title: Development and characterization of sorafenib-loaded PLGA nanoparticles for the systemic treatment of liver fibrosis.
abstract: Sorafenib is a tyrosine kinase inhibitor that has recently been shown to be a potential antifibrotic agent. However, a narrow therapeutic window limits the clinical use and therapeutic efficacy of sorafenib. Herein, we have developed and optimized nanoparticle (NP) formulations prepared from a mixture of poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (PEG-PLGA) copolymers with poly(lactic-co-glycolic acid) (PLGA) for the systemic delivery of sorafenib into the fibrotic livers of CCl4-induced fibrosis mouse models. We characterized and compared the pharmaceutical and biological properties of two different PLGA nanoparticles (NPs)--PEG-PLGA NPs (PEG-PLGA/PLGA=10/0) and PEG-PLGA/PLGA NPs (PEG-PLGA/PLGA=5/5). Increasing the PLGA content in the PEG-PLGA/PLGA mixture led to increases in the particle size and drug encapsulation efficacy and a decrease in the drug release rate. Both PEG-PLGA and PEG-PLGA/PLGA NPs significantly prolonged the blood circulation of the cargo and increased the uptake by the fibrotic livers. The systemic administration of PEG-PLGA or PEG-PLGA/PLGA NPs containing sorafenib twice per week for a period of 4 weeks efficiently ameliorated liver fibrosis, as indicated by decreased α-smooth muscle actin (α-SMA) content and collagen production in the livers of CCl4-treated mice. Furthermore, sorafenib-loaded PLGA NPs significantly shrank the abnormal blood vessels and decreased microvascular density (MVD), leading to vessel normalization in the fibrotic livers. In conclusion, our results reflect the clinical potential of sorafenib-loaded PLGA NPs for the prevention and treatment of liver fibrosis.
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Ts-Ting
authors.initials: TsT
authors.lastname: Lin
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Dong-Yu
authors.initials: DY
authors.lastname: Gao
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Ya-Chi
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Yun-Chieh
authors.initials: YC
authors.lastname: Sung
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Dehui
authors.initials: D
authors.lastname: Wan
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Jia-Yu
authors.initials: JY
authors.lastname: Liu
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Tsaiyu
authors.initials: T
authors.lastname: Chiang
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Liying
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, Taiwan. Electronic address: yunching@mx.nthu.edu.tw.
authors.forename: Yunching
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D004337:Drug Carriers / Q000737:chemistry*; D061307:Human Umbilical Vein Endothelial Cells; D019344:Lactic Acid / Q000737:chemistry; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011098:Polyglactin 910 / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000077157:Sorafenib
chemical_list: D004337:Drug Carriers; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; C102418:poly(lactic-glycolic acid)-poly(ethyleneglycol) copolymer; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D009536:Niacinamide; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011098:Polyglactin 910; D011092:Polyethylene Glycols; D000077157:Sorafenib; D002251:Carbon Tetrachloride
keywords: Liver fibrosis; Nanoparticle; PLGA; Sorafenib