Glycyrrhetinic acid-decorated and reduction-sensitive micelles to enhance the bioavailability and anti-hepatocellular carcinoma efficacy of tanshinone IIA.
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.
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.
Fengqian
F
Chen
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.
Jinming
J
Zhang
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.
Yao
Y
He
Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Xiefan
X
Fang
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.
Yitao
Y
Wang
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.
Meiwan
M
Chen
D045784:Abietanes / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations; D004317:Doxorubicin / Q000008:administration & dosage*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D065546:Drug Liberation / Q000187:drug effects*; D006034:Glycyrrhetinic Acid / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D056945:Hep G2 Cells; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry* / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy*; D051379:Mice; D008823:Micelles; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000494:pharmacology; D011100:Polyglycolic Acid / Q000737:chemistry* / Q000494:pharmacology; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D013388:Succinimides / Q000737:chemistry* / Q000494:pharmacology
D045784:Abietanes; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008823:Micelles; D013388:Succinimides; C021751:tanshinone; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D004317:Doxorubicin; C050761:polyethylene glycol bis(succinimidyl succinate); D006034:Glycyrrhetinic Acid