2005 MIPS/Philips Medical
Molecular Imaging Seminar Series

Reception 5:30 - 6:00 pm
Seminar 6:00 - 6:45 pm
Discussion 6:46 - 7:00 pm

January 3, 2005

Ge Wang, PhD 
Director, Bioluminescence Tomography Laboratory 
Professor, Depts of Radiology, Biomedical Engineering, Mathematics & Civil Engineering
University of Iowa

Bioluminescence Tomography 

Small animal imaging becomes increasingly important for biomedical research at anatomical, functional, cellular and molecular levels. For molecular imaging, our group has been developing bioluminescence tomography since 2002. This new imaging mode is to reconstruct a bioluminescent source distribution inside a mouse from external flux measurement on the surface of the mouse. To achieve a satisfactory reconstruction, we use a modality fusion approach and incorporate constraints on the source distribution. Specifically, we use X-ray CT/micro-CT to provide an image volume of the mouse, which is segmented into major anatomical components and assigned with appropriate optical parameters. This optical property mapping is used to facilitate tomographic reconstruction of the bioluminescent source distribution inside the same mouse. In this presentation, we briefly report our progress on bioluminescence tomography. Theoretically, we have studied the solution uniqueness in bioluminescence tomography under practical constraints despite the illposedness of this inverse source problem in the general case. Specifically, we have established the uniqueness of the solution in the cases of impulse sources and solid/hollow ball sources (up to non-radiating sources). Technically, we have developed a prototype system and several reconstruction algorithms, and tested them in numerical simulation, phantom experiments, and in vivo mouse studies. Finally, we discuss related issues and research directions. Hopefully, the versatility and performance of this modality would make it a unique molecular imaging tool. 

February 14, 2005

Sarah J Nelson, PhD 
Professor of Radiology & Bioengineering

Characterization of Brain Tumors using MR Molecular Imaging and Spectroscopy 

Gliomas are heterogeneous, infiltrative lesions that have poorly defined margins on conventional MR images. This presents a considerable challenge for defining tumor burden and for planning radiation or other forms of focal therapy. While clinical trials have demonstrated a relationship between histological grade and outcome, there is significant variability in response to therapy and survival between patients with similar grades. Our studies have focused on developing and applying MR data acquisition and analysis techniques that are able to predict the biological behavior of gliomas and will provide objective criteria for tailoring treatment protocols to specific individuals. The most promising of these are Magnetic Resonance Spectroscopic Imaging (MRSI), Perfusion Weighted Imaging (PWI) and Diffusion Weighted Imaging (DWI). Our results have shown that MRSI is likely to be more reliable than conventional MRI in defining tumor burden for newly diagnosed and recurrent gliomas, and that all three modalities provide information relevant for treatment planning and evaluating response to therapy. Despite promising results with the methodology that has been developed, there is room for improvements in the spatial resolution and chemical specificity obtained at the conventional field strength of 1.5T. The recent availability of clinical MR scanners with field strength of 3T and radiofrequency coils with improved sensitivity has provided significant advances in the signal-to-noise of the MRSI and PWI data. These techniques are currently being applied in prospective clinical studies of patients with gliomas as part of the UCSF Brain Tumor SPORE project.

March 14, 2005

Trevor Douglas, PhD
Department of Chemistry and Biochemistry
Montana State University

Protein Cage: Multifunctional Materials for Imaging and Therapeutic Delivery Architectures

Protein cage architectures are self-assembled hollow spheres derived from viruses and other biological cage structures. Using a biomimetic approach we have demonstrated that viruses, and other protein cage architectures, can be genetically and chemically modified in order to create multifunctional targeted drug delivery and imaging platforms. The coat protein of the Cowpea chlorotic mottle virus (CCMV) has been used as a model for understanding the assembly of protein cage architectures for applications in We have explored modifications to the exterior and interior interfaces while maintaining assembly of stable icosahedral capsid This has allowed us to utilize the high symmetry of the viral capsid to engineer unique functionality for highly ordered multivalent presentation of cell targeting ligands, paramagnetic metal chelates, and superparamagnetic These modifications have a profound influence on packaging and interaction of the capsid In addition, modifications to the interfaces between subunits have been made, which influence structural transitions of the capsid as well as metal binding Using a solid-state approach we have shown that the symmetry of the CCMV capsid can be broken to allow differentiation of modified sites within the high symmetry capsids. A robust in vitro assembly system has also allowed us to direct the mixed assembly of differentially modified subunits to generate symmetry broken, multiply labeled capsids. The role of protein interfaces in assembled protein cage architectures has been explored to understand and exploit packaging of materials as diverse as nucleic acid, drugs, and inorganic magnetic This approach has been applied to other non-viral protein cage-like architectures including mammalian ferritin, the ferritin-like protein from Listeria innocua, and the small heat shock protein from Methanococcus This library of protein cages has allowed us to explore the size dependent magnetic properties, imaging, and delivery of protein-encapsulated materials.

April 11, 2005

D. Scott Wilbur, PhD
Prof. Radiation Oncology 
University of Washington

Considerations for In Vivo Applications employing the Biotin-Streptavidin Binding Pair

Biotin (vitamin H) has extremely high binding affinities with the proteins avidin (1015 M-1) and streptavidin (1013 M-1). Thus, these binding pairs are being considered, and tested, for a number of in vivo radionuclide targeting applications. Due to the rapid clearance and higher non-target interaction of avidin, the biotin-streptavidin binding pair is most often preferred for in vivo applications. Our studies have focused on development of new reagents from these chemical entities for targeting radionuclides to cancer cells in vivo. The developed reagents are used in multi-step ("pretargeting") approaches to deliver halogen radionuclides for cancer therapy.

May 9, 2005

Michael Welch, PhD
Professor, Radiology, Chemistry, Molecular Biology and Pharmacology
Wahington University
St. Louis

Advances in PET Imaging Using Nonstandard Radionuclides 

Radiopharmaceuticals for use with positron emission tomography are usually labeled with the radionuclide 15O, 13N, 11C and 18F. Other positron emitting radionuclides include 64Cu, 66Ga, 86Y, 76Br, 124I. Targetry that can utilized on small biomedical cyclotrons has been developed to produce all of these non-standard radionuclides in high yields. Washington University is currently providing 64Cu, 76Br, 124I and 86Y to researchers at over 30 institutions in the United States. 

Radiopharmaceuticals with various biological targets have been labeled and evaluated using these nuclides. These radiopharmaceuticals include Cu-ATSM for imaging hypoxia, various peptides targeting tumor receptors as well as labeled steroid hormone receptor ligands. 

We are also utilizing 64Cu to label targeted nanoparticles to allow delivery of large amounts of radioactivity to specific targets. 

This work was support by National Institutes of Health and the U.S. Department of Energy.

June 13, 2005

Robert Gilles, Ph.D.
Dept of Biochemistry & Molecular Biophysics
University of Arizona

Imag(in)ing the causes and consequences of the tumor microenvironment 

This talk will present a theory regarding the role of the microenvironment in cancer progression generated using data from functional and molecular imaging. We begin this study asking a simple question: Why do cancers have high glycolysis? This question has been part of our mental wallpaper for decades, yet it has more recently regained prominance due to extensive investigatnions of fluorodeoxyglucose uptake using positron emission tomography. This FdG PET imaging has shown that virtually all metastatic cancers exhibit high rates of glucose trapping. We propose that this is not a mere coincidence but must have conferred a selective advantage at some time during the carcinogenesis program. Early stage epithelial cancers (carcinoma in situ) are avascular and hence, hyperplastic cells are exposed to environments with intermittant hypoxia. We propose that this selects for a glycolytic phenotype that can occur through stabilization of transcription factors, such as HIF-1a. Elevated glycolysis is exhibited even in the presence of oxygen (the Warburg Effect) and results in local metabolic acidosis, measured with MR or fluorescence intravital microscopy. This low pH exerts a further pressure which selects for cells with increased migration, invasion and metastasic behaviors.

July 11, 2005

David Benaron, MD
Associate Professor (Consulting)
Stanford University School of Medicine
Department of Pediatrics and Medical Device Networks
CEO, Spectros Corp

Speed Bumps, Brick Walls, and Home Runs - Molecular Imaging in the Marketplace 2005-2010 

August 8, 2005

Zaver M. Bhujwalla, PhD
The Johns Hopkins University School of Medicine

Molecular and Functional Imaging of Cancer 

One of the most justifiable, and widely accepted, concepts about cancer, is that the malignant cell arises from genetic alterations. However, it is possible, that several of the lethal phenotypic traits of cancer, such as invasion and metastasis, may arise from the unique physiological environment, generated to a large extent by the abnormal tumor vasculature. This unique physiological environment of solid tumors, is frequently characterized by areas of poor flow, hypoxia, high lactate and low pHe, all of which influence vascularization, invasion and metastasis. Thus, vascularization and the physiological and metabolic environment appear to play permissive (and conversely preventive) roles in invasion and metastasis. We have developed and applied noninvasive Magnetic Resonance (MR) Imaging (I) and Spectroscopy (S) techniques to understand the role of vascular, physiological and metabolic properties in cancer invasion and metastasis. These MR studies are performed with human breast and prostate cancer cells maintained in culture, or grown as solid tumors in immune suppressed mice. We have developed an invasion assay system to dynamically track invasion of cancer cells and simultaneously characterize oxygen tensions, and physiological and metabolic parameters. A layer of endothelial cells between the Matrigel layer and cancer cells can be added to this invasion assay to understand the impact of the presence of endothelial cells on cancer cell invasion, during normoxia and in the presence of hypoxia and extracellular acidosis. MRI and MRS studies of cells and solid tumors have revealed significant differences in vascular, physiological and metabolic characteristics of metastatic and non metastatic human breast and prostate cancer models. Specifically we have observed that the malignant and metastatic phenotype is characterized by high total choline, high lactate and low extracellular pH and high permeability. Recent initiatives in molecular imaging have provided unique opportunities to further characterize the tumor environment using co-localized MR methods and optical imaging, and understand the dynamics between vascularization, metabolism and hypoxia. We are currently performing combined vascular and metabolic MRI/MRSI and optical imaging on tumors derived from cancer cells engineered to express fluorescence under hypoxia. Using a combined MRI/MRS and optical imaging approach we can acquire metabolic, extracellular pH, hypoxia and vascular images from co-localized regions within a solid tumor to further understand the dynamics between these parameters during growth, and following therapy.

September 12, 2005

Albert Sinusas, MD 
Yale University School of Medicine
Nuclear Cardiology

Targeted Imaging of Ischemia-Induced Angiogenesis and Post-MI Remodeling 

Non-invasive imaging strategies will be critical for defining the temporal characteristics of angiogenesis and post-infarction remodeling, and assessing efficacy of novel gene or medical therapies for management of myocardial infarction. The presentation will review; 1) non-invasive imaging strategies for identifying the hypoxic stimulus for angiogenesis, as well as the physiological consequences of angiogenesis, and the use of targeted imaging to non-invasively track the angiogenic process over time, and 2) the role of non-invasive targeted imaging of matrix matelloproteinases for evaluation of post-infarction LV remodeling. 

The angiogenic response is modulated by the composition of the extracellular matrix and intercellular adhesions, including integrins. Integrins are family of heterodimeric cell surface receptors capable of mediating an array of cellular processes, including cell adhesion, migration, proliferation, differentiation, and survival. The specific avb3 integrin has been identified as a critical modulator of angiogenesis. Therefore, the angiogenic process can be directly tracked non-invasively by SPECT imaging of radiolabeled ligands targeted to modulators of angiogenesis, like the avb3 integrin. To evaluate the ability of SPECT imaging to directly track the angiogenic process in vivo, we have compared SPECT imaging strategies employing both 99mTc- and 111In-labeled peptides and peptidomimetics targeted at the avb3 integrin with measures of regional myocardial flow, 201Tl perfusion, and immuno-histological analysis of angiogenesis, using chronic rodent and canine models of ischemia induced angiogenesis. 

It is well recognized that the extent of left ventricular (LV) remodeling is an independent determinant of morbidity and mortality in patients following myocardial infarction (MI), and is associated with important changes within the myocardial extracellular matrix (ECM). The matrix metalloproteinases (MMPs) constitute a large family of proteolytic enzymes responsible for ECM degradation and LV remodeling. Real time in vivo spatio-temporal profiling of myocardial MMP activation would provide both diagnostic and prognostic potential in patients following MI. The enhanced expression/activation of specific MMPs can be tracked non-invasively with MMP targeted radiotracers and multi-modality microSPECT/CT imaging, and was correlated with adverse LV remodeling following MI. The application of target radiotracer imaging of regional MMP activation holds the potential to directly quantify the extent and localization of MMP activation in vivo, and relate these biological events to the post-MI remodeling process. This novel targeted MMP imaging approach may permit early risk stratification of patients post-MI. More importantly the proposed non-invasive imaging approach offers the opportunity to track novel therapeutic interventions directed at MMP inhibition and reduction of post-MI remodeling.

October 10, 2005

Dan Turnbull, PhD 
Associate Professor, Radiology & Pathology
Director, Mouse Imaging Facility
Skirball Inst of Biomolecular Imaging

Looking inside the mouse: In vivo micro-imaging with ultrasound and MRI 

Extensive genetic information and techniques available to manipulate the genome of the mouse have led to its widespread use in studies of development and to model many human diseases. In this rapid proliferation of methods to genetically alter mice, in vivo technologies to analyze structure and function in the mouse are required to understand the underlying developmental and disease processes which are dynamic and three-dimensional. We are developing ultrasound and magnetic resonance micro-imaging approaches to provide noninvasive, structural and functional information related to cardiovascular and neural development and disease in the mouse. This seminar will focus on the recent development and application of novel contrast agents for in vivo imaging in the mouse at multiple levels, from the organ to the cellular levels.

November 14, 2005

Shimon Weiss, PhD 
Professor, Department of Chemistry & Biochemistry and Physiology, UCLA

In-vitro and in-vivo single molecule molecular rulers 

Advances in single molecule studies of: (1) protein folding; (2)initiation of transcription by e-coli RNA polymerase; (3) targeting and detection of individual proteins in live cells using peptide-coated quantum dots; and (4) their utilization to the study of lipid rafts in membranes and (5) the possibilities for their use in molecular imaging will be reviewed.

December 12, 2005

Marc K. Jenkins, PhD 
Distinguished McKnight University Professor
Distinguished University Teaching Professor
Center for Immunology and Dept. of Microbiology
University of Minnesota Medical School

Visualizing the activation of T lymphocytes in the body during an immune response 

CD4+ T cells produce lymphokines when their antigen receptors bind to foreign peptides displayed on the surface of other cells. The lymphokines produced by CD4+ T cells regulate many aspects of the immune response including antibody production by B cells and microbe killing by phagocytes. The talk will focus on the development of systems in which the activation of CD4+ T cells of known peptide specificity can be monitored by flow cytometry, immunohistology, or confocal microscopy in lymphoid organs during an immune response. Animations will be included to make the complex cellular interactions involved in this process more understandable to a multidisciplinary audience. 

Sponsored by: Molecular Imaging Program at Stanford (MIPS);
Host: Director, Sanjiv Sam Gambhir, MD, PhD (sgambhir@stanford.edu)
Supported by: Philips Medical

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Molecular Imaging