（乙二醇）的共聚物。

BPseP胶束的制备与表征

将PseP二甲亚砜与小檗碱二甲亚砜均匀混合，然后在磁搅拌时滴加磷酸盐生理盐水中。然后，用密封的透析袋在超纯水中对平衡的混合物进行透析，间歇性改变透析液，通过针孔瓶膜后将透析液收集到透析袋中。

图：BPseP的平均粒径和zeta势

结论：实验证明了PLGA参与制备ROS响应的小檗碱聚合物胶束，提高了RA胚层细胞对小檗碱的吸收，提高了体内外活性的10倍。在机制上，AMPK抑制剂或棕榈酸共同处理阻断了胶束的抗RA缺陷，表明该胶束的机制具有靶向性。