https://scholars.lib.ntu.edu.tw/handle/123456789/613125
標題: | Delivery of sorafenib by myofibroblast-targeted nanoparticles for the treatment of renal fibrosis | 作者: | HUI-TENG CHENG Huang, Hsi-Chien Lee, Tsung-Ying Liao, Yu-Hui Sheng, Yi-Hua Jin, Pei-Ru Huang, Kuan-Wei Chen, Ling-Hsuan YI-TING CHEN Liu, Zi-Yan Lin, Tzu-Chieh Wang, Hsueh-Cheng CHENG-HAN CHAO Juang, I Pu CHI-TING SU KUO-HOW HUANG SHUEI-LIONG LIN JANE WANG Sung, Yun-Chieh Chen, Yunching |
關鍵字: | Phage display; Renal fibrosis; Sorafenib | 公開日期: | 六月-2022 | 卷: | 346 | 來源出版物: | Journal of controlled release : official journal of the Controlled Release Society | 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. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/613125 | ISSN: | 01683659 | DOI: | 10.1016/j.jconrel.2022.04.004 |
顯示於: | 醫學系 |
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