Dual-Ligand-Functionalized Liposomes Based on Glycyrrhetinic Acid and cRGD for Hepatocellular Carcinoma Targeting and Therapy

Mingxing Qiu; Jiong Wang; Jiaojiao Bai; Xiaoxu Li; Cuiqing Tian; Zhi Liu; Chaoran Zheng; Andrew R Clark; Xinwei Cheng; Xiaoyan Liao; Song Wu; Robert J Lee; Xiaoju Zhou

doi:10.1021/acs.molpharmaceut.2c00842

Dual-Ligand-Functionalized Liposomes Based on Glycyrrhetinic Acid and cRGD for Hepatocellular Carcinoma Targeting and Therapy

Mol Pharm. 2023 Apr 3;20(4):1951-1963. doi: 10.1021/acs.molpharmaceut.2c00842. Epub 2023 Mar 23.

Authors

Mingxing Qiu¹, Jiong Wang^{1

2}, Jiaojiao Bai¹, Xiaoxu Li¹, Cuiqing Tian¹, Zhi Liu¹, Chaoran Zheng¹, Andrew R Clark³, Xinwei Cheng⁴, Xiaoyan Liao¹, Song Wu¹, Robert J Lee⁴, Xiaoju Zhou¹

Affiliations

¹ Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China.
² Wuhan Grand Hoyo Pharmaceutical Co., Ltd., Wuhan 430074, China.
³ Indiana Center for Regenerative Medicine & Engineering, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States.
⁴ Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.

PMID: 36952242
DOI: 10.1021/acs.molpharmaceut.2c00842

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers, with high mortality. Chemotherapy is one of the main treatment options for HCC. However, the high toxicity and poor specificity of chemotherapeutic drugs have limited their clinical application. In this study, dual-ligand liposomes modified with glycyrrhetinic acid (GA) and cyclic arginine-glycine-aspartic acid (cRGD) (GA/cRGD-LP) were designed to target the GA receptor and αvβ3 integrin, respectively. The aim was to develop a highly selective targeted drug delivery system and further enhance the antitumor efficiency of drugs by targeting both hepatic tumor cells and vasculature. A novel lipid conjugate (mGA-DOPE) by coupling dioleoylphosphatidyl ethanolamine (DOPE) with methyl glycyrrhetinic acid (mGA) was synthesized, and its structure was confirmed. The targeting efficiency of GA/cRGD-LP by in vitro cellular uptake and ex vivo imaging was assessed. GA- and cRGD-modified doxorubicin-loaded liposomes (GA/cRGD-LP-DOX) were prepared, and their cytotoxicity in HepG2 and antitumor activity were evaluated. The results showed that the average particle size of the GA/cRGD-LP-DOX was 114 ± 4.3 nm, and the zeta potential was -32.9 ± 2.0 mV. The transmission electron microscopy images showed that the shapes of our liposomes were spherical. cGA/cRGD-LP-DOX displayed an excellent cellular uptake in both HepG2 and human umbilical vein endothelial cells. In the in vivo study, pharmacokinetic parameters indicated that cGA/cRGD-LP can prolong the circulation time of DOX in the blood. GA/cRGD-LP-DOX showed greater inhibition of tumor growth for HepG2-bearing mice than either the single-ligand-modified liposomes or nontargeted liposomes. GA/cRGD-LP-DOX displayed higher liver tumor localization than that of single-ligand-modified liposomes or free DOX. GA/cRGD-LP is a promising drug delivery system for liver cancer targeting and therapy and is worthy of further study.

Keywords: cRGD; dual-ligand; glycyrrhetinic acid; hepatocellular carcinoma; liposomes; targeted therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Hepatocellular* / drug therapy
Carcinoma, Hepatocellular* / pathology
Cell Line, Tumor
Doxorubicin
Endothelial Cells
Glycyrrhetinic Acid* / chemistry
Humans
Ligands
Liposomes / chemistry
Liver Neoplasms* / drug therapy
Liver Neoplasms* / pathology
Mice

Substances

Liposomes
Ligands
Glycyrrhetinic Acid
liposomal doxorubicin
Doxorubicin