Development of stealth liposome coencapsulating doxorubicin and fluoxetine
- 12 January 2011
- journal article
- Published by Taylor & Francis Ltd in Journal of Liposome Research
- Vol. 21 (4), 261-271
- https://doi.org/10.3109/08982104.2010.545070
Abstract
Stealth liposomes form an important subset of liposomes, demonstrating prolonged circulation half-life and improved safety in vivo. Caelyx® (liposomal doxorubicin; Merck & Co., Whitehouse Station, New Jersey, USA) is a successful example of the application of stealth liposomes in anticancer treatment. However, multidrug resistance (MDR) to chemotherapy still remains a critical problem, accounting for more than 90% of treatment failure in patients with advanced cancer. To circumvent MDR, fluoxetine and doxorubicin were tested in combination for synergistic activity in MCF-7 (human breast carcinoma) and MCF-7/adr (doxorubicin-resistant human breast carcinoma) cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell-viability assay. Coencapsulation of doxorubicin and fluoxetine, using an ammonium sulphate gradient, was investigated, and a factorial experiment was designed to determine the optimal drug-to-lipid (D/L) ratio for coencapsulation. Drug release from Dox-Flu-SL (stealth liposome coencapsulating doxorubicin and fluoxetine) under both in vitro and in vivo conditions was determined. In MCF-7 cells, synergism was demonstrated at specific doxorubicin:fluoxetine ratios of between 0.09 and 0.5 (molar ratio), while MCF/7/adr cells demonstrated synergism across all drug ratios. Coencapsulation of doxorubicin and fluoxetine (Dox-Flu-SL) was successfully achieved (optimal doxorubicin:fluoxetine:lipid molar ratio of 0.02:0.05:1), obtaining a mean concentration of 257 ± 12.1 and 513 ± 29.3 μM for doxorubicin and fluoxetine, respectively. Most important, Dox-Flu-SL demonstrated drug release in synergistic ratios in cell-culture media, accounting for the improved cytotoxicity of Dox-Flu-SL over liposomal doxorubicin (LD) in both MCF-7 and MCF-7/adr cells. Pharmacokinetic studies also revealed that Dox-Flu-SL effectively prolonged drug-circulation time and reduced tissue biodistribution. Dox-Flu-SL presents a promising anticancer formulation, capable of effective reversal of drug resistance, and may constitute a novel approach for cancer therapy.Keywords
This publication has 46 references indexed in Scilit:
- Treatment of resistant human colon cancer xenografts by a fluoxetine–doxorubicin combination enhances therapeutic responses comparable to an aggressive bevacizumab regimenCancer Letters, 2009
- Influence of Drug-to-Lipid Ratio on Drug Release Properties and Liposome Integrity in Liposomal Doxorubicin FormulationsJournal of Liposome Research, 2008
- Remote loading of doxorubicin into liposomes driven by a transmembrane phosphate gradientBiochimica et Biophysica Acta (BBA) - Biomembranes, 2006
- Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination StudiesPharmacological Reviews, 2006
- An evaluation of transmembrane ion gradient-mediated encapsulation of topotecan within liposomesJournal of Controlled Release, 2004
- Reduced cardiotoxicity and comparable efficacy in a phase IIItrial of pegylated liposomal doxorubicin HCl(CAELYX™/Doxil®) versus conventional doxorubicin forfirst-line treatment of metastatic breast cancerAnnals of Oncology, 2004
- Formation of transition metal–doxorubicin complexes inside liposomesBiochimica et Biophysica Acta (BBA) - Biomembranes, 2002
- Cellular resistance to anthracyclinesGeneral Pharmacology: The Vascular System, 1996
- Growth-Inhibitory Effects of Serotonin Uptake Inhibitors on Human Prostate Carcinoma Cell LinesJournal of Urology, 1995
- Diffusion of univalent ions across the lamellae of swollen phospholipidsJournal of Molecular Biology, 1965