In vitro and in vivo characterization of doxorubicin and vincristine coencapsulated within liposomes through use of transition metal ion complexation and pH gradient loading.
OBJECTIVE
There is an opportunity to augment the therapeutic potential of drug combinations through use of drug delivery technology. This report summarizes data obtained using a novel liposomal formulation with coencapsulated doxorubicin and vincristine. The rationale for selecting these drugs is due in part to the fact that liposomal formulations of doxorubicin and vincristine are being separately evaluated as components of drug combinations.


METHODS
Doxorubicin and vincristine were coencapsulated into liposomes using two distinct methods of drug loading. A manganese-based drug loading procedure, which relies on drug complexation with a transition metal, was used to encapsulate doxorubicin. Subsequently the ionophore A23187 was added to induce formation of a pH gradient, which promoted vincristine encapsulation.


RESULTS
Plasma elimination studies in mice indicated that the drug:drug ratio before injection [4:1 doxorubicin:vincristine (wt:wt ratio)] changed to 20:1 at the 24-h time point, indicative of more rapid release of vincristine from the liposomes than doxorubicin. Efficacy studies completed in MDA MB-435/LCC6 tumor-bearing mice suggested that at the maximum tolerated dose, the coencapsulated formulation was therapeutically no better than liposomal vincristine. This result was explained in part by in vitro cytotoxicity studies evaluating doxorubicin and vincristine combinations analyzed using the Chou and Talalay median effect principle. These data clearly indicated that simultaneous addition of vincristine and doxorubicin resulted in pronounced antagonism.


CONCLUSIONS
These results emphasize that in vitro drug combination screens can be used to predict whether a coformulated drug combination will act in an antagonistic or synergistic manner.
Abraham
Sheela A
SA
Division of Medical Oncology, Department of Advanced Therapeutics, BC Cancer Agency, Vancouver, British Columbia, Canada.
McKenzie
Cheryl
C
Masin
Dana
D
Ng
Rebecca
R
Harasym
Troy O
TO
Mayer
Lawrence D
LD
Bally
Marcel B
MB
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology; D000001:Calcimycin / Q000494:pharmacology; D045744:Cell Line, Tumor; D004396:Coloring Agents / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D007476:Ionophores / Q000494:pharmacology; D007477:Ions; D050356:Lipid Metabolism; D008081:Liposomes / Q000378:metabolism*; D008345:Manganese / Q000494:pharmacology; D017895:Manganese Compounds / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011522:Protons; D013431:Sulfates / Q000494:pharmacology; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014750:Vincristine / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D004396:Coloring Agents; D007476:Ionophores; D007477:Ions; D008081:Liposomes; D017895:Manganese Compounds; D011522:Protons; D013431:Sulfates; D013778:Tetrazolium Salts; D013844:Thiazoles; D000001:Calcimycin; D008345:Manganese; D014750:Vincristine; D004317:Doxorubicin; C022616:thiazolyl blue; C039798:manganese sulfate