Asialoglycoprotein receptor-targeted liposomes loaded with a norcantharimide derivative for hepatocyte-selective targeting.
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 C14alkyl 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.
Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, PR China.
Xiaolin
X
Liu
Department of Science and Biotechnology, College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, PR China.
Mengting
M
Han
Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, PR China.
Jiawen
J
Xu
Chemical & Pharmaceutical Profiling(CPP), Technical Research and Development(TRD), Novartis Institutes for BioMedical Research(NIBR), Inc., PR China.
Sicong
S
Geng
Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, PR China; Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang, Jiangsu, PR China. Electronic address: pharmzy@163.com.
Yu
Y
Zhang
Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, PR China.
Xaohui
X
Ye
Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, PR China.
Jingxin
J
Gou
School of Functional food and Wine, Shenyang Pharmaceutical University, PR China; School of Chinese Materia Media, Shenyang Pharmaceutical University, PR China.
Tian
T
Yin
Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, PR China.
Haibing
H
He
Department of Pharmaceutics, College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, PR China. Electronic address: tanglab@126.com.
Xing
X
Tang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D037263:Asialoglycoprotein Receptor / Q000378:metabolism*; D002193:Cantharidin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D004355:Drug Stability; D004705:Endocytosis; D005690:Galactose / Q000737:chemistry; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007677:Kidney Function Tests; D008081:Liposomes / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics*; D008111:Liver Function Tests; D008297:Male; D051381:Rats
C000623124:2-tetradecylhexahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione; D037263:Asialoglycoprotein Receptor; D008081:Liposomes; D002193:Cantharidin; D005690:Galactose
Arabinogalactan (PubChem CID: 24847856); Asialoglycoprotein receptor; Galactose (PubChem CID: 6036); Galactosylated liposomes; Hep G2 cells; Liver targeting; N-14NCTDA; Norcantharidin (PubChem CID: 93004)