Asialoglycoprotein receptor-targeted liposomes loaded with a norcantharimide derivative for hepatocyte-selective targeting
| Autor: | Jiawen Xu, Jingxin Gou, Mengting Han, Xiaolin Liu, Haibing He, Tian Yin, Yu Zhang, Xaohui Ye, Sicong Geng, Xing Tang |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Pharmaceutical Science Apoptosis 02 engineering and technology Asialoglycoprotein Receptor Pharmacology Endocytosis Kidney Function Tests 03 medical and health sciences chemistry.chemical_compound Drug Delivery Systems Drug Stability Liver Function Tests In vivo Animals Humans Cytotoxicity Liposome Norcantharidin Asialoglycoprotein Galactose Hep G2 Cells 021001 nanoscience & nanotechnology Rats Hep G2 030104 developmental biology chemistry Biochemistry Cantharidin Liposomes Hepatocytes Asialoglycoprotein receptor 0210 nano-technology |
| Zdroj: | International journal of pharmaceutics. 520(1-2) |
| ISSN: | 1873-3476 |
| Popis: | In order to overcome the shortcomings associated with the clinical application of norcantharidin (NCTD), including intense irritation and a short half-life, and to obtain a hepatocyte-selective liposome system with high encapsulation efficiency (EE) and low leakage, we synthesized a C14 alkyl chain norcantharimide derivative of NCTD (2-tetradecylhexahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione, N-14NCTDA). Asialoglycoprotein receptor-targeted, galactosylated liposomes loaded with N-14NCTDA (GAL-Lipo) were prepared by the lipid film hydration method. GAL-Lipo with a satisfactory particle size of approximately 120nm has a higher encapsulation efficiency of more than 98.0%, which is markedly increased compared with NCTD loaded liposomes (EE%=47.6%). In addition, GAL-Lipo remained stable for at least 1 month at 4°C. In cytotoxicity assays, GAL-Lipo demonstrated stronger cytotoxicity effects (IC50=24.58μmolL-1) on Hep G2 cells than free N-14NCTDA (100μmol/L) and conventional liposomes (Con-Lipo, 39.49μmol/L) without the GAL modification. GAL-Lipo can continuously accumulate in Hep G2 cells and be internalized into cells via two pathways, namely caveolin-dependent endocytosis and clathrin-dependent asialoglycoprotein receptors (ASGP-R) mediated endocytosis and produces considerably more significant cellular apoptosis. The results of vivo toxicity studies showed that GAL-Lipo dramatically reduced renal toxicity. In addition, GAL-Lipo has a markedly improved pharmacokinetic profile in vivo and a longer circulation time (AUC=6.700±2.964mgL-1h, t1/2z=1.347±0.519h) than Con-Lipo (AUC=2.319±0.121mgL-1h, t1/2z=0.413±0.238h). In conclusion, N-14NCTDA with an ideal logP is a better alternative for the treatment of primary hepatic carcinoma. GAL-Lipo offers an attractive strategy to specifically target hepatocytes via caveolin-dependent and clathrin-dependent asialoglycoprotein receptor-mediated endocytosis resulting in higher anticancer activity and fewer side-effects. |
| Databáze: | OpenAIRE |
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