Reactive Oxygen Species-Responsive Polypeptide Drug Delivery System Targeted Activated Hepatic Stellate Cells to Ameliorate Liver Fibrosis

Abstract

Hepatic fibrosis is a chronic liver disease that lacks effective pharmacotherapeutic treatments. As part of the disease's mechanism, hepatic stellate cells (HSCs) are activated by damage-related stimuli to secrete excessive extracellular matrix, leading to collagen deposition. Currently, the drug delivery system that targets HSCs in the treatment of liver fibrosis remains an urgent challenge due to the poor controllability of drug release. Since the level of reactive oxygen species (ROS) increases sharply in activated HSCs (aHSCs), we designed ROS-responsive micelles for the HSC-specific delivery of a traditional Chinese medicine, resveratrol (RES), for treatment of liver fibrosis. The micelles were prepared by the ROS-responsive amphiphilic block copolymer poly(L-methionine-block-N ε -trifluoro-acetyl-L-lysine) (PMK) and a PEG shell modified with a CRGD peptide insertion. The CRGD-targeted and ROS-responsive micelles (CRGD-PMK-MCs) could target aHSCs and control the release of RES under conditions of high intracellular ROS in aHSCs. The CRGD-PMK-MCs treatment specifically enhanced the targeted delivery of RES to aHSCs both in vitro and in vivo. In vitro experiments show that CRGD-PMK-MCs could significantly promote ROS consumption, reduce collagen accumulation, and avert activation of aHSCs. In vivo results demonstrate that CRGD-PMK-MCs could alleviate inflammatory infiltration, prevent fibrosis, and protect hepatocytes from damage in fibrotic mice. In conclusion, CRGD-PMK-MCs show great potential for targeted and ROS-responsive controlled drug release in the aHSCs of liver fibrosis.

Comment on “Reactive Oxygen Species-Responsive Polypeptide Drug Delivery System Targeted Activated Hepatic Stellate Cells to Ameliorate Liver Fibrosis”

“…R ecently, Hao and colleagues described a novel reactive oxygen species (ROS)-responsive drug release system for hepatic stellate cell (HSC)-targeted delivery of resveratrol for liver fibrosis treatment. 1 The authors extend previous findings about resveratrol-delivering strategies. 2 They constructed a new nanocarrier induced by ROS in HSCs, and the nanocarrier enhanced the HSC-oriented delivery of resveratrol, which alleviated both the transition of HSCs and the production of collagen to slow the progression of liver fibrosis.…”

“…Recently, Hao and colleagues described a novel reactive oxygen species (ROS)-responsive drug release system for hepatic stellate cell (HSC)-targeted delivery of resveratrol for liver fibrosis treatment . The authors extend previous findings about resveratrol-delivering strategies .…”

Nanostructures in Chinese herbal medicines (CHMs) for potential therapy

“…These micelles have been shown to reduce inflammation in fibrotic mice, prevent fibrosis, and protect hepatocytes from damage. 100 Liposomes contribute to the treatment of digestive system diseases. The utilization of nanoliposomes to encapsulate aloe emodin and deliver it for transfection of the r-caspase-3 gene, along with photodynamic therapy, has demonstrated efficient inhibition of proliferation and induction of apoptosis in human gastric cancer cells.…”

“…Resveratrol is designed as ROS-responsive micelles, which penetrated hepatic stellate cells for delivery into the target organ to treat liver fibrosis, demonstrating the great potential of CHM-derived micelles for targeting liver diseases. 100 The same function of ROS-responsive micelles is applied to target hepatoma by loading celastrol into a glycyrrhetinic acid-modified CMCS–thioketal–rhein conjugate 101 and to target inflammatory bowel diseases by incorporating aryl boronic ester as a responsive linker of covalently linked quercetin and biocompatible glycol chitosan. 102 Vinegar baked Radix Bupleuri (VBRB) has the ability to guide drugs to the liver, and thus it is co-administered with 10-hydroxycamptothecin (HCPT)-loaded polymer micelles to enhance HCPT liver targeting.…”

Reply to “Comment on ‘Reactive Oxygen Species-Responsive Polypeptide Drug Delivery System Targeted Activated Hepatic Stellate Cells to Ameliorate Liver Fibrosis’”

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Metrics & MoreArticle Recommendations S un et al made reasonable suggestions for some of the results of our recent article. 1 As follows: (i) the expression levels of α-SMA and collagen I in the RES/ CRGD-PMK-MCs group, (ii) the ability of resveratrol and CRGD to alleviate the progression of liver fibrosis, and (iii) the effect of RES/CRGD-PMK-MCs on the lung tissue of healthy mice, etc. As described in this Reply, we interpreted the results of our article by reviewing and referring to other published articles.A Note on the Expression Levels of α-SMA and Collagen I in the RES/CRGD-PMK-MCs Group.

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