Targeted delivery of celastrol to renal interstitial myofibroblasts using fibronectin-binding liposomes attenuates renal fibrosis and reduces systemic toxicity

纤维化 医学 毒性 药理学 脂质体 肌成纤维细胞 纤维连接蛋白 肾脏疾病 病理 癌症研究 内科学 化学 细胞外基质 生物化学
作者
Rui Li,Yanping Li,Jinhang Zhang,Qinhui Liu,Tong Wu,Jian Zhou,Hui Huang,Qin Tang,Cuiyuan Huang,Ya Huang,Zijing Zhang,Guorong Zhang,Yingnan Zhao,Liang Ma,Yanhuan Feng,Li Mo,Min Han,Jinhan He
出处
期刊:Journal of Controlled Release [Elsevier]
卷期号:320: 32-44 被引量:50
标识
DOI:10.1016/j.jconrel.2020.01.017
摘要

Renal fibrosis often occurs in chronic kidney disease, and effective treatment is needed. Celastrol (CEL) may attenuate renal fibrosis, but it distributes throughout the body, leading to severe systemic toxicities. Here we designed a system to deliver CEL specifically to interstitial myofibroblasts, which is a key driver of renal fibrogenesis. Fibronectin is highly expressed in fibrotic kidney. The pentapeptide CREKA, which specifically binds fibronectin, was conjugated to PEGylated liposomes (CREKA-Lip). CREKA-coupled liposomes significantly increased the uptake of unmodified liposomes by activated NRK-49F renal fibroblasts. Systemic administration of CREKA-Lip to mice led to their accumulation in fibrotic kidney, where they were specifically internalized by interstitial myofibroblasts. Loading CEL into CREKA-Lip effectively inhibited the activation and proliferation of NRK-49F cells in vitro, and they markedly alleviated renal fibrosis, injury and inflammation induced by unilateral ureteral obstruction in mice. Besides, CEL-loaded CREKA-Lip was associated with significantly lower toxicity to major organs than free CEL. These results suggest that encapsulating CEL in CREKA-Lip can increase its therapeutic efficacy and reduce its systemic toxicity as a potential treatment for renal fibrosis.
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