Targeted drug delivery by high intensity focused ultrasound mediated hyperthermia combined with temperature-sensitive liposomes: computational modelling and preliminary in vivovalidation.

PURPOSE: To develop and validate a computational model that simulates (1) tissue heating with high intensity focused ultrasound (HIFU), and (2) resulting hyperthermia-mediated drug delivery from temperature-sensitive liposomes (TSL).
MATERIALS AND METHODS: HIFU heating in tissue was simulated using a heat transfer model based on the bioheat equation, including heat-induced cessation of perfusion. A spatio-temporal multi-compartment pharmacokinetic model simulated intravascular release of doxorubicin from TSL, its transport into interstitium, and cell uptake. Two heating schedules were simulated, each lasting 30 min: (1) hyperthermia at 43 °C (HT) and (2) hyperthermia followed by a high temperature (50 °C for 20 s) pulse (HT+). As preliminary model validation, in vivo studies were performed in thigh muscle of a New Zealand White rabbit, where local hyperthermia with a clinical magnetic resonance-guided HIFU system was applied following TSL administration.
RESULTS: HT produced a defined region of high doxorubicin concentration (cellular concentration ∼15-23 µg/g) in the target region. Cellular drug uptake was directly related to HT duration, with increasing doxorubicin uptake up to ∼2 h. HT+ enhanced drug delivery by ∼40% compared to HT alone. Temperature difference between model and experiment within the hyperthermia zone was on average 0.54 °C. Doxorubicin concentration profile agreed qualitatively with in vivo fluorescence profile.
CONCLUSIONS: Computational models can predict temperature and delivered drug from combination of HIFU with TSL. Drug delivery using TSL may be enhanced by prolonged hyperthermia up to 2 h or by local cessation of vascular perfusion with a high temperature pulse following hyperthermia.