NDLI: Glycyrrhetinic acid-decorated and reduction-sensitive micelles to enhance the bioavailability and anti-hepatocellular carcinoma efficacy of tanshinone IIA.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Chen, Fengqian Zhang, Jinming He, Yao Fang, Xiefan Wang, Yitao Chen, Meiwan
Description	Author Affiliation: Chen F ( State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China. ytwang@umac.mo mwchen@umac.mo.); Zhang J ( State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China. ytwang@umac.mo mwchen@umac.mo.); He Y ( Pharmacy College, State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.); Fang X ( Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.); Wang Y ( State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China. ytwang@umac.mo mwchen@umac.mo.); Chen M ( State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China. ytwang@umac.mo mwchen@umac.mo.)
Abstract	It remains a challenge to increase drug tumor-specific accumulation as well as to achieve intracellular-controlled drug release for hepatocellular carcinoma (HCC) chemotherapy. Herein, we developed a dual-functional biodegradable micellar system constituted by glycyrrhetinic acid coupling poly(ethylene glycol)-disulfide linkage-poly(lactic-co-glycolic acid) (GA-PEG-SS-PLGA) to achieve both hepatoma-targeting and redox-responsive intracellular drug release. Tanshinone IIA (TAN IIA), an effective anti-HCC drug, was encapsulated. Notably, it exhibited rapid aggregation and faster drug release in 10 mM dithiothreitol compared with the redox-insensitive control. Furthermore, GA-decorated micelles revealed HCC-specific cellular uptake in human liver cancer HepG2 cells with an energy-dependent manner, in which micropinocytosis and caveolae-mediated endocytosis were demonstrated as the major cellular pathways. The enhanced cytotoxicity and pro-apoptotic effects against HepG2 cells in vitro were observed, mediated by up-regulation of the intracellular ROS level, the increased cell cycle arrest at S phase, enhanced necrocytosis and up-regulation of caspase 3/7, P38 protein expression. In addition, TAN IIA-loaded micelles had a significantly prolonged circulation time, improved bioavailability, and resulted in an increased accumulation of TAN IIA in the liver. With the synergistic effects of HCC-targeting and controlled drug release, TAN IIA-loaded GA-PEG-SS-PLGA micelles significantly inhibited tumor growth and increased survival time in a mouse HCC-xenograft model. Collectively, the GA-PEG-SS-PLGA micelles with HCC-targeting and redox-sensitive characters would provide a novel strategy to deliver TAN IIA effectively for HCC therapy.
File Format	HTM / HTML
ISSN	20474830
Issue Number	1
Journal	Biomaterials Science
Volume Number	4
e-ISSN	20474849
Language	English
Publisher	Royal Society of Chemistry
Publisher Date	2016-01-01
Publisher Place	Great Britain (UK)
Access Restriction	Subscribed
Subject Keyword	Discipline Biomedical Engineering Discipline Therapeutics
Content Type	Text
Resource Type	Article
Subject	Materials Science Biomedical Engineering

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