A mathematical model for comparison of bolus injection, continuous infusion, and liposomal delivery of doxorubicin to tumor cells

Determining the optimal mode of delivery for doxorubicin is important given the wide use of the drug against many tumor types. The relative performanc es of bolus injection, continuous infusion, liposomal and thermoliposomal d elivery are not yet definitely established from clinical trials. Here, a ma thematical model is used to compare bolus injection, continuous infusion fo r various durations, liposomal and thermoliposomal delivery of doxorubicin. Effects of the relatively slow rate, and saturability, of doxorubicin upta ke by cells are included. Peak concentrations attained in tumor cells are p redicted and used as a measure of antitumor effectiveness. To measure toxic ity, plasma area under the curve (AUC) and peak plasma concentrations of fr ee doxorubicin are computed. For continuous infusion, the duration of infus ion significantly affects predicted outcome. The optimal infusion duration increases with dose, and is in the range 1 to 3 hours at typical doses. The simulations suggest that continuous infusion for optimal durations is supe rior to the other protocols. Nonthermosensitive liposomes approach the effi cacy of continuous infusion only if they release drug at optimal rates. Pre dictions for thermosensitive liposomes indicate a potential advantage at so me doses, but only if hyperthermia is applied locally so that the blood is not significantly heated.