Vidhya Kumar, Abstract Co-Author: Nothing to Disclose

Diego Santos Ferreira PhD, Abstract Co-Author: Nothing to Disclose

Yves Boucher PhD, Abstract Co-Author: Nothing to Disclose

Rakesh K. Jain PhD, Abstract Co-Author: Board of Directors, XTuit Pharmaceuticals Stockholder, XTuit Pharmaceuticals

Alexander Ramos Guimaraes MD, PhD, Presenter: Speakers Bureau, Siemens AG Expert Witness, Rice, Dolan, Kershaw

Pancreatic ductal adenocarcinoma (PDAC) responds poorly to chemotherapy partly due to a collagen rich desmoplastic response that is a barrier to drug delivery. Angiotensin receptor blockade (ARB) with Losartan ® has been shown to enhance the intratumoral penetration and efficacy of therapeutics in mice using in vitro techniques. Because of its steady state approach, we hypothesize that MRI using clinically available magnetic nanoparticles (MNP)(ferumoxytol – Feraheme ®, AMAG Pharmaceuticals, Inc.), will be sensitive to changes in tumor microvasculature that result from ARB in PDAC. The purpose of this study was to test this hypothesis in an orthotopic mouse model of PDAC

All experiments were approved by the local ethical review panel. Orthotopic tumors were generated by implanting 1mm3 chunks of AK4.4 spontaneously generated tumors (from a Ptfl-Cre/LSL-KrasG12D/p53Lox mouse model) into the pancreas of 6-8 week old FVB mice. Tumors were allowed to grow for 1 week prior to treatment. Animals were treated daily with an ip injection of 70mg/kg Losartan for 5 days. MRI was performed using a home built bird-cage coil at 4.7T and included multiecho gradient echo (TE 3.5, 8.5, 13.5, 18.5 msec; TR 750msec) and multiecho spin echo (TE 10, 20, 30, 40, 50, 60msec; TR 2000msec) pulse sequences and were performed prior to and following iv administration of 3 mg/kg iron ferumoxytol. Data analysis was performed by (ROI) analysis of 3 central slices within each tumor calculating ΔR2 and ΔR2*. fBV (~ΔR2*) was normalized to an assumed fBV in muscle of 3%. Vessel size index (VSI) (~ΔR2*/ ΔR2) was also calculated comparing control and Losartan treated animals. Statistical analyses compared both cohorts using a two-tailed unpaired t-test.

Losartan treated animals (n=7) demonstrated a statistically significant difference in fBV (mean ± sem) (9.5 ± 1.3) as compared to the control population (n=5) (3.1± 2.2) (p<0.05), and VSI (1.8 ± 0.4 vs. 0.7 ± 0.2) (p<0.05).

MRI using clinically available MNP provided a non-invasive assessment of tumor blood vessel changes following ARB in a PDAC model. The approximate 2.5 fold increase in mean VSI and fBV is in concert with recently published in vitro results.

MRI using MNP may provide a readily translatable, quantitative assay of PDAC tumor microvasculature.

Kumar, V, Ferreira, D, Boucher, Y, Jain, R, Guimaraes, A, MRI Using Magnetic Nanoparticles Measures Changes in Tumor Microvasculature Following Modulation of the Tumor Microenvironment with Angiotensin Receptor Blockade.  Radiological Society of North America 2014 Scientific Assembly and Annual Meeting, - ,Chicago IL. http://archive.rsna.org/2014/14015002.html