title: Hyperthermia in bone generated with MR imaging-controlled focused ultrasound: control strategies and drug delivery.
abstract: OBJECTIVE
  To evaluate the feasibility of achieving image-guided drug delivery in bone by using magnetic resonance (MR) imaging-controlled focused ultrasound hyperthermia and temperature-sensitive liposomes.
  
  
  METHODS
  Experiments were approved by the institutional animal care committee. Hyperthermia (43°C, 20 minutes) was generated in 10-mm-diameter regions at a muscle-bone interface in nine rabbit thighs by using focused ultrasound under closed-loop temperature control with MR thermometry. Thermosensitive liposomal doxorubicin was administered systemically during heating. Heating uniformity and drug delivery were evaluated for control strategies with the temperature control image centered 10 mm (four rabbits) or 0 mm (five rabbits) from the bone. Simulations estimated temperature elevations in bone. Drug delivery was quantified by using the fluorescence of doxorubicin extracted from bone marrow and muscle and was compared between treated and untreated thighs by using the one-sided Wilcoxon signed rank test.
  
  
  RESULTS
  With ultrasound focus and MR temperature control plane 0 mm and 10 mm from the bone interface, average target region temperatures were 43.1°C and 43.3°C, respectively; numerically estimated bone temperatures were 46.8°C and 78.1°C. The 10-mm offset resulted in thermal ablation; numerically estimated muscle temperature was 66.1°C at the bone interface. Significant increases in doxorubicin concentration occurred in heated versus unheated marrow (8.2-fold, P = .002) and muscle (16.8-fold, P = .002). Enhancement occurred for 0- and 10-mm offsets, which suggests localized drug delivery in bone is possible with both hyperthermia and thermal ablation.
  
  
  CONCLUSIONS
  MR imaging-controlled focused ultrasound can achieve localized hyperthermia in bone for image-guided drug delivery in bone with temperature-sensitive drug carriers.
authors.affiliation: Centre for Research in Image-Guided Therapeutics, Sunnybrook Health Sciences Centre, Toronto, ON, Canada M4N 3M5. staruchr@sri.utoronto.ca
authors.forename: Robert
authors.initials: R
authors.lastname: Staruch
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chopra
authors.forename: Kullervo
authors.initials: K
authors.lastname: Hynynen
mesh_terms: D000818:Animals; D001853:Bone Marrow; D003287:Contrast Media / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage*; D004337:Drug Carriers; D005240:Feasibility Studies; D019786:Gadolinium DTPA / Q000008:administration & dosage; D007036:Hypothermia, Induced / Q000379:methods*; D008081:Liposomes / Q000008:administration & dosage*; D053783:Magnetic Resonance Imaging, Interventional / Q000379:methods*; D008297:Male; D011817:Rabbits; D018709:Statistics, Nonparametric; D013848:Thigh; D014159:Transducers; D018084:Ultrasonography, Interventional / Q000379:methods*
chemical_list: D003287:Contrast Media; D004337:Drug Carriers; D008081:Liposomes; D004317:Doxorubicin; C064925:gadodiamide; D019786:Gadolinium DTPA