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Glycyrrhetinic Acid-Mediated Polymeric Drug Delivery Targeting the Acidic Microenvironment of Hepatocellular Carcinoma

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ABSTRACT

Purpose

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.

A novel dual-functional polymeric micellar system loading andrographolide (AGP) was formulated for HCC treatment to target to hepatoma tissue actively and release drugs in hepatoma cells selectively. The synergetic cytotoxicity in vitro and anticancer efficiency in vivo of micelles mediated by hepatoma-guide of glycyrrhetinic acid (GA) and pH-sensitive of Poly(L-histidine)(PHIS) moiety were demonstrated.

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Abbreviations

AFM:

Atomic force microscopy

AGP:

Andrographolide

ANOVA:

Analysis of variance

6-C/GA-PPP:

6-C loaded GA-PPP micelles

CLSM:

Confocal laser scanning microscopy

DCC:

N, N’-Dicyclohexylcarbodiimide

DCU:

N, N’-Dicyclohexylurea

DMEM:

Dulbecco’s modified eagle medium

EPR:

Enhanced permeability and retention

FBS:

Fetal bovine serum

FTIR:

Fourier transform infrared spectroscopy

GA:

Glycyrrhetinic acid

GA-PEG-NH2:

GA coupled-poly(ethylene glycol) with NH2 terminal

GA-PPP:

GA-PEG-PHIS-PLGA

HCC:

Hepatocellular carcinoma

H&E:

Haematoxylin/eosin

ICG:

Indocyanine green

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide

NHS:

N-hydroxysuccinimide

NMR:

Nuclear magnetic resonance

PHIS:

Poly(l-histidine)

PI:

Propidium iodide

PLGA-PHIS:

Poly(lactic-co-glycolic acid)-block-poly(L-histidine)

PP:

PEG-PLGA

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was supported by the Macao Science and Technology Development Fund (062/2013/A2), and the Research Fund of the University of Macau (MRG004/CMW/2014/ICMS, MYRG 208 (Y3-L4)-ICMS11-WYT, MYRG2014-00051-ICMS-QRCM, MYRG2014-00033-ICMS-QRCM), and the fund from National Natural Science Foundation of China (81403120, 21101080).

The authors declare no competing financial interest.

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Authors and Affiliations

  1. 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

    Jinming Zhang, Yitao Wang & Meiwan Chen

  2. School of Chemistry and Chemical engineering, South China University of Technology, Guangzhou, 510640, China

    Min Zhang

  3. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China

    Juan Ji, Xin Pan & Chuanbin Wu

  4. Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, 32610, USA

    Xiefan Fang

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  1. Jinming Zhang
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  2. Min Zhang
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  3. Juan Ji
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  5. Xin Pan
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Correspondence to Yitao Wang or Meiwan Chen.

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Zhang, J., Zhang, M., Ji, J. et al. Glycyrrhetinic Acid-Mediated Polymeric Drug Delivery Targeting the Acidic Microenvironment of Hepatocellular Carcinoma. Pharm Res 32, 3376–3390 (2015). https://doi.org/10.1007/s11095-015-1714-2

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  • DOI: https://doi.org/10.1007/s11095-015-1714-2

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