Preparation Of Reduction-sensitive Micelles Modified By Glycyrrhetinic Acid And Their Antitumor Activities

Tumor is a serious threat to human health and quality of life.Liver cancer is one of the common malignant tumors.At present,surgery and chemotherapy still play an important role in the treatment of liver cancer.Unfortunately,when patients are diagnosed with liver cancer,most of them are already in the advanced stage of liver cancer and miss the best time for surgery.Therefore,systemic chemotherapy is still the best methods for the treatment of liver cancer.Chemotherapeutic agents also encountered some problems,such as nonselective biodistribution,poor bioavailability and solubility,and low specificity.Moreover,the application of conventional chemotherapy always leads to severe side-effects,such as cardiotoxicity and neurotoxicity.And long-term application of chemotherapeutics will trigger multidrug resistance(MDR)of tumor cells and reduce efficacy.In recent years,in order to target chemotherapeutic drugs to hepatoma cells more effectively,increase local drug concentration and reduce drug toxicity,ligand-based active drug delivery system targeted hepatocellular carcinoma have become more and more popular among researchers.It has been found that many receptors could mediate the active hepatocellular carcinoma-targeting drug delivery systems for the treatment of liver cancer.A number of specific binding sites of glycyrrhetinic acid(GA)had been reported in the cell membrane of rat liver cell.The GA binding sites on liver showed higher affinity activity than other organs.GA is the hydrolysis product of glycyrrhizin.It is extracted from the traditional Chinese medicine licorice.It has similar pharmacological activity to glycyrrhizin.Its hepatoprotective activity has been used in the treatment of liver diseases in Asia for more than 30 years.Therefore,nano drug delivery system modified by glycyrrhetinic acid has broad application prospects.In this study,we developed a dual-functional micellar system constituted by glycyrrhetinic acid-disulfide-poly(ethylene glycol)(mPEG-SS-GA)to achieve both hepatoma-targeting and redox-responsive drug release.Firstly,we synthesized the amphiphilic carrier materials mPEG2000-SS-GA(mPSG)and mPEG2000-SS-CA(mPSC)connected by disulfide bonds.We confirmed the structure of the two kinds of materials by using hydrogen nuclear magnetic resonance spectrum and infrared spectrum.Doxorubicin(DOX),a common antitumor drug,was encapsulated.DOX-loaded micelles(DOX/mPSG)displayed a mean particle size of 225.1±1.882 nm with a poly-dispersity index(0.144±0.038)and negative zeta potential(-16.0±0.404mV).The drug loading and entrapment efficiency of DOX/mPSG were 13.10%and 75.58%,respectively.DOX-loaded micelles(DOX/mPSC)displayed a mean particle size of 226.4±1.102 nm with a low poly-dispersity index(0.061±0.026)and negative zeta potential(-34.1±0.404mV).DOX/mPSG displayed significant cytotoxicity towards HepG2 cells,compared to the control groups.DOX/mPSG weakly inhibited tumor growth in a mouse hepatocellular carcinoma-xenograft model.