title: Glycyrrhetinic Acid-Mediated Polymeric Drug Delivery Targeting the Acidic Microenvironment of Hepatocellular Carcinoma.
abstract: OBJECTIVE
  The major hurdle of current drug carrier against hepatocellular carcinoma (HCC) is the lack of specific and selective drug delivery to HCC. In this study, a novel glycyrrhetinic acid (GA) and poly(L-Histidine) (PHIS) mediated polymeric drug delivery system was developed to target HCC that have GA binding receptors and release its encapsulated anticancer drug in the acidic microenvironment of HCC.
  
  
  METHODS
  Firstly, GA and PHIS were conjugated to form poly (ethylene glycol)-poly(lactic-co-glycolic acid) (GA-PEG-PHIS-PLGA, GA-PPP) micelles by grafting reaction between active terminal groups. Secondly, andrographolide (AGP) was encapsulated to GA-PPP to make AGP/GA-PPP using the solvent evaporation method. The pH-responsive property of AGP/GA-PPP micelles was validated by monitoring its stability and drug release behavior in different pH conditions. Furthermore, selective hepatocellular uptake of GA-PPP micelles in vitro, liver specific drug accumulation in vivo, as well as the enhanced antitumor effects of AGP/GA-PPP micelles confirmed the HCC targeting property of our novel drug delivery system.
  
  
  RESULTS
  Average size of AGP/GA-PPP micelles increased significantly and the encapsulated AGP released faster in vitro at pH 5.0, while micelles keeping stable in pH 7.4. AGP/GA-PPP micelles were uptaken more efficiently by human Hep3B liver cells than that by human MDA-MB-231 breast cancer cells. GA-PPP micelles accumulated specifically in the liver and possessed long retention time in vivo. AGP/GA-PPP micelles significantly inhibited tumor growth and provided better therapeutic outcomes compared to free AGP and AGP/PEG-PLGA(AGP/PP) micelles without GA and PHIS decoration.
  
  
  CONCLUSIONS
  This novel GA-PPP polymeric carrier is promising for targeted treatment of HCC.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Av. Padre Tomas Pereira S.J., Taipa, Macau, 999078, China.
authors.forename: Jinming
authors.initials: J
authors.lastname: Zhang
authors.affiliation: School of Chemistry and Chemical engineering, South China University of Technology, Guangzhou, 510640, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Ji
authors.affiliation: Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, 32610, USA.
authors.forename: Xiefan
authors.initials: X
authors.lastname: Fang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Pan
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Av. Padre Tomas Pereira S.J., Taipa, Macau, 999078, China. ytwang@umac.mo.
authors.forename: Yitao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
authors.forename: Chuanbin
authors.initials: C
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Av. Padre Tomas Pereira S.J., Taipa, Macau, 999078, China. mwchen@umac.mo.
authors.forename: Meiwan
authors.initials: M
authors.lastname: Chen
mesh_terms: D000143:Acids / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D006034:Glycyrrhetinic Acid / Q000008:administration & dosage* / Q000737:chemistry; D006639:Histidine / Q000008:administration & dosage / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000008:administration & dosage* / Q000737:chemistry; D008099:Liver / Q000187:drug effects; D008113:Liver Neoplasms / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D011091:Polyesters / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D011100:Polyglycolic Acid / Q000008:administration & dosage* / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer
chemical_list: D000143:Acids; D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D011091:Polyesters; C000589473:polyethylene glycol-poly(lactide-co-glycolide); D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; C033223:polyhistidine; D019344:Lactic Acid; D011092:Polyethylene Glycols; D006639:Histidine; D006034:Glycyrrhetinic Acid
keywords: andrographolide; glycyrrhetinic acid; hepatocellular carcinoma; micelles; pH-sensitive