title: Enhanced drug delivery in rabbit VX2 tumours using thermosensitive liposomes and MRI-controlled focused ultrasound hyperthermia.
abstract: OBJECTIVE
  The efficacy of anticancer drugs in solid tumours is impaired by their inability to reach all cancer cells in sufficient concentration to cause cytotoxicity. Hyperthermia-triggered release of drugs from thermosensitive liposomes can increase tumour drug concentration, but tumour-specific drug delivery requires precise temperature control, and effects on microregional distribution of anticancer drugs in tumours are unknown. Here we evaluate thermally triggered release of doxorubicin in a rabbit tumour model by comparing free versus thermosensitive liposomal doxorubicin administered systemically during magnetic resonance imaging (MRI)-controlled focused ultrasound hyperthermia.
  
  
  METHODS
  Twelve rabbits with a transplanted VX2 tumour in each thigh had a 10 mm diameter region in one tumour heated to 43°C using focused ultrasound with temperature control by MRI thermometry. Delivery of doxorubicin to tumours and normal tissues was quantified by fluorescence in tissue homogenates, and by fluorescence microscopy.
  
  
  RESULTS
  Using thermosensitive liposomal doxorubicin (2.5 mg/kg), doxorubicin concentrations in heated tumours were 26.7 times higher than in unheated tumours (n = 7, p = 0.017, two-sided Wilcoxon signed-rank test). There was no significant enhancement with free doxorubicin in heated versus unheated tumours (n = 3, p = 0.5). With thermosensitive liposomes (8.3 mg/kg), fluorescence microscopy demonstrated increased doxorubicin fluorescence in heated versus unheated tumours, co-localised with nuclear staining throughout the tumour.
  
  
  CONCLUSIONS
  Localised image-guided delivery of high concentrations of doxorubicin to cancer cells was achieved non-invasively in implanted tumours with temperature-sensitive drug carriers and a preclinical MRI-controlled focused ultrasound hyperthermia system.
authors.affiliation: Centre for Research in Image-Guided Therapeutics, Sunnybrook Research Institute, Toronto, Ontario, Canada. staruchr@sri.utoronto.ca
authors.forename: Robert M
authors.initials: RM
authors.lastname: Staruch
authors.forename: Milan
authors.initials: M
authors.lastname: Ganguly
authors.forename: Ian F
authors.initials: IF
authors.lastname: Tannock
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*; D016503:Drug Delivery Systems; D008081:Liposomes; D008279:Magnetic Resonance Imaging; D008297:Male; D009369:Neoplasms / Q000628:therapy*; D011817:Rabbits; D014464:Ultrasonic Therapy
chemical_list: D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D004317:Doxorubicin