Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital of Sichuan University, Chengdu 610041, China.
Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China.
Mol Pharm. 2021 Mar 1;18(3):1373-1385. doi: 10.1021/acs.molpharmaceut.0c01182. Epub 2021 Feb 5.
Renal fibrosis is the final manifestation of various chronic kidney diseases. Interstitial myofibroblasts, which are reported to highly express integrin αvβ3, are the effector cells in renal fibrogenesis. Since current therapies do not efficiently target these cells, there is no effective therapeutic method for preventing or mitigating the disease. Here, we modified sterically stable PEGylated liposomes with the pentapeptide cRGDfC (RGD-Lip), which has a high affinity for αvβ3, to specifically deliver drug to renal interstitial myofibroblasts. Our results showed that attaching cRGDfC to liposomes significantly increased their uptake by activated renal fibroblasts NRK-49F cells, and this effect was greatly abolished by adding excess-free cRGDfC or a knockdown of αvβ3. Systemic administration of RGD-Lip gave rise to significant accumulation in a fibrotic kidney, which is ascribed to the specific recognition with integrin αvβ3 on interstitial myofibroblasts. When loaded with celastrol, RGD-guided liposomes dramatically depressed the proliferation and activation of NRK-49F cells . Additionally, celastrol-loaded RGD-Lip markedly attenuated renal fibrosis, injury, and inflammation induced by unilateral ureteral obstruction (UUO) in mice, without inducing significant systemic toxicity. Thus, this liposomal system shows great promise for delivering therapeutic agents to interstitial myofibroblasts for renal fibrosis treatment with minimal side effects.
肾纤维化是各种慢性肾脏病的终末表现。研究报道，高度表达整合素 αvβ3 的间质肌成纤维细胞是肾纤维化发生的效应细胞。由于目前的治疗方法不能有效地靶向这些细胞，因此没有有效的治疗方法来预防或减轻这种疾病。在这里，我们用五肽 cRGDfC（RGD- Lip）修饰了空间稳定的聚乙二醇化脂质体，该五肽对 αvβ3 具有高亲和力，以将药物特异性递送至肾间质肌成纤维细胞。我们的结果表明，将 cRGDfC 连接到脂质体上可显著增加其被激活的肾成纤维细胞 NRK-49F 细胞的摄取，而添加过量的游离 cRGDfC 或敲低 αvβ3 则大大抑制了这种作用。RGD-Lip 的系统给药导致在纤维化肾脏中产生明显的蓄积，这归因于与间质肌成纤维细胞上的整合素 αvβ3 的特异性识别。当负载雷公藤红素时，RGD 引导的脂质体可显著抑制 NRK-49F 细胞的增殖和激活。此外，雷公藤红素负载的 RGD-Lip 可显著减轻单侧输尿管梗阻（UUO）诱导的小鼠肾纤维化、损伤和炎症，而不会引起明显的全身毒性。因此，这种脂质体系统在将治疗剂递送至间质肌成纤维细胞以治疗肾纤维化方面具有很大的潜力，副作用极小。
