title: Targeted drug delivery by high intensity focused ultrasound mediated hyperthermia combined with temperature-sensitive liposomes: computational modelling and preliminary in vivovalidation.
abstract: OBJECTIVE
  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).
  
  
  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.
authors.affiliation: Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Astrid
authors.initials: A
authors.lastname: Gasselhuber
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Dreher
authors.forename: Ari
authors.initials: A
authors.lastname: Partanen
authors.forename: Pavel S
authors.initials: PS
authors.lastname: Yarmolenko
authors.forename: David
authors.initials: D
authors.lastname: Woods
authors.forename: Bradford J
authors.initials: BJ
authors.lastname: Wood
authors.forename: Dieter
authors.initials: D
authors.lastname: Haemmerich
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D003198:Computer Simulation; D004317:Doxorubicin / Q000008:administration & dosage; D016503:Drug Delivery Systems / Q000379:methods*; D057086:High-Intensity Focused Ultrasound Ablation; D006979:Hyperthermia, Induced / Q000379:methods*; D008081:Liposomes; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy; D011817:Rabbits; D013696:Temperature
chemical_list: D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D004317:Doxorubicin