Delivery of sorafenib by myofibroblast-targeted nanoparticles for the treatment of renal fibrosis

Hui Teng Cheng, Hsi Chien Huang, Tsung Ying Lee, Yu Hui Liao, Yi Hua Sheng, Pei Ru Jin, Kuan Wei Huang, Ling Hsuan Chen, Yi Ting Chen, Zi Yan 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

*此作品的通信作者

研究成果: Article同行評審

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. Significance statement: 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.

原文English
頁(從 - 到)169-179
頁數11
期刊Journal of Controlled Release
346
DOIs
出版狀態Published - 6月 2022

指紋

深入研究「Delivery of sorafenib by myofibroblast-targeted nanoparticles for the treatment of renal fibrosis」主題。共同形成了獨特的指紋。

引用此