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Graduate Category: Health Science Degree Level: PhD Abstract ID# 1298 Curing cancer: Using MRI to understand how and why therapeutic nanoparticles work Ju Qiao, Liam Timms, Codi Gharagouzloo, Zihang Fang, Joseph Nneji, Kristofer Patel, Paige Baldwin, Anne L. van de Ven, Srinivas Sridhar Experimental design Visualization of nanoparticles in tumors 24hr accumulation (4hr vehicle) No ferumoxytol (No treatment) We have developed a quantitative ultra-short time-to-echo contrast-enhanced (QUTE-CE) magnetic resonance imaging (MRI) technique to quantify nanoparticle delivery in blood vessels and tissues using FDA-approved iron oxide nanoparticles as a surrogate. Here we show, for the firsttime, that this cutting-edge imaging technique can provide us with new insights into the mechanisms of nanoOlaparib, a nanoformulated DNA repair inhibitor. Visualization of nanoparticles in blood 24hr accumulation (4hr nanoOlaparib) T1 T2 Before ferumoxytol Treatment of prostate cancer using nanoOlaparib QUTE-CE produces positive-contrast images UTE % nanoparticles 14 1 day 3 months 12 10 0.5mm 8 6 Fig 4. Comparison of different MRI imaging techniques of ferumoxytol accumulation in a mouse prostate tumor 4 0 10 100 Diameter (nm) nanoOlaparib is created by inserting drug into the bilayer of liposomes 1000 nanoOlaparib has a uniform diameter and is stable with time Individual nanoparticles are visualized using TEM Fig. 1. Characterization of Olaparib nanoformulation nanoOlaparib alone slows but does not prevent tumor growth 6 5 4 3 1 0 7 14 21 Days 28 35 24hr accumulation (4hr nanoOlaparib) 6 Drug-loaded particles yield brighter signal than empties = MORE ACCUMULATION 4 2 0 500 42 1000 1500 UTE voxel intensity (AU) Inset: Ferumoxytol signal in untreated (L) and nanoOlaparib-treated (R) tumors 25 Fig. 2. Change in mouse prostate tumor size following treatment Untreated 10Gy radiation nanoOlaparib nanoOlaparib + 10Gy 100 80 % Surviving 8 24hr accumulation (4hr vehicle) 60 40 nanoOlaparib + radiation cures 50% of mice 20 0 2 4 6 Weeks 8 10 12 Fig. 3. Mouse survival time following treatment • What to test next: Does nanoOlaparib increase its own efficacy by enhancing its own ability to accumulate in tumors? References of interest 1) Codi Gharagouzloo et al. Magnetic Resonance in Medicine. 2015, 74(2): 431-441 2) Yixiang Wang. Quantitative Imaging in Medicine and Surgery. 2011, 1(1): 35-40 18x signal enhancement 3) J. C. Brisset, et al. Mol. Imag. Biol. 2011, 13: 672–678 20 4) Y. Okuhata, Adv. Drug Deliv. Rev. 1999, 37:121–137 15 Acknowledgements 10 5 0 1 0 • nanoOlaparib enhances nanoparticle accumulation in tumors by as much as 18x 2000 Fig. 5. Quantification of UTE signal intensity across the entire tumor volume following repeat ferumoxytol administration 2 0 empty control • QUTE-CE MRI provides quantitative, positivecontrast images of nanoparticle accumulation in both tumor tissue and tumor vasculature • nanoOlaparib treatment causes tumors to lose their resistance to radiation therapy 0 nanoOlaparib + radiation greatly reduces tumor growth % signal-enahnced voxels with significant accumulation Fold change in tumor size Untreated 10Gy radiation nanoOlaparib No ferumoxytol (No treatment) 10 ln (voxel number) 1 7 Fig. 7. Ferumoxytol in the tumor vasculature following nanoOlaparib administration What we learned 2 8 After ferumoxytol 2 3 No treatment 4 5 6 Radiation 7 8 9 10 11 nanoOlaparib Fig. 6. Enhancement of nanoparticle accumulation following nanoOlaparib administration This work was supported by the following grants: NSF-DGE-0965843, NIH HHS/IU54CA151881, CIMIT 13-1807, NIH NCI R01CA082328, NIH 5 P30 CA06516, and the Mazzone Foundation. The FK01 mouse prostate cancer cells were kindly donated by the Pandolfi group at the Beth Israel Deaconess Cancer Center