Christin Y. Sander¹, Jacob M. Hooker¹, Ciprian Catana¹, Bruce R. Rosen^1,2, and Joseph B. Mandeville^1
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.

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 Luo^1
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.

Michael Valdez¹, Shelby Yuan¹, Zhonglin Liu¹, Paul Helquist², Terry Matsunaga¹, Russell Witte¹, Lars Furenlid¹, Marek Romanowski¹, and Ted Trouard^1
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.

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. Willmann^1
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.

Sayuan Liang¹, Dominiek Staelens², Bernard Appeltans³, Marlies Van de Wouwer^3,4, Guy Van den Mooter³, Gert Van Assche², Greetje Vande Velde¹, and Uwe Himmelreich^1
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.

Michael Peller¹, Linus Willerding^1,2, Simone Limmer², Martin Hossann^2,3, Olaf Dietrich¹, Michael Ingrisch¹, Lars Lindner^2,3, and Maximilian F. Reiser^1
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.

Yuguo Li^1,2, Kannie W.Y. Chan^1,2, Theodore Ewachiw³, Michael T McMahon^1,2, Peter C.M. Van Zijl^1,2, Zeshaan Rasheed³, and Guanshu Liu^1,2
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.

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. Strijkers^3,5, Zahi A. Fayad¹, and Willem J.M. Mulder^1,5
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.

Bradley D Hann¹ and Kevin M Bennett^1
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.

Zhihang Chen¹, Marie-France Penet¹, Balaji Krishnamachary¹, Sangeeta Ray Banerjeee¹, Martin G. Pomper¹, and Zaver M. Bhujwalla^1
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.