Cellular uptake mechanism and clearance kinetics of fluorescence-labeled glycyrrhetinic acid and glycyrrhetinic acid–modified liposome in hepatocellular carcinoma cells

Sun, Yuqi; Lu, Junfu; Yan, Dongxue; Shen, Liping; Hu, Haiyang; Chen, Dawei

doi:10.1016/j.etap.2017.05.003

Cited by 20 publications

(14 citation statements)

References 32 publications

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“…Sun et al developed GA-modified liposomes (GA-LPs), where GA was first covalently bonded to the distal end of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)] (DSPE-PEG) by amide and, second, loaded onto the liposome surface [92]. GA-LPs were then labeled with fluorescein isothiocyanate (FITC) or coumarin-6 (Cou6) to in vitro study the cellular uptake mechanism and clearance kinetics in the human liver cancer cell line (HepG2), proving the affinity of GA with the hepatocellular carcinoma cells.…”

Section: Liposomesmentioning

confidence: 99%

Glycyrrhizic Acid and Its Hydrolyzed Metabolite 18β-Glycyrrhetinic Acid as Specific Ligands for Targeting Nanosystems in the Treatment of Liver Cancer

et al. 2021

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Glycyrrhizic acid and its hydrolyzed metabolite 18β-glycyrrhetinic acid, obtained from the plant Glycyrrhiza glabra, have numerous pharmacological activities, such as anti-inflammatory, anti-ulcerative, antiallergic, immunomodulatory, antiviral, antitumor, hepatoprotective, and antioxidant effects, and others. In addition to the pharmacological activities, in the 1980s, an interaction and uptake of these molecules by the liver was verified, which was later confirmed by other studies through the discovery of specific receptors in the hepatocytes. The presence of these specific receptors in the liver led to vectorization and delivery of drugs, by the introduction of glycyrrhizic acid or glycyrrhetinic acid on the surface of nanosystems, for the treatment of liver diseases. This review describes experimental evidence of vectorization by conjugating glycyrrhizic acid or glycyrrhetinic acid to nanosystems and delivery of antitumor drugs for the treatment of liver cancer and also describes the techniques used to perform this conjugation. We have shown that due to the existence of specific receptors for these molecules, in addition to the targeting of nanosystems to hepatocytes, nanosystems having glycyrrhizic acid or glycyrrhetinic acid on their surface had the same therapeutic effect in a significantly lower dose compared to the free drug and unconjugated nanosystems, with consequent reduction of side effects and toxicity.

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Section: Liposomesmentioning

confidence: 99%

Glycyrrhizic Acid and Its Hydrolyzed Metabolite 18β-Glycyrrhetinic Acid as Specific Ligands for Targeting Nanosystems in the Treatment of Liver Cancer

et al. 2021

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“…1 Apart from surgical resection and liver transplantation, chemotherapy is an important treatment strategy for liver cancer. 2 Although various chemotherapeutic agents are used to treat this serious disease, the lack of targeted ability and systemic cytotoxicity are the two main problems that the chemotherapeutic agents encounter. 3 For liver cancer therapy, targeted drug-delivery system is highly desired in order to increase the therapeutic effect and decrease the side effect.…”

Section: Introductionmentioning

confidence: 99%

Targeted pharmacokinetics of polymeric micelles modified with glycyrrhetinic acid and hydrazone bond in H22 tumor-bearing mice

et al. 2019

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Liver cancer is one of the most common malignant tumors. Chemotherapy drugs have been widely used in the anti-hepatoma research. However, low targeting efficiency and serious adverse reaction are their main drawbacks. Liver tumor was proved to have a slightly acidic microenvironment (pH 4.5–5.5) and many glycyrrhetinic-acid-specific binding sites. Therefore, in the present study, the glycyrrhetinic acid- and hydrazone bond-modified micelles were designed. mPEG-HZ-PLA and GA-PEG-PLA copolymer were synthesized to prepare glycyrrhetinic-acid-modified pH-sensitive polymeric micelles (GA-PEG-HZ-PLA). The targeted pharmacokinetics was used to evaluate the effect in hepatoma 22 tumor-bearing mice after the micelles were administered intravenously. The contents of coumarin-6 in blood and tissues were determined through high-performance liquid chromatography using a fluorescence detection (HPLC-FLD) with coumarin-30 as inner standard. The micelles have shown long-circulation effects and two-department models. In the targeting pharmacokinetics, the relative intake efficiency, targeted efficiency, relative targeting efficiency, and concentration ratio of GA-PEG-HZ-PLA in the tumor were 3.24, 4.04, 3.00, and 2.47, respectively. We have demonstrated that GA-PEG-HZ-PLA was more effectively accumulated in the liver and tumor. Thus, the prepared active-targeted and pH-sensitive micelles modified with glycyrrhetinic acid structure and hydrazone bond are promising tools for effective liver cancer therapy.

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“…Glycyrrhetinic acid (GA) is the active aglycone of glycyrrhizin, which belongs to a pentacyclic triterpene derivate. 27 Specific receptors for GA on the cytomembrane of hepatocytes have been verified. 28,29 Protein kinase Cα is the target binding protein of GA that shows higher expression in HCC cells than that in adjacent nontumor liver cells.…”

Section: Introductionmentioning

confidence: 93%

<p>Liver-targeted liposomes for codelivery of curcumin and combretastatin A4 phosphate: preparation, characterization, and antitumor effects</p>

Jiang¹,

Li²,

Tian³

et al. 2019

IJN

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Background: Recent efforts have been focused on combining two or more therapeutic approaches with different mechanisms to enhance antitumor therapy. Moreover, nanosize drugdelivery systems for codelivering two drugs with proapoptotic and antiangiogenic activities have exhibited great potential in efficient treatment of cancers. Methods: Glycyrrhetinic acid (GA)-modified liposomes (GA LPs) for liver-targeted codelivery of curcumin (Cur) and combretastatin A4 phosphate (CA4P) were prepared and characterized. In vitro cellular uptake, cytotoxicity, cell migration, in vivo biodistribution, antitumor activity, and histopathological studies were performed. Results: Compared with unmodified LPs (Cur-CA4P LPs), Cur-CA4P/GA LPs were taken up effectively by human hepatocellular carcinoma cells (BEL-7402) and showed higher cytotoxicity than free drugs. In vivo real-time near-infrared fluorescence-imaging results indicated that GA-targeted LPs increased accumulation in the tumor region. Moreover, Cur-CA4P/GA LPs showed stronger inhibition of tumor proliferation than Cur, Cur + CA4P, and Cur-CA4P LPs in vivo antitumor studies, which was also verified by H&E staining. Conclusion: GA-modified LPs can serve as a promising nanocarrier for liver-targeted co-delivery of antitumor drugs against hepatocellular carcinoma.

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Cellular uptake mechanism and clearance kinetics of fluorescence-labeled glycyrrhetinic acid and glycyrrhetinic acid–modified liposome in hepatocellular carcinoma cells

Cited by 20 publications

References 32 publications

Glycyrrhizic Acid and Its Hydrolyzed Metabolite 18β-Glycyrrhetinic Acid as Specific Ligands for Targeting Nanosystems in the Treatment of Liver Cancer

Glycyrrhizic Acid and Its Hydrolyzed Metabolite 18β-Glycyrrhetinic Acid as Specific Ligands for Targeting Nanosystems in the Treatment of Liver Cancer

Targeted pharmacokinetics of polymeric micelles modified with glycyrrhetinic acid and hydrazone bond in H22 tumor-bearing mice

<p>Liver-targeted liposomes for codelivery of curcumin and combretastatin A4 phosphate: preparation, characterization, and antitumor effects</p>

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