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.

Nanomaterials in Targeting Cancer Stem Cells for Cancer Therapy

“…The anticancer drug ESC8 connected with dexamethasone (Dex)-associated liposome (DX) to form ESC8-entrapped liposome named DXE. The results showed DXE was a promising liposomal formulation with potent pharmacokinetic and tumor regressing profile that could sensitize and kill highly aggressive and drug-resistive tumor progenitor cells (Ahmad et al, 2016). Since liposomes provide a biocompatible and biodegradable container for loading drugs and the surface of which can be modified with various targeting ligand, they hold great possibility to deliver drugs for targeted cancer therapy.…”

Glucocorticoid Receptor-Targeted Liposomal Codelivery of Lipophilic Drug and Anti-Hsp90 Gene: Strategy to Induce Drug-Sensitivity, EMT-Reversal, and Reduced Malignancy in Aggressive Tumors

“…31,33 We have recently shown the in vivo utility of this proof-of-concept of using DXE lipoplex carrying another type of anticancer gene such as, antineuropilin shRNA plasmid as a cargo, for eliciting effective tumor growth regression in a tumor model of severely drug-resistant breast cancer stem cell-like cells. 54 However, induction of drug-sensitivity and reversal of EMT could not be established clearly, especially with respect to the indulgence of GR. The observations as reported herein clearly indicate that cancer cell-associated GR can be selectively manipulated with these special formulations.…”

Targeted delivery of in situ PCR-amplified Sleeping Beauty transposon genes to cancer cells with lipid-based nanoparticle-like protocells

“…For FA modification, 5% FA-PEG 2000 -DSPE of total lipid was added in chloroform to make the thin film for protocell preparation. To integrate DEX into the protocells, DEX, instead of cholesterol, was added in chloroform with other lipid to prepare the thin film [18,19]. Then, the PCR solution, containing the transposon/transposase DNA template (0.1 ng/µL), primers (0.8 µM), dNTPs (0.2 mM each) and polymerase (0.025 U/µl), was added and the thin film was hydrated and dispersed by vortex mixing.…”

“…DEX, a well-known synthetic steroidal glucocorticoid, shows structural resemblance with cholesterol (Chol) and hence afforded stable formulation in the presence of lipid [18,20]. Thus, DEX was directly incorporated alongside the regular phospholipid in the lipid–associated gene delivery formulation.…”