ISMRM 23rd Annual Meeting & Exhibition • 30 May - 05 June 2015 • Toronto, Ontario, Canada

Scientific Session • Imaging Drug Delivery & Drug Function

Tuesday 2 June 2015

Room 701 B

13:30 - 15:30


Zaver M. Bhujwalla, Ph.D., Willem M. Mulder, Ph.D.

13:30 0364.   
Classification of in vivo drug function through a coupling model and PET/fMRI
Christin Y. Sander1, Jacob M. Hooker1, Ciprian Catana1, Bruce R. Rosen1,2, and Joseph B. Mandeville1
1A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States, 2Health Sciences and Technology, Harvard-MIT, Cambridge, MA, United States

The pharmacological response of a drug is currently defined through in vitro studies and characterized by parameters such as in vitro efficacy and affinity. We propose an in vivo classification of drug function by PET/fMRI and demonstrate a coupling model that can predict the functional response measured by fMRI. Experimental results at the D2/D3 dopamine system show that we can classify agonists and antagonists according to their fMRI response, suggesting that we can characterize drug function and efficacy to inform about the in vivo potency of a drug.

13:42 0365.   Comparison of the Central Effects of Ketamine and the NR2B-Selective NMDA Receptor Antagonist Traxoprodil Using Pharmacological MRI in Conscious Rats
Haiying Tang1, Yu-Wen Li1, Matthew Fronheiser1, Daniel Kukral1, Harold Malone1, Adrienne Pena1, Gabriel Tobon2, Kurex Sidik1, Patrick Chow1, Linda Bristow1, Wendy Hayes1, and Feng Luo1
1Bristol-Myers Squibb, Princeton, NJ, United States, 2InviCRO, Boston, MA, United States

Major depressive disorder (MDD), a leading cause of disability globally, has an enormous social and economic impact. Improvements in the efficacy of antidepressant therapy are needed. Ketamine is a nonselective NMDA antagonist which has been reported to have antidepresseant effects in patients with MDD. Significant efforts have been reported in the development of NR2B subtype-selective antagonists, to minimize adverse side effects observed with nonselective NMDA antagonists. In the present study we implemented pharmacological MRI (phMRI) in conscious rats to map the central effects of ketamine and traxoprodil, and to study the neurocircuitry that might attribute to the antidepressant effects.

13:54 0366.   
Comparison of MRI Contrast Enhancement with Molecular Distribution Following FUS-Mediated BBB Opening
Michael Valdez1, Shelby Yuan1, Zhonglin Liu1, Paul Helquist2, Terry Matsunaga1, Russell Witte1, Lars Furenlid1, Marek Romanowski1, and Ted Trouard1
1University of Arizona, Tucson, Arizona, United States, 2University of Notre Dame, Indiana, United States

Treatment of neurological disorders is often hampered by the inability of therapeutics to cross the blood-brain barrier (BBB). Techniques that use focused ultrasound (FUS) and microbubbles have been developed that temporarily open the BBB. While the opening of the BBB is readily seen on contrast-enhanced MRI, this only shows the distribution of contrast agent and not necessarily the opening to therapeutics. In this work, we have employed MRI, SPECT, CT, autoradiography, and fluorescence microscopy in mice to compare the distribution of contrast agents and model therapeutics within the brain following FUS-mediated BBB opening.

14:06 0367.   In vivo monitoring of ultrasound-mediated nanoparticle delivery in human colon cancer xenografts using magnetization-prepared rapid gradient echo (MPRAGE) imaging
Steven B Machtaler1, Bragi Svensson1, Tzu-Yin Wang1, Jung Woo Choe2, Kanyi Pu1, James Rioux1, Brian Rutt1, Pierre Khuri-Yakub2, Brian A. Hargreaves1, and Juergen K. Willmann1
1Radiology, Stanford, Stanford, CA, United States, 2Stanford, CA, United States

Ultrasound-mediated vascular permeabilization is currently being explored as a mechanism for site-specific delivery of therapeutics; however, a method to quantify therapeutic delivery in vivo is required for clinical translation. We investigated the feasibility of assessing ultrasound-mediated nanoparticle delivery into colon cancer xenografts by quantifying gadolinium-conjugated fluorescent nanoparticle accumulation using MPRAGE imaging. We observed a detectable drop in T1 in tumours after US-mediated treatment that corresponded to an increase in the nanoparticle accumulation observed ex vivo. This approach has the potential to non-invasively quantify drug delivery efficiency within a targeted tissue and spatially map regions where successful delivery has occurred.

14:18 0368.   
Combined 19F MRI and CT imaging for the visualization of delayed release of compounds using pH-sensitive polymers coated capsules in vitro and in a hamster animal model
Sayuan Liang1, Dominiek Staelens2, Bernard Appeltans3, Marlies Van de Wouwer3,4, Guy Van den Mooter3, Gert Van Assche2, Greetje Vande Velde1, and Uwe Himmelreich1
1Department of Imaging & Pathology, KU Leuven, Leuven, Flemish Brabant, Belgium, 2Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Flemish Brabant, Belgium, 3Department of pharmaceutical and pharmacological sciences, KU Leuven, Leuven, Flemish Brabant, Belgium, 4PharmAbs, KU Leuven, Leuven, Flemish Brabant, Belgium

In vivo imaging of controlled release in the gastrointestinal tract is of major importance to assess its efficacy. In this study, we establish a dual modal imaging platform by combining 19F MRI and CT using 19FDG and BaSO4 as contrast agent respectively which can provides information on the location, integrity and release of material from the capsule into the gastrointestinal tract of small animal models for the first time.

14:30 0369.   T1 based surrogate MRI marker for hyperthermia-induced release of doxorubicin from thermosensitive liposomes in solid tumors - permission withheld
Michael Peller1, Linus Willerding1,2, Simone Limmer2, Martin Hossann2,3, Olaf Dietrich1, Michael Ingrisch1, Lars Lindner2,3, and Maximilian F. Reiser1
1Department of Clinical Radiology, University Hospital of Munich, Munich, Germany, 2Department of Internal Medicine III, University Hospital of Munich, Munich, Germany, 3CCG Tumor Therapy through Hyperthermia, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany

Effectiveness of anti-cancer drugs can be improved by tumor-targeting. Using thermosensitive liposomes such targeting is realized by tumor specific hyperthermia and visualization by loading the TSL with MRI-contrast agents. Purpose of this in vivo study is to test T1-based assessment of hyperthermia induced doxorubicin release in tumors using a mixture of thermosensitive liposomes loaded with a clinically approved contrast agent or doxorubicin, respectively. Assessment of doxorubicin accumulated in heterogeneous tumors tissue seems feasible. This was the first time that a mixture of thermosensitive liposomes loaded either with contrast agent or doxorubicin has been investigated.

14:42 0370.   Direct imaging of gemcitabine delivery in pancreatic ductal adenocarcinoma (PDAC) using CEST MRI
Yuguo Li1,2, Kannie W.Y. Chan1,2, Theodore Ewachiw3, Michael T McMahon1,2, Peter C.M. Van Zijl1,2, Zeshaan Rasheed3, and Guanshu Liu1,2
1F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States, 2Department of Radiology, Johns Hopkins University, Baltimore, MD, United States, 3Department of Oncology, Johns Hopkins University, Baltimore, MD, United States

One formidable challenge in treating advanced pancreatic ductal adenocarcinoma (PDAC) is the highly heterogeneous vascular barriers that hinder efficacious drug delivery. Here, we propose a new approach to monitor delivery directly using the inherent Chemical Exchange Saturation Transfer (CEST) MRI signal carried by the drug. Our results first showed that gemcitabine, the first-line treatment for PDAC, could be readily detected by CEST MRI via its exchangeable amino (2.3 ppm) and hydroxyl (1.0 ppm) protons. We conclude that direct CEST MR imaging of the uptake and distribution of gemcitabine in PDAC tumors can be accomplished without the use of additional imaging agents.

14:54 0371.   Multimodal in vivo evaluation of a surface-switching nanoparticle platform
Francois Fay1, Line Hansen2, Stephanie J. Hectors3, Jun Tang1, Anita Gianella1, Brenda L. Sanchez-Gaytan1, Yiming Zhao1, Aneta J. Mieszawska1, Robert Langer4, Claudia Calcagno1, Gustav J. Strijkers3,5, Zahi A. Fayad1, and Willem J.M. Mulder1,5
1Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, United States, 2Interdisciplinary Nanoscience Center, Aarhus University, Aarhus, Denmark, 3Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands, 4Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States,5Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands

We have developed a hybrid lipid-polymer nanoparticle platform, which has a matrix metalloproteinase-2 (MMP2) cleavable polyethylene glycol (PEG)-lipid corona. Near infrared fluorescent dyes and paramagnetic lipids were incorporated to enable dual in vivo optical and magnetic resonance imaging. In the current study we demonstrated that upon incubation with MMP2 the PEG shielding is removed enabling the targeting ligands (RGD peptides) to bind to αvβ3 integrin expressing cells. In vivo mouse imaging revealed that following an intravenous administration our nanoparticles accumulated in the rim of orthotopically implanted breast tumors.

15:06 0372.   On-off switchable nanoparticles for improved detection with MRI
Bradley D Hann1 and Kevin M Bennett1
1Biology, University of Hawaii at Manoa, Honolulu, HI, United States

If contrast agent relaxivity could be temporally modulated from an external source, it may lower the minimum detectable concentration of in inhomogeneous tissue. We have developed a thermally on-off switchable nanoparticle that decreases in r1 when raised above the switching temperature threshold. Next we simulated the tissue regions where a switchable particle would be detectable in lower concentrations than a non-switchable one. This may be useful for molecular imaging in inhomogeneous tissue such as the liver, kidney, or spleen.

15:18 0373.   PSMA-Specific Theranostic Nanoplexes for Combination Gene and Prodrug Therapy of Prostate Cancer
Zhihang Chen1, Marie-France Penet1, Balaji Krishnamachary1, Sangeeta Ray Banerjeee1, Martin G. Pomper1, and Zaver M. Bhujwalla1
1Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Prostate cancer (PCa) is the second leading cause of death from cancer in men in the U.S., and there is a compelling need for the development of effective treatments for metastatic PCa. Prostate-specific membrane antigen (PSMA) is a membrane protein that has abundant and restricted expression on the surface of castrate-resistant PCa, and is therefore a promising target for combined diagnosis and therapy of metastatic PCa. Here we achieved PSMA-specific delivery of a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) cDNA gene and a prodrug enzyme bacterial cytosine deaminase (bCD) using a nanoplex based polyethyleneimine (PEI) platform.