During liver fibrogenesis, liver sinusoidal capillarization and extracellular matrix (ECM) deposition construct dual pathological barriers to drug delivery. Upon capillarization, the vanished fenestrae in liver sinusoidal endothelial cells (LSECs) significantly hinder substance exchange between blood and liver cells, while excessive ECM further hinders the delivery of nanocarriers to activated hepatic stellate cells (HSCs). Herein, an efficient nanodrug delivery system was constructed to sequentially break through the capillarized LSEC barrier and the deposited ECM barrier. For the first barrier, LSEC-targeting and fenestrae-repairing nanoparticles (named HA-NPs/SMV) were designed on the basis of the modification with hyaluronic acid and the loading of simvastatin (SMV). For the second barrier, collagenase I and vitamin A codecorated nanoparticles with collagen-ablating and HSC-targeting functions (named CV-NPs/siCol1α1) were prepared to deliver siCol1α1 with the goal of inhibiting collagen generation and HSC activation. Our in vivo results showed that upon encountering the capillarized LSEC barrier, HA-NPs/SMV rapidly released SMV and exerted a fenestrae-repairing function, which allowed more CV-NPs/siCol1α1 to enter the space of Disse to degrade deposited collagen and finally to achieve higher accumulation in activated HSCs. Scanning electronic microscopy images showed the recovery of liver sinusoids, and analysis of liver tissue sections demonstrated that HA-NPs/SMV and CV-NPs/siCol1α1 had a synergetic effect. Our pathological barrier-normalization strategy provides an antifibrotic therapeutic regimen.
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 (siCol1α1) 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 siCol1α1 , 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 (siCol1α1)-loaded PVMs (GPVMs) only. These results indicate that CGPVMs are a promising tool for targeted delivery of chemogenes to activated HSCs in the treatment of liver fibrosis.
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