E-selectin-targeted Sialic Acid-PEG-dexamethasone Micelles for Enhanced Anti-Inflammatory Efficacy for Acute Kidney Injury.
E-selectin-targeted Sialic Acid-PEG-dexamethasone Micelles for Enhanced Anti-Inflammatory Efficacy for Acute Kidney Injury.
复制标题
E-选择素靶向唾液酸-PEG-地塞米松胶束增强急性肾损伤的抗炎功效
作者：
Hu JB;Kang XQ;Liang J;Wang XJ;Xu XL;Yang P;Ying XY;Jiang SP;Du YZ
急性肾损伤（阿基）的有效治疗目前有限，护理主要是支持性的。唾液酸（SA）是哺乳动物细胞表面唾液酸化Lewisx抗原的主要成分，参与E-选择素结合。因此，地塞米松（DXM）负载的E-选择素靶向唾液酸-聚乙二醇-地塞米松（SA-PEG-DXM/DXM）缀合物胶束被设计用于改善阿基。通过PEG和SA或DXM之间的酯化反应合成缀合物，并且可以在水溶液中自发形成胶束，临界胶束浓度为65.6 µg/mL。游离DXM以6.28 ± 0.21%的载药量掺入胶束中。SA-PEG-DXM/DXM胶束的体外释药时间可延长至48 h。与PEG-DXM胶束相比，由于SA与表达在HUVECs上的E-选择素之间的特异性相互作用，更多的SA-PEG-DXM胶束可以被脂多糖（LPS）激活的人脐静脉内皮细胞（HUVECs）内化，因此更多的SA-PEG-DXM胶束在阿基小鼠模型的肾脏中积累。此外，SA-PEG-DXM缀合物中的SA可以通过抑制LPS激活的Beclin-1/Atg 5-Atg 12介导的自噬来显著改善LPS诱导的促炎细胞因子的产生，从而减轻毒性。与游离DXM和PEG-DXM/DXM胶束相比，SA-PEG-DXM/DXM胶束显示出更好的治疗效果，表现为改善肾功能、组织病理学改变、促炎细胞因子、氧化应激和凋亡相关蛋白的表达。
The effective treatment for acute kidney injury (AKI) is currently limited, and care is primarily supportive. Sialic acid (SA) is main component of Sialyl Lewisx antigen on the mammalian cell surface, which participates in E-selectin binding. Therefore, dexamethasone(DXM)-loaded E-selectin-targeting sialic acid-polyethylene glycol-dexamethasone (SA-PEG-DXM/DXM) conjugate micelles are designed for ameliorating AKI. The conjugates are synthesized via the esterification reaction between PEG and SA or DXM, and can spontaneously form micelles in an aqueous solution with a 65.6 µg/mL critical micelle concentration. Free DXM is incorporated into the micelles with 6.28 ± 0.21% drug loading content. In vitro DXM release from SA-PEG-DXM/DXM micelles can be prolonged to 48h. Much more SA-PEG-DXM micelles can be internalized by lipopolysaccharide (LPS)-activated human umbilical vein endothelial cells (HUVECs) in comparison to PEG-DXM micelles due to specific interaction between SA and E-selectin expressed on HUVECs, and consequently more SA-PEG-DXM micelles are accumulated in the kidney of AKI murine model. Furthermore, SA in SA-PEG-DXM conjugates can significantly ameliorate LPS-induced production of pro-inflammatory cytokines via suppressing LPS-activated Beclin-1/Atg5-Atg12-mediated autophagy to attenuate toxicity. Compared with free DXM and PEG-DXM/DXM micelles, SA-PEG-DXM/DXM micelles show better therapeutical effects, as reflected by the improved renal function, histopathological changes, pro-inflammatory cytokines, oxidative stress and expression of apoptotic related proteins.
登录
查看更多内容
影响因子：
6.4
作者：
Auvinen, Kaisa;Jalkanen, Sirpa;Salmi, Marko
通讯作者：
Salmi, Marko
影响因子：
6.1
作者：
Oppert, Michael;Engel, Christoph;John, Stefan
通讯作者：
John, Stefan
影响因子：
10.8
作者：
Lin, Yan;Li, Yanping;Sun, Xun
通讯作者：
Sun, Xun
影响因子：
3.8
作者：
Yang, Chih-Ching;Yao, Chien-An;Chien, Chiang-Ting
通讯作者：
Chien, Chiang-Ting
用于肾脏靶向治疗的低分子量羟乙基壳聚糖-泼尼松龙缀合物：合成、表征和体内研究
影响因子：
12.4
作者：
He XK;Yuan ZX;Wu XJ;Xu CQ;Li WY
通讯作者：
Li WY