Journal
ACS NANO
Volume 16, Issue 12, Pages 20739-20757Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.2c07796
Keywords
liver fibrosis; hepatic stellate cells; targeted delivery; endogenous ROS-responsive nanocarrier; polypeptide biomacromolecule
Categories
Funding
- CAMS Innovation Fund for Medical Sciences (CIFMS) [2021-I2M-1-026, 2022-I2M-2-002, 2022-I2M-JB-012, 2021-I2M-1-070, 2022-I2M-1-016]
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Hepatic fibrosis is a chronic liver disease that lacks effective pharmacotherapeutic treatments. Researchers have designed targeted and reactive oxygen species (ROS)-responsive micelles for the specific delivery of resveratrol (RES), a traditional Chinese medicine, to activated hepatic stellate cells (aHSCs) for the treatment of liver fibrosis. In vitro and in vivo experiments demonstrate that these micelles enhance the targeted delivery of RES to aHSCs, reduce collagen accumulation, and protect hepatocytes from damage.
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-epsilon-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.
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