Computational modeling of high-intensity focused ultrasound mediated drug delivery

Low temperature sensitive liposomes (LTSL) are drug delivery vehicles with long plasma half-life, which release the drug upon heating above similar to 40 degrees C. The combination of LTSL with local heat generated by image-guided focused ultrasound may thus allow non-invasively targeted drug delivery. We combined a heat-transfer model with a drug delivery model to determine temperature-dependent release and tumor tissue accumulation of drug in extravascular-extracellular space, and inside cells. Tissue was heated with a 16 mm focal spot for 7 min at 43 degrees C target temperature. In addition we examined the effect of an additional subsequent high-temperature pulse to eliminate blood flow after drug release. Our results show high local plasma concentration during hyperthermia at the target site, during which drug is taken up by tissue and finally by cells. Following heating, local plasma concentration rapidly drops off and drug not taken up by cells is removed from tissue by blood flow. Elimination of blood flow following hyperthermia by a high-temperature pulse avoided this removal and resulted in similar to 2x higher intracellular concentration.