title: Noninvasive Assessment of Losartan-Induced Increase in Functional Microvasculature and Drug Delivery in Pancreatic Ductal Adenocarcinoma.
abstract: OBJECTIVE
  Losartan, an angiotensin II receptor blocker, can reduce desmoplasia and enhance drug delivery and efficacy through improving interstitial transport and vascular perfusion in pancreatic ductal adenocarcinoma (PDAC) models in mice. The purpose of this study was to determine whether magnetic resonance imaging (MRI) of magnetic iron oxide nanoparticles (MNPs) and micro-positron emission tomography (PET) measurements could respectively detect improvements in tumor vascular parameters and drug uptake in orthotopic PDAC in mice treated with losartan.
  
  
  METHODS
  All experiments were approved by the local Institutional Animal Care and Use Committee. FVB mice with orthotopic PDAC were treated daily with an i.p. injection of losartan (70 mg/kg) or saline (control vehicle) for 5 days. In order to calculate the fractional blood volume, vessel size index, and vessel density index, MRI was performed at 4.7 T following the injection of 3 mg/kg iron ferumoxytol (i.v.). Dynamic PET images were also acquired for 60 minutes using an18F-5FU tracer dose of 200 μCi and analyzed for time activity curves normalized to muscle. Statistical analyses compared both cohorts using an unpaired two-tailed t test.
  
  
  RESULTS
  In comparison to the control treatment, the losartan administration significantly increased the fractional blood volume (mean±SEM) [12.1±1.7 (n=19) vs 6.7±1.1 (n=20); P<.02] and vessel size index (128.2±35.6 vs 57.5±18; P<.05). Losartan also induced a significant increase in the intratumoral uptake of18F-5FU by 53% (P<.0001).
  
  
  CONCLUSIONS
  MRI using FDA-approved MNPs provides a noninvasive, translatable means of assaying microvascular parameters induced by losartan in pancreatic cancer. PET measurements demonstrated that losartan significantly increased the uptake of18F-5FU.
authors.affiliation: Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA.
authors.forename: Vidhya
authors.initials: V
authors.lastname: Kumar
authors.affiliation: E.L. Steele Laboratories Department of Radiation Oncology Harvard Medical School and Massachusetts General Hospital 100 Blossom Street, Cox 7 Boston, MA 02114.
authors.forename: Yves
authors.initials: Y
authors.lastname: Boucher
authors.affiliation: E.L. Steele Laboratories Department of Radiation Oncology Harvard Medical School and Massachusetts General Hospital 100 Blossom Street, Cox 7 Boston, MA 02114.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA.
authors.forename: Diego
authors.initials: D
authors.lastname: Ferreira
authors.affiliation: Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Hooker
authors.affiliation: Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA.
authors.forename: Ciprian
authors.initials: C
authors.lastname: Catana
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hoover
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States; Max-Planck-Institut fü r Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mü lheim an der Ruhr, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Ritter
authors.affiliation: E.L. Steele Laboratories Department of Radiation Oncology Harvard Medical School and Massachusetts General Hospital 100 Blossom Street, Cox 7 Boston, MA 02114.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.affiliation: Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA; Division of Body Imaging, Department of Diagnostic Radiology, Oregon Health Sciences University, Portland, OR. Electronic address: guimaraa@ohsu.edu.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Guimaraes