title: Development of Liposomal Formulation for Delivering Anticancer Drug to Breast Cancer Stem-Cell-Like Cells and its Pharmacokinetics in an Animal Model.
abstract: The objective of the present study is to develop a liposomal formulation for delivering anticancer drug to breast cancer stem-cell-like cells, ANV-1, and evaluate its pharmacokinetics in an animal model. The anticancer drug ESC8 was used in dexamethasone (Dex)-associated liposome (DX) to form ESC8-entrapped liposome named DXE. ANV-1 cells showed high-level expression of NRP-1. To enhance tumor regression, we additionally adapted to codeliver the NRP-1 shRNA-encoded plasmid using the established DXE liposome. In vivo efficacy of DXE-NRP-1 was carried out in mice bearing ANV-1 cells as xenograft tumors and the extent of tumor growth inhibition was evaluated by tumor-size measurement. A significant difference in tumor volume started to reveal between DXE-NRP-1 group and DXE-Control group. DXE-NRP-1 group showed ∼4 folds and ∼2.5 folds smaller tumor volume than exhibited by untreated and DXE-Control-treated groups, respectively. DXE disposition was evaluated in Sprague-Dawley rats following an intraperitoneal dose (3.67 mg/kg of ESC8 in DXE). The plasma concentrations of ESC8 in the DXE formulation were measured by liquid chromatography mass spectrometry and pharmacokinetic parameters were determined using a noncompartmental analysis. ESC8 had a half-life of 11.01 ± 0.29 h, clearance of 2.10 ± 3.63 L/kg/h, and volume of distribution of 33.42 ± 0.83 L/kg. This suggests that the DXE liposome formulation could be administered once or twice daily for therapeutic efficacy. In overall, we developed a potent liposomal formulation with favorable pharmacokinetic and tumor regressing profile that could sensitize and kill highly aggressive and drug-resistive cancer stem-cell-like cells.
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, King Saud University , Riyadh 11451, Saudi Arabia.
authors.forename: Ajaz
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Biomaterials Group, CSIR-Indian Institute of Chemical Technology , Hyderabad 500007, India.|Department of Biochemistry and Molecular Biology, Mayo Clinic , Jacksonville, Florida 32224, United States.|Academy of Scientific & Innovative Research (AcSIR) , 2 Rafi Marg, New Delhi 110001, India.
authors.forename: Sujan Kumar
authors.initials: SK
authors.lastname: Mondal
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic , Jacksonville, Florida 32224, United States.
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukhopadhyay
authors.affiliation: Biomaterials Group, CSIR-Indian Institute of Chemical Technology , Hyderabad 500007, India.|Academy of Scientific & Innovative Research (AcSIR) , 2 Rafi Marg, New Delhi 110001, India.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Banerjee
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, King Saud University , Riyadh 11451, Saudi Arabia.
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Alkharfy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004339:Drug Compounding; D016503:Drug Delivery Systems; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D034741:RNA, Small Interfering; D039942:Neuropilin-1
keywords: ANV-1 cells; Hsp90; NRP-1; cancer stem cell -like cells; drug-sensitivity; liposomes; pharmacokinetics; tumor