Longer heating duration increases localized doxorubicin deposition and therapeutic index in Vx2 tumors using MR-HIFU mild hyperthermia and thermosensitive liposomal doxorubicin

AbstractThermosensitive liposomal doxorubicin(LTSL-Dox) combined with mild hyperthermiaenhances the localized delivery of doxorubicin(Dox) within a heated region. The optimal heating duration and the impact of extended heating on systemic drug distribution are unknown. Here we evaluated local and systemic Dox delivery with two different mild hyperthermiadurations (42 °C for 10 or 40 minutes) in a Vx2 rabbit tumor model. We hypothesized that longer duration of hyperthermiawould increase Dox concentration in heated tumors without increasing systemic exposure. Temporally and spatially accurate controlled hyperthermiawas achieved using a clinical MR-HIFU system for the prescribed heating durations. Forty-minutes of heating resulted in a nearly 6-fold increase in doxorubicinconcentration in heated vs unheated tumors in the same animals. Therapeutic ratio, defined as the ratio of Dox delivered into the heated tumor vs the heart, increased from 1.9-fold with 10 minutes heating to 4.4-fold with 40 minutes ...