Journal
JOURNAL OF CONTROLLED RELEASE
Volume 283, Issue -, Pages 113-125Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2018.05.032
Keywords
Vitamin A; Micelle; Chemogene therapy; Liver fibrosis; Silibinin; siRNA
Funding
- National Science and Technology Major Project [2017YFA0205400]
- National Natural Science Foundation of China [81773667, 81573369]
- Outstanding Youth Fund of Jiangsu Province of China [BK20160031]
- Open Project of Jiangsu Key Laboratory of Druggability of Biopharmaceuticals [1131730003]
- 111 Project from the Ministry of Education of China
- State Administration of Foreign Experts Affairs of China [B16046]
- Fundamental Research Funds for the Central Universities [2632018PT01, 2632018ZD12]
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Liver fibrosis refers to excessive accumulation of hepatic collagen, which is primarily produced by activated hepatic stellate cells (HSCs). No effective drugs are clinically available to treat this condition, reflecting the fact that antifibrotic drugs do not specifically target activated HSCs. Here, we report the synthesis and evaluation of poly (lactide-co-glycolide)-polyspermine-poly (ethylene glycol)-vitamin A (PLGA-PSPE-PEG-VA), and activated HSC-targeted, biocompatible amphiphilic polymers for co-delivery of chemical (silibinin) and genetic (siCol1 alpha 1) drugs that synergistically suppress collagen I accumulation in fibrogenesis. PLGA-PSPE-PEG-VA self-assembled into core-shell polymeric micelles (PVMs) at low concentrations. After loading with silibinin and siCol1 alpha 1, the resulting chemical/ genetic drug-loaded PVMs (CGPVMs) exhibited a small particle size and a slightly positive surface. CGPVMs had very low cytotoxicity and hemolytic activity in vitro and were well tolerated in mice, with no liver toxicity or inflammation. Importantly, CGPVMs effectively accumulated in fibrotic livers and specifically targeted activated HSCs. As expected CGPVMs more efficiently decreased collagen I production and ameliorated liver fibrosis compared with chemical drug (silibinin)-loaded PVMs (CPVMs) or genetic drug (siCol1 alpha 1)-loaded PVMs (GPVMs) only. These results indicate that CGPVMs are a promising tool for targeted delivery of chemo-genes to activated HSCs in the treatment of liver fibrosis.
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