title: Hyperthermia-mediated doxorubicin release from thermosensitive liposomes using MR-HIFU: therapeutic effect in rabbit Vx2 tumours.
abstract: OBJECTIVE
  The aim of this study was to determine whether localised drug release using thermosensitive liposomal doxorubicin (TLD) and mild hyperthermia produced by a clinical magnetic resonance high intensity focused ultrasound (MR-HIFU) system improves anti-tumour efficacy over TLD alone in rabbit Vx2 tumours.
  
  
  METHODS
  Rabbits bearing one Vx2 thigh tumour (n = 6 per group) were administered TLD (1.67 mg/kg) either with or without MR-HIFU mild hyperthermia (20 min, 42.0 °C). Tumour progression was measured using contrast-enhanced T1-weighted MR imaging. Toxicity was evaluated by changes in body weight, blood counts, and blood chemistry. Tumour volume, body weight, and blood data were acquired weekly for the first month and biweekly thereafter.
  
  
  RESULTS
  Rabbits treated with TLD plus MR-HIFU mild hyperthermia had target region temperatures with spatial-median, temporal-mean of 41.4° ± 0.6 °C; 10th and 90th percentile temperatures were 40.2 and 42.7 °C. All six rabbits that received TLD alone had rapid tumour progression and reached the tumour size end point (maximum dimension >6 cm) within 24 days. Four of six rabbits treated with TLD plus MR-HIFU mild hyperthermia survived to the study end point of 60 days; one reached tumour size end point, one had hyperthermia-related toxicity, all had at least a transient decrease in tumour volume. Weekly body weight, complete blood counts, and blood chemistry did not reveal additional evidence of drug or hyperthermia-related toxicity.
  
  
  CONCLUSIONS
  Rabbit Vx2 tumours treated with a single infusion of TLD during MR-HIFU mild hyperthermia had reduced tumour growth vs. tumours treated with TLD alone. These findings are an important step toward clinical translation of localised drug delivery using MR-HIFU and TLD.
authors.affiliation: Physical Sciences Platform, Sunnybrook Research Institute , Toronto, Ontario , Canada .
authors.forename: Robert M
authors.initials: RM
authors.lastname: Staruch
authors.forename: Kullervo
authors.initials: K
authors.lastname: Hynynen
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chopra
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016503:Drug Delivery Systems; D057086:High-Intensity Focused Ultrasound Ablation / Q000379:methods*; D006979:Hyperthermia, Induced; D053783:Magnetic Resonance Imaging, Interventional / Q000379:methods*; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011817:Rabbits; D062125:Thermometry / Q000379:methods
chemical_list: D000903:Antibiotics, Antineoplastic; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Heat targeted drug delivery; high intensity focused ultrasound; image-guided therapy; non-invasive thermometry; prediction and monitoring of tumour response