title: Magnetic resonance guided high-intensity focused ultrasound mediated hyperthermia improves the intratumoral distribution of temperature-sensitive liposomal doxorubicin.
abstract: OBJECTIVE
  The aim of this study was to investigate the intratumoral distribution of a temperature-sensitive liposomal carrier and its encapsulated compounds, doxorubicin, and a magnetic resonance (MR) imaging contrast agent after high-intensity focused ultrasound (HIFU)-mediated hyperthermia-induced local drug release.
  
  
  METHODS
  (111)In-labeled temperature-sensitive liposomes encapsulating doxorubicin and [Gd(HPDO3A) (H(2)O)] were injected intravenously in the tail vein of rats (n = 12) bearing a subcutaneous rhabdomyosarcoma tumor on the hind leg. Immediately after the injection, local tumor hyperthermia (2 × 15 minutes) was applied using a clinical 3 T MR-HIFU system. Release of [Gd(HPDO3A)(H(2)O)] was studied in vivo by measuring the longitudinal relaxation rate R(1) with MR imaging. The presence of the liposomal carriers and the intratumoral distribution of doxorubicin were imaged ex vivo with autoradiography and fluorescence microscopy, respectively, for 2 different time points after injection (90 minutes and 48 hours).
  
  
  RESULTS
  In hyperthermia-treated tumors, radiolabeled liposomes were distributed more homogeneously across the tumor than in the control tumors (coefficient of variation(hyp, 90 min) = 0.7 ± 0.2; coefficient of variation(cntrl, 90 min) = 1.1 ± 0.2). At 48 hours after injection, the liposomal accumulation in the tumor was enhanced in the hyperthermia group in comparison with the controls. A change in R(1) was observed in the HIFU-treated tumors, suggesting release of the contrast agent. Fluorescence images showed perivascular doxorubicin in control tumors, whereas in the HIFU-treated tumors, the delivered drug was spread over a much larger area and also taken up by tumor cells at a larger distance from blood vessels.
  
  
  CONCLUSIONS
  Treatment with HIFU hyperthermia not only improved the immediate drug delivery, bioavailability, and intratumoral distribution but also enhanced liposomal accumulation over time. The sum of these effects may have a significant contribution to the therapeutic outcome.
authors: Department of Biomedical Engineering, Biomedical NMR, Eindhoven University of Technology, Eindhoven, The Netherlands.
authors: Mariska
authors: M
authors: de Smet
authors: Nicole M
authors: NM
authors: Hijnen
authors: Sander
authors: S
authors: Langereis
authors: Aaldert
authors: A
authors: Elevelt
authors: Edwin
authors: E
authors: Heijman
authors: Ludwig
authors: L
authors: Dubois
authors: Philippe
authors: P
authors: Lambin
authors: Holger
authors: H
authors: Grüll
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D057086:High-Intensity Focused Ultrasound Ablation / Q000379:methods*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D012208:Rhabdomyosarcoma / Q000378:metabolism* / Q000628:therapy*; D025321:Surgery, Computer-Assisted / Q000379:methods*; D013696:Temperature; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin