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Targeted delivery of celastrol to renal interstitial myofibroblasts using fibronectin-binding liposomes attenuates renal fibrosis and reduces systemic toxicity.
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2020-01-10 , DOI: 10.1016/j.jconrel.2020.01.017 Rui Li 1 , Yanping Li 1 , Jinhang Zhang 1 , Qinhui Liu 2 , Tong Wu 1 , Jian Zhou 1 , Hui Huang 1 , Qin Tang 1 , Cuiyuan Huang 1 , Ya Huang 1 , Zijing Zhang 1 , Guorong Zhang 1 , Yingnan Zhao 1 , Liang Ma 3 , Yanhuan Feng 3 , Li Mo 4 , Min Han 5 , Jinhan He 1
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2020-01-10 , DOI: 10.1016/j.jconrel.2020.01.017 Rui Li 1 , Yanping Li 1 , Jinhang Zhang 1 , Qinhui Liu 2 , Tong Wu 1 , Jian Zhou 1 , Hui Huang 1 , Qin Tang 1 , Cuiyuan Huang 1 , Ya Huang 1 , Zijing Zhang 1 , Guorong Zhang 1 , Yingnan Zhao 1 , Liang Ma 3 , Yanhuan Feng 3 , Li Mo 4 , Min Han 5 , Jinhan He 1
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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.
中文翻译：
使用纤连蛋白结合脂质体将Celastrol靶向递送至肾间质成纤维细胞可减轻肾纤维化并降低全身毒性。
肾纤维化常发生在慢性肾脏疾病中，需要有效的治疗。Celastrol（CEL）可能会减轻肾脏纤维化，但会在全身分布，导致严重的全身毒性。在这里，我们设计了一个系统，专门将CEL传递至间质性成纤维细胞，这是肾纤维化的关键驱动因素。纤连蛋白在纤维化肾脏中高度表达。将特异结合纤连蛋白的五肽CREKA与PEG化脂质体（CREKA-Lip）偶联。CREKA偶联脂质体显着增加了活化NRK-49F肾成纤维细胞对未修饰脂质体的吸收。对小鼠的全身给药CREKA-Lip导致它们在纤维化肾脏中积累，在那里它们被间质性成肌纤维细胞特异性内化。将CEL装入CREKA-Lip可有效抑制NRK-49F细胞在体外的活化和增殖，并显着减轻小鼠单侧输尿管梗阻引起的肾纤维化，损伤和炎症。此外，载有CEL的CREKA-Lip与游离CEL相比，对主要器官的毒性明显较低。这些结果表明，将CEL封装在CREKA-Lip中可以提高其治疗效果，并降低其全身毒性，作为肾纤维化的潜在治疗方法。
更新日期：2020-01-11
中文翻译：
使用纤连蛋白结合脂质体将Celastrol靶向递送至肾间质成纤维细胞可减轻肾纤维化并降低全身毒性。
肾纤维化常发生在慢性肾脏疾病中，需要有效的治疗。Celastrol（CEL）可能会减轻肾脏纤维化，但会在全身分布，导致严重的全身毒性。在这里，我们设计了一个系统，专门将CEL传递至间质性成纤维细胞，这是肾纤维化的关键驱动因素。纤连蛋白在纤维化肾脏中高度表达。将特异结合纤连蛋白的五肽CREKA与PEG化脂质体（CREKA-Lip）偶联。CREKA偶联脂质体显着增加了活化NRK-49F肾成纤维细胞对未修饰脂质体的吸收。对小鼠的全身给药CREKA-Lip导致它们在纤维化肾脏中积累，在那里它们被间质性成肌纤维细胞特异性内化。将CEL装入CREKA-Lip可有效抑制NRK-49F细胞在体外的活化和增殖，并显着减轻小鼠单侧输尿管梗阻引起的肾纤维化，损伤和炎症。此外，载有CEL的CREKA-Lip与游离CEL相比，对主要器官的毒性明显较低。这些结果表明，将CEL封装在CREKA-Lip中可以提高其治疗效果，并降低其全身毒性，作为肾纤维化的潜在治疗方法。
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