ISMRM 24th Annual Meeting & Exhibition • 07-13 May 2016 • Singapore

Combined Educational & Scientific Session: Imaging Drug Delivery & Drug Function

Skill Level: Intermediate

Organizer: Peter Caravan, Ph.D. & David P. Cormode, D.Phil.

Tuesday 10 May 2016

The favorable properties of MR as an imaging modality (noninvasive, deep tissue penetration, multiple signal/ contrast mechansisms, lack of ionizing radiation, good temporal and spatial resolution) make it a useful tool to image drug delivery and drug function. In this educational session we will cover direct and indirect methods of imaging drug delivery. We will also discuss different functional readouts that can be used to monitor drug function. This will be followed by 5 short talks selected from the scientific abstracts.

Target Audience
Physicians, Imaging scientists, chemists, drug developers and others interested in using MR to report on drug delivery and drug function.

Educational Objectives
Upon completion of this course, participants should be able to:

  • List different MR techniques for imaging drug delivery;
  • Describe the characteristics of a useful theranostic;
  • Understand the challenges and benefits of combining MR with focused ultrasound for drug delivery; and
  • Explain the mechanism of pharmacologic MRI.

Moderators: Peter Caravan, David Cormode
Direct & Indirect MRI Methods to Detect Drug Delivery
Christin Y. Sander1,2
1A. A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, United States, 2Harvard Medical School, Boston, MA, United States
Drug properties are initially defined through in vitro studies and characterized by parameters such as efficacy and affinity. However, in vivo drug profiles can vary widely and depend on the type of imaging modality used, species, methods of administration, and what we define as outcome measures. In this talk, we will show how we can use PET as a direct and fMRI as an indirect method to image drug delivery and its functional response. Taken together, we can establish models that link drug occupancy to functional output and classify drugs according to their in vivo potency.

Theranostics: Delivering Drug & Contrast Agent Simultaneously
Willem Mulder1
1MSSM, United States
In this educational imaging-facilitated optimization of nanomedicine and the “companion diagnostic" concept, the latest advances in these fields, and translational considerations will be discussed.

Use of MRI to Monitor Drug Delivery in Combination with Focused Ultrasound
Chrit T. Moonen1 and Clemens Bos1
1UMC Utrecht
The recently published examples of the use of MR-HIFU for local drug delivery illustrate the important role of multi-modal molecular imaging in the various aspects of ultrasound triggered IGDD. Ultrasound triggered IGDD has been shown to be feasible (1,2), and initial clinical applications have started. (Real-time) molecular imaging methods based on MRI, optical and ultrasound, are used for guidance of actions to release or activate drugs and/or permeabilize membranes, and for evaluation of biodistribution, PK/PD. MRI offers many advantages in this field such as: excellent target definition, temperature monitoring, nanoparticle monitoring, biomarkers for drug release, and biomarkers for BBB opening.

Assessment of atherosclerotic burden using a novel tropoelastin-specific MR contrast agent
Alkystis Phinikaridou1, Sara Lacerda1, Begoña L Plaza1, Marcelo Andia2, and René M Botnar1
1Biomedical Engineering, King's College London, London, United Kingdom, 2Radiology, Pontificia Universidad Católica de Chile, Santiago, Chile
The extracellular matrix protein (ECM) elastin contributes to 30% of the dry weight of the vascular wall. Vascular injury leads to de novo synthesis of tropoelastin molecules, the precursor of cross-linked mature elastin. Cross-linking has been shown to be inhibited in the presence of inflammation and low-density lipoproteins (LDL), both hallmarks of atherosclerosis and plaque instability. The accumulation of tropoelastin molecules in the pathologically altered vessel wall thus, may serve as a new imaging biomarker to detect atherosclerosis, and potentially plaque instability [1-4]. In this study, we developed a novel tropoelastin-specific MR contrast agent and investigated its merits to quantify disease progression in a murine model of accelerated of atherosclerosis. 

Development of nitroxide-based theranostics probes for brain redox research by MRI
Miho C Emoto1, Shingo Sato2, and Hirotada G Fujii1
1Sapporo Medical Univeristy, Sapporo, Japan, 2Yamagata University, Yonezawa, Japan
Theranostics probes, which have both therapeutic and diagnostic imaging capabilities in one dose, show great promise for use in MRI examinations. In the present study, we synthesized nitroxide-based theranostics probes by connecting anti-inflammatory drugs, ibuprofen and ketoprofen, to nitroxides that act as T1 contrast agents in MRI. MRI of mouse heads after injection of these synthesized probes showed that they worked as T1 contrast agents in mouse brains. Production of nitric oxide in septic mouse brains was remarkably inhibited by the addition of these probes, indicating that they also acted as anti-inflammatory drugs.

Initial Experience in a Pilot Study of Blood-Brain Barrier Opening for Chemo-Drug Delivery to Brain Tumors by MR-Guided Focused Ultrasound
Yuexi Huang1, Ryan Alkins2, Martin Chapman3, James Perry4, Arjun Sahgal5, Maureen Trudeau6, Todd Mainprize7, and Kullervo Hynynen1,2
1Sunnybrook Research Institute, Toronto, ON, Canada, 2Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada, 3Department of Anaesthesia, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, 4Division of Neurology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, 5Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, 6Division of Medical Oncology and Hematology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, 7Division of Neurosurgery, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
In the first case of a pilot clinical study to establish the feasibility, safety and preliminary efficacy of focused ultrasound to temporarily open blood brain barrier (BBB) to deliver chemotherapy to brain tumors, BBB was successfully opened at two targeted volumes close to the peripheral margin of the tumor, approximately 4cm lateral from the midline of the brain. This may provide a new way to deliver therapeutic agents into brain for the treatment of tumors and other brain diseases.

Development of Gadoxetate DCE-MRI to Evaluate Liver Transporter Function: Reproducibility of Established Technique and Application in OATP KO Rats
Apoorva Mondal1, Xiangjun Meng2, Richard Kennan3, Jocelyn Yabut4, Cristian Salinas5, and Catherine D. G. Hines2
1Telecommunications Engineering, University of Maryland-College Park, College Park, MD, United States, 2Translational Imaging Biomarkers, Merck Research Laboratories, West Point, PA, United States,3Translational Imaging Biomarkers, Merck Research Laboratories, Kenilworth, NJ, United States, 4Pharmacokinetics, Merck Research Laboratories, Rahway, NJ, United States, 5Biogen, Inc., Cambridge, MA, United States
Recently, Ulloa et al described a compartmental modeling approach to measure gadoxetate influx and efflux as a potential biomarker of hepatobiliary transporter function, as uptake and efflux are mediated by known transporters. The purpose of this study was to reproduce the described acquisition and post-processing, and apply the MRI assay to variations of liver influx transporter Oatp1a/1b knock-out (KO) rats to potentially differentiate between degrees of transporter function. In vivo results demonstrate significant differences in influx constants between groups of KO rats, and that this assay may be suitable for investigating drug-induced liver injury and drug-drug interactions.

MRI assessment of Changes in Tumor Oxygenation post Hypoxia-targeted Therapy
Shubhangi Agarwal1, Troy Kozlowski1, Rohini Vidya Shankar1, Landon J. Inge2, and Vikram D. Kodibagkar1
1SBHSE, Arizona State University, Tempe, AZ, United States, 2St. Joseph's Hospital and Medical Center, Phoenix, AZ, United States
Solid tumors have hypoxic foci that be targeted using hypoxia activated/targeting drugs. Utilizing quantitative MR oximetry techniques such as the PISTOL (Proton Imaging of Siloxanes to map Tissue Oxygenation Levels) technique could allow for patient stratification for personalized therapy. This study uses the PISTOL technique to evaluate how the hypoxia activated drug TPZ (Tirapazamine) depends on and affects the oxygenation and edema fraction of epidermoid carcinoma (A431) and non-small cell lung cancer (H1975).  Surprisingly, TPZ was more effective on the H1975 tumors than A431, in spite of higher pre-treatment pO2 levels, potentially due to perfusion-related differences in tumor drug delivery.

Adjournment & Meet the Teachers

The International Society for Magnetic Resonance in Medicine is accredited by the Accreditation Council for
Continuing Medical Education to provide continuing medical education for physicians.