Matrix metalloproteinase-1 decorated polymersomes, a surface-active extracellular matrix therapeutic, potentiates collagen degradation and attenuates early liver fibrosis
Date
2021-03
Journal Title
Journal ISSN
Volume Title
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Abstract
Liver fibrosis affects millions of people worldwide and is rising vastly over the past decades. With no viable
therapies available, liver transplantation is the only curative treatment for advanced diseased patients. Excessive
accumulation of aberrant extracellular matrix (ECM) proteins, mostly collagens, produced by activated hepatic
stellate cells (HSCs), is a hallmark of liver fibrosis. Several studies have suggested an inverse correlation between
collagen-I degrading matrix metalloproteinase-1 (MMP-1) serum levels and liver fibrosis progression highlighting
reduced MMP-1 levels are associated with poor disease prognosis in patients with liver fibrosis. We
hypothesized that delivery of MMP-1 might potentiate collagen degradation and attenuate fibrosis development.
In this study, we report a novel approach for the delivery of MMP-1 using MMP-1 decorated polymersomes
(MMPsomes), as a surface-active vesicle-based ECM therapeutic, for the treatment of liver fibrosis. The storagestable
and enzymatically active MMPsomes were fabricated by a post-loading of Psomes with MMP-1.
MMPsomes were extensively characterized for the physicochemical properties, MMP-1 surface localization,
stability, enzymatic activity, and biological effects. Dose-dependent effects of MMP-1, and effects of MMPsomes
versus MMP-1, empty polymersomes (Psomes) and MMP-1 + Psomes on gene and protein expression of collagen-
I, MMP-1/TIMP-1 ratio, migration and cell viability were examined in TGFβ-activated human HSCs. Finally, the
therapeutic effects of MMPsomes, compared to MMP-1, were evaluated in vivo in carbon-tetrachloride (CCl4)-
induced early liver fibrosis mouse model. MMPsomes exhibited favorable physicochemical properties, MMP-1
surface localization and improved therapeutic efficacy in TGFβ-activated human HSCs in vitro. In CCl4-induced
early liver fibrosis mouse model, MMPsomes inhibited intra-hepatic collagen-I (ECM marker, indicating early
liver fibrosis) and F4/80 (marker for macrophages, indicating liver inflammation) expression. In conclusion, our
results demonstrate an innovative approach of MMP-1 delivery, using surface-decorated MMPsomes, for alleviating
liver fibrosis.
Description
CITATION: Geervliet E, Moreno S, Baiamonte L, et al. 2021. Matrix metalloproteinase-1 decorated polymersomes, a surface-active extracellular matrix therapeutic, potentiates collagen degradation and attenuates early liver fibrosis. Journal of Controlled Release : Official Journal of the Controlled Release Society. 332:594-607. doi.10.1016/j.jconrel.2021.03.016.
The original publication is available at: europepmc.org
The original publication is available at: europepmc.org
Keywords
Surface active agents, Extracellular polymeric substances, Liver -- Fibrosis, Metalloproteinases
Citation
Geervliet E, Moreno S, Baiamonte L, et al. 2021. Matrix metalloproteinase-1 decorated polymersomes, a surface-active extracellular matrix therapeutic, potentiates collagen degradation and attenuates early liver fibrosis. Journal of Controlled Release : Official Journal of the Controlled Release Society. 332:594-607. doi.10.1016/j.jconrel.2021.03.016.