title: In vivo characterization of changing blood-tumor barrier permeability in a mouse model of breast cancer metastasis: a complementary magnetic resonance imaging approach.
abstract: OBJECTIVE
  The current lack of efficacy for any chemo- or molecular therapeutic in the treatment of brain metastases is thought to be due, in part, to the heterogeneous permeability of the blood-brain-barrier (BBB). Little is known about how heterogeneous permeability develops, or how it varies among individual metastases. Understanding the BBB's role in metastasis will be crucial to the development of new, more effective therapies. In this article, we developed the first magnetic resonance imaging-based strategy to detect and measure the volumes of BBB permeable and nonpermeable metastases and studied the development of altered BBB permeability in metastases in vivo, over time in a mouse model of breast cancer metastasis to the brain.
  
  
  METHODS
  Animals bearing human experimental brain metastases of breast cancer (231-BR cells) were imaged, using 3-dimensional balanced steady-state free precession to visualize total metastases, and contrast-enhanced T1-weighted spin echo with gadopentetic acid (Gd-DTPA) to visualize which of these displayed contrast enhancement, as Gd-DTPA leakage is indicative of altered BBB permeability.
  
  
  RESULTS
  Metastases detected 20 days after injection showed no Gd-DTPA enhancement. At day 25, 6.1% ± 6.3% (mean ± standard deviation) of metastases enhanced, and by day 30, 28.1% ± 14.2% enhanced (P < 0.05). Enhancing metastases (mid: 0.14 ± 0.18 mm, late: 0.24 ± 0.32 mm) had larger volumes than nonenhancing (mid: 0.04 ± 0.04 mm, late: 0.09 ± 0.09 mm, P < 0.05); however, there was no significant difference between the growth rates of the 2.
  
  
  CONCLUSIONS
  A significant number of brain metastases were uniformly nonpermeable, which highlights the need for developing treatment strategies that can overcome the permeability of the BBB. The model developed herein can provide the basis for in vivo evaluation of both BBB permeable and nonpermeable metastases response to therapy.
authors.affiliation: Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Dean B
authors.initials: DB
authors.lastname: Percy
authors.forename: Emeline J
authors.initials: EJ
authors.lastname: Ribot
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Chen
authors.forename: Catherine
authors.initials: C
authors.lastname: McFadden
authors.forename: Carmen
authors.initials: C
authors.lastname: Simedrea
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Steeg
authors.forename: Ann F
authors.initials: AF
authors.lastname: Chambers
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Foster
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D003287:Contrast Media / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D005260:Female; D019786:Gadolinium DTPA / Q000493:pharmacokinetics*; D006801:Humans; D021621:Imaging, Three-Dimensional; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence
chemical_list: D003287:Contrast Media; D019786:Gadolinium DTPA