肌成纤维细胞
索拉非尼
归巢(生物学)
纤维化
药物输送
癌症研究
肾
医学
体内
药理学
化学
病理
内科学
生物
肝细胞癌
生态学
生物技术
有机化学
作者
Hui‐Teng Cheng,Hsi‐Chien Huang,Tsung‐Ying Lee,Yuhui Liao,Yi-Hua Sheng,Pei-Ru Jin,Kuan‐Wei Huang,Ling-Hsuan Chen,Yi‐Ting Chen,Ziyan Liu,Tzu‐Chieh Lin,Hsueh‐Cheng Wang,Cheng‐Han Chao,I. Pu Juang,Chi-Ting Su,Kuo‐How Huang,Shuei‐Liong Lin,Jane Wang,Yun‐Chieh Sung,Yunching Chen
标识
DOI:10.1016/j.jconrel.2022.04.004
摘要
Fibrosis is an excessive accumulation of the extracellular matrix within solid organs in response to injury and a common pathway that leads functional failure. No clinically approved agent is available to reverse or even prevent this process. Herein, we report a nanotechnology-based approach that utilizes a drug carrier to deliver a therapeutic cargo specifically to fibrotic kidneys, thereby improving the antifibrotic effect of the drug and reducing systemic toxicity. We first adopted in vitro-in vivo combinatorial phage display technology to identify peptide ligands that target myofibroblasts in mouse unilateral ureteral obstruction (UUO)-induced fibrotic kidneys. We then engineered lipid-coated poly(lactic-co-glycolic acid) nanoparticles (NPs) with fibrotic kidney-homing peptides on the surface and sorafenib, a potent antineoplastic multikinase inhibitor, encapsulated in the core. Sorafenib loaded in the myofibroblast-targeted NPs significantly reduced the infiltration of α-smooth muscle actin-expressing myofibroblasts and deposition of collagen I in UUO-treated kidneys and enhanced renal plasma flow measured by Technetium-99m mercaptoacetyltriglycine scintigraphy. This study demonstrates the therapeutic potential of the newly identified peptide fragments as anchors to target myofibroblasts and represents a strategic advance for selective delivery of sorafenib to treat renal fibrosis. Renal fibrosis is a pathological feature accounting for the majority of issues in chronic kidney disease (CKD), which may progress to end-stage renal disease (ESRD). This manuscript describes a myofibroblast-targeting drug delivery system modified with phage-displayed fibrotic kidney-homing peptides. By loading the myofibroblast-targeting nanoparticles (NPs) with sorafenib, a multikinase inhibitor, the NPs could suppress collagen synthesis in cultured human myofibroblasts. When given intravenously to mice with UUO-induced renal fibrosis, sorafenib loaded in myofibroblast-targeting NPs significantly ameliorated renal fibrosis. This approach provides an efficient therapeutic option to renal fibrosis. The myofibroblast-targeting peptide ligands and nanoscale drug carriers may be translated into clinical application in the future.
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