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Reversal of multidrug resistance by transferrin-conjugated liposomes co-encapsulating doxorubicin and verapamil.
- Source :
-
Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques [J Pharm Pharm Sci] 2007; Vol. 10 (3), pp. 350-7. - Publication Year :
- 2007
-
Abstract
- Purpose: Liposomes co-encapsulating doxorubicin (DOX) and verapamil (VER), and conjugated to transferrin (Tf-L-DOX/VER) were synthesized and evaluated in K562 leukemia cells. The design of this formulation was aimed at selective targeting of tumor cells, reducing cardiotoxicity of DOX and VER, as well as overcoming P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) phenotype.<br />Methods: The liposomes were prepared by polycarbonate membrane extrusion, followed by pH-gradient driven remote loading and Tf conjugation. Kinetics of in vitro release of DOX and VER from liposomes was determined by measuring changes in the concentration of encapsulated drugs. Uptake of Tf-conjugated liposomes by K562 cells was evaluated by fluorescence microscopy and by fluorometry. Cytotoxicities of various formulations of DOX were determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolum bromide (MTT) assay.<br />Results: Efficiencies for liposomal loading of DOX and VER were 95% and 70%, respectively. The mean particle diameter for the liposomes was approximately 110nm. Rates of release for DOX and VER were similar in singly-loaded and co-loaded liposomes. Tf-L-DOX/VER showed efficient uptake by the TfR+ K562 cells. In DOX-resistant K562 cells (K562/DOX), Tf-L-DOX/VER showed 5.2 and 2.8 times greater cytotoxicity (IC50 = 4.18 muM) than non-targeted liposomes (L-DOX/VER) (IC50 = 21.7 muM) and Tf-targeted liposomes loaded with DOX alone (Tf-L-DOX) (IC50 = 11.5 muM), respectively.<br />Conclusions: The combination of TfR targeting and co-encapsulation of DOX and VER was highly effective in overcoming drug resistance in K562 leukemia cells.
- Subjects :
- Antibiotics, Antineoplastic administration & dosage
Antibiotics, Antineoplastic adverse effects
Antibiotics, Antineoplastic chemistry
Calcium Channel Blockers administration & dosage
Calcium Channel Blockers adverse effects
Calcium Channel Blockers chemistry
Dose-Response Relationship, Drug
Doxorubicin administration & dosage
Doxorubicin adverse effects
Doxorubicin chemistry
Drug Combinations
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Fluorometry
Humans
Inhibitory Concentration 50
K562 Cells
Liposomes
Microscopy, Fluorescence
Particle Size
Transferrin chemistry
Verapamil administration & dosage
Verapamil adverse effects
Verapamil chemistry
Antibiotics, Antineoplastic pharmacology
Calcium Channel Blockers pharmacology
Doxorubicin pharmacology
Drug Delivery Systems
Verapamil pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1482-1826
- Volume :
- 10
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques
- Publication Type :
- Academic Journal
- Accession number :
- 17727798