Noninvasive assessment of losartan-induced increase in functional microvasculature and drug delivery in pancreatic ductal adenocarcinoma

Vidhya Kumar, Yves Boucher, Hao Liu, Diego Ferreira, Jacob Hooker, Ciprian Catana, Andrew J. Hoover, Tobias Ritter, Rakesh K. Jain, Alexander Guimaraes

Research output: Contribution to journalArticle

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Abstract

PURPOSE: 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. METHOD AND MATERIALS: 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 60minutes using an 18F-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 b.05). Losartan also induced a significant increase in the intratumoral uptake of 18F-5FU by 53%(P <.0001).CONCLUSION: MRI using FDA-approved MNPs provides a noninvasive, translatablemeans of assaying microvascular parameters induced by losartan in pancreatic cancer. PET measurements demonstrated that losartan significantly increased the uptake of 18F-5FU.

Original languageEnglish (US)
Pages (from-to)431-437
Number of pages7
JournalTranslational Oncology
Volume9
Issue number5
DOIs
StatePublished - Oct 1 2016

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Losartan
Microvessels
Adenocarcinoma
Pharmaceutical Preparations
Fluorouracil
Positron-Emission Tomography
Blood Vessels
Magnetic Resonance Imaging
Blood Volume
Nanoparticles
Animal Care Committees
Ferrosoferric Oxide
Injections
Angiotensin Receptor Antagonists
Pancreatic Neoplasms
Iron
Perfusion
Muscles
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Noninvasive assessment of losartan-induced increase in functional microvasculature and drug delivery in pancreatic ductal adenocarcinoma. / Kumar, Vidhya; Boucher, Yves; Liu, Hao; Ferreira, Diego; Hooker, Jacob; Catana, Ciprian; Hoover, Andrew J.; Ritter, Tobias; Jain, Rakesh K.; Guimaraes, Alexander.

In: Translational Oncology, Vol. 9, No. 5, 01.10.2016, p. 431-437.

Research output: Contribution to journalArticle

Kumar, Vidhya ; Boucher, Yves ; Liu, Hao ; Ferreira, Diego ; Hooker, Jacob ; Catana, Ciprian ; Hoover, Andrew J. ; Ritter, Tobias ; Jain, Rakesh K. ; Guimaraes, Alexander. / Noninvasive assessment of losartan-induced increase in functional microvasculature and drug delivery in pancreatic ductal adenocarcinoma. In: Translational Oncology. 2016 ; Vol. 9, No. 5. pp. 431-437.
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AU - Boucher, Yves

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AU - Ferreira, Diego

AU - Hooker, Jacob

AU - Catana, Ciprian

AU - Hoover, Andrew J.

AU - Ritter, Tobias

AU - Jain, Rakesh K.

AU - Guimaraes, Alexander

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N2 - PURPOSE: 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. METHOD AND MATERIALS: 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 60minutes using an 18F-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 b.05). Losartan also induced a significant increase in the intratumoral uptake of 18F-5FU by 53%(P <.0001).CONCLUSION: MRI using FDA-approved MNPs provides a noninvasive, translatablemeans of assaying microvascular parameters induced by losartan in pancreatic cancer. PET measurements demonstrated that losartan significantly increased the uptake of 18F-5FU.

AB - PURPOSE: 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. METHOD AND MATERIALS: 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 60minutes using an 18F-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 b.05). Losartan also induced a significant increase in the intratumoral uptake of 18F-5FU by 53%(P <.0001).CONCLUSION: MRI using FDA-approved MNPs provides a noninvasive, translatablemeans of assaying microvascular parameters induced by losartan in pancreatic cancer. PET measurements demonstrated that losartan significantly increased the uptake of 18F-5FU.

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