Abstract
Sorafenib, a tyrosine kinase inhibitor, has been shown as a potential antifibrotic agent. However, a narrow therapeutic window limits its clinical use and therapeutic efficacy of sorafenib. Herein we have developed and designed a drug delivery system - nanoparticle (NP) formulations prepared from mixture of poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (PEG-PLGA) copolymers with poly(lactic-co-glycolic acid) (PLGA) as a vehicle to deliver sorafenib into fibrotic livers of CCl4-induced fibrosis mouse model. We characterized and compared pharmaceutical and biological properties of two different PLGA nanoparticles: PEG-PLGA (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, leading to vessel normalization in the fibrotic livers. In conclusion, our results support the clinical potential of sorafenib-loaded PLGA NPs for the prevention and treatment of liver fibrosis.