Co-encapsulation of collagenase type I and silibinin in chondroitin sulfate coated multilayered nanoparticles for targeted treatment of liver fibrosis. (1st July 2021)

• Record Type: Journal Article
• Authors: Luo, Jingwen; Zhang, Zhiwei; Zeng, Yingchun; Dong, Yanming; Ma, Lixin
• Is Part Of: Carbohydrate polymers. Volume 263(2021)
• Publication Date: 2021-07-01
• Subjects: Liver fibrosis -- Extracellular matrix barrier -- Activated hepatic stellate cells -- Co-administration drug delivery system -- Biomacromolecular drug; Polysaccharides -- Periodicals; Polysaccharides -- Periodicals; Polysaccharides -- Périodiques; Electronic journals; 547.78
• DOI: 10.1016/j.carbpol.2021.117964
• Languages: English
• ISSNs: 0144-8617

Abstract

Graphical abstract: Highlights: A new biocompatible material, oleic acid modified polyethyleneimine, was synthesized and characterized. Chondroitin sulfate coated multilayered nanoparticles for co-delivery of biomacromolecular and small-molecule drugs. Silibinin and collagenase type I were first used in combination for the treatment of liver fibrosis. Detailed and in-depth evaluations about the multilayered nanoparticles had been made in vitro and in vivo . Abstract: Components of the extracellular matrix (ECM) are overexpressed in fibrotic liver. Collagen is the main component of the liver fibrosis stroma. Here we demonstrate that chondroitin sulfate coated multilayered 50-nm nanoparticles encapsulating collagenase and silibinin (COL + SLB-MLPs) break down the dense collagen stroma, while silibinin inhibits activated hepatic stellate cells. The nanoparticles were taken up to a much greater extent by hepatic stellate cells than by normal hepatocytes, and they down-regulated production of type I collagen. In addition, chondroitin sulfate protected the collagenase from premature deactivation. COL + SLB-MLPs were delivered to the cirrhotic liver, and the collagenase and silibinin synergistically inhibited fibrosis in mice. Immunofluorescence staining of liver tissues revealed that CD44, mediated by chondroitin sulfate, delivered the nanoparticles to hepatic stellate cells. This strategy holds promise for degrading extracellular stroma and thereby facilitating drug penetration into fibrotic liver and related diseases such as liver cirrhosis and liver cancer.