2006 MIPS/Philips Medical
Molecular Imaging Seminar Series
Seminar 5:00 - 5:45 pm
Discussion 5:45 - 6:00 pm
January 9, 2006
Collecting Molecular Probes for Biological Imaging
In vivo optical imaging of specific molecular targets, biological pathways and disease progress has recently been made possible through continued developments of novel molecular probes. To obtain information of specific targets, fluorescent probes need to be custom-designed to sense various structures and functions. Recently we have constructed several imaging probes with molecular switches which can only be turned on by the targeted enzymes leading to significant changes in fluorescence intensity. The potential clinical applications of these molecular probes have been demonstrated in various animal models and the obtained information has been applied to detection, diagnosis, and therapy evaluation.
January 26, 2006
High-resolution Biophotonic Imaging
We develop novel biophotonic tomography for early-cancer detection and functional imaging by physically combining non-ionizing electromagnetic and ultrasonic waves. Unlike ionizing x-ray radiation, non-ionizing electromagnetic waves, such as optical and radio waves, pose no health hazard and, at the same time, reveal new contrast mechanisms. For example, our spectroscopic oblique-incidence reflectometry can detect skin cancers accurately based on functional hemoglobin parameters and cell nuclear size. Unfortunately, electromagnetic waves in the non-ionizing spectral region do not penetrate biological tissue in straight paths as x-rays do. Consequently, high-resolution tomography based on non-ionizing electromagnetic waves alone, as demonstrated by confocal microscopy and two-photon microscopy as well as optical coherence tomography, is limited to superficial imaging within about one transport mean free path (~1 mm) into biological tissues. Ultrasonic imaging, on the contrary, furnishes good image resolution but has strong speckle artifacts as well as poor contrast in early-stage tumors. We have developed ultrasound-mediated imaging modalities by combining electromagnetic and ultrasonic waves synergistically to overcome the above problems. The hybrid modalities yield speckle-free images of high electromagnetic contrast at high ultrasonic resolution in relatively large volumes of biological tissues. The specific technologies to be reviewed in the talk are summarized below.
Mueller optical coherence tomography provides microscopic-scale depth-resolved tomographic images of the complete polarization properties in scattering biological tissues. Polarization properties are related to the orientation and density of fibril structures (such as collagen) in skin, retina, cartilage, muscle, and other anisotropic biological tissues. Potential applications include the imaging of burns, detection of glaucoma, study of osteoporosis, and detection of cancer.
In ultrasound-modulated optical tomography, a focused ultrasonic wave tags diffuse laser light in scattering biological tissue, which is analogous to the encoding concept in MRI. Because the tagged photons that carry the ultrasonic frequency originate from the localized ultrasonic wave, they can be extracted from the observed optical speckles to achieve high-resolution tomographic imaging.
In photo-acoustic tomography, an expanded pulsed laser beam diffuses into the biological tissue and generates a small but rapid temperature rise, which causes the emission of ultrasonic waves as a result of thermoelastic expansion. The short-wavelength ultrasonic waves are then detected to form high-resolution tomographic images.
Thermo-acoustic tomography is similar to photo-acoustic tomography except that low-energy radio-frequency pulses, instead of laser pulses, are used. Although the long-wavelength radio-frequency waves diffract rapidly in the tissue, the short-wavelength ultrasonic waves provide high spatial resolution.
February 13, 2006
Alice Ting, PhD
Assistant Professor, Chemistry
Small-molecule and Genetically-encoded Reporters of Protein Trafficking and Function in Living Cells
New reporters and methodologies for optical imaging of protein trafficking and function in living cells will be described. Topics include: site-specific protein labeling by biotin ligase; imaging of single AMPA receptor molecules using quantum dots; protein-protein interaction detection methodology using biotin ligase, and FRET reporters of enzyme activity.
Mar 13, 2006
Gregory Lanza, MD, PhD
Associate Professor, Medicine/Bioengineering
Division of Cardiology
Nanomedicine: New Diagnostic and Therapeutic Opportunities in Cardiovascular Disease
Despite myriad advances, cardiovascular related diseases continue to remain our greatest health problem. In more than half of patients with atherosclerotic disease, their first presentation to medical attention becomes their last. Patients often survive their first cardiac event through acute revascularization and placement of drug eluting stents (DES), but only select coronary lesions are amenable to DES placement, resulting in the use of bare metal or no stent, both of which lack the benefit of antirestenotic therapy. In other patients, transient ischemic attacks (TIAs) and stroke constitute the initial presentation of disease. In these patients, the diagnostic and therapeutic options are woefully inadequate. Nanomedicine offer options to each of these challenges.
Anti-angiogenic paramagnetic nanoparticles may be used to serially assess the severity of atherosclerotic disease in asymptomatic, high-risk patients by detecting the development of plaque neovasculature, which reflects the underlying lesion activity and vulnerability to rupture. Moreover, the nanoparticles can locally deliver anti-angiogenic therapy, which may acutely retard plaque progression, allowing aggressive statin therapy to become effective. Moreover, these agents may be useful as a quantitative marker to guide atherosclerotic management in an asymptomatic patient.
In those cases proceeding to the catheterization laboratory for revascularization, nanoparticles incorporating antirestenotic drugs can be delivered directly into the wall of lesions not amenable to DES placement. Targeted nanoparticles could help ensure that antirestenotic drugs are available for all lesions. Moreover, displacement of antiproliferative agents from the intimal surface into the vascular wall is likely to improve rehealing of the endothelium, improving post procedural management of these patients.
April 10, 2006
Kenneth A Krohn, PhD
Professor, Radiology & Rad Onc
Adjunct Professor Chemistry
University of Washington
Development and Validation of Hypoxia Imaging
The development of [18F]-fluoromisonidazole as an imaging agent for hypoxia required much more than developing a robust synthesis for a novel molecule and target. The story started by defining a biological problem and answering the question "If my radiopharmaceutical works as well as I think it might, how would it help my clinical colleagues deal with the individual cancer patient." This is an essential first step in radiopharmaceutical chemistry research. The intermediate steps are widely appreciated and start with development of an initial synthesis for preclinical testing to validate the mechanism for uptake and retention. Radiochemistry, cell biology and small animal studies proceed in parallel through the preclinical phase to work out biodistribution kinetics, metabolism, toxicology and radiation dosimetry as well as a robust automated radiosynthesis. At this time a data analysis strategy should be developed and tested. Molecular imaging is more than taking pictures; when we give a patient a dose of radiation, we accept an obligation to get the most possible information from that dose and this often requires a dynamic imaging protocol. Keeping in mind the purpose for which the radiopharmaceutical was developed, the chemist now faces a critical decision: on to patients or back to the lab. A clever scientist can always defend a plan to make a better molecule and it will probably get more NIH support. The more challenging research is to take the radiopharmaceutical to the clinic and develop evidence that imaging the target, hypoxia in this case, makes a difference. This seminar will discuss issues involved in testing how well the imaging procedure can select an appropriate cohort of patients for a specific treatment and/or follow response to that treatment. Sometimes this clinical trial is complicated when an experimental imaging test is coupled with an experimental therapy, a situation that we will face increasingly as we image molecular targets.
May 8, 2006
Katherine W. Ferrara, PhD
Professor & Chair
Biomedical Engineering, UCD
Can Ultrasound Drive Your Imaging Vehicle?
Ultrasound contrast agents are particles with a gas or liquid center on the order of 0.1 to 1 micron, typically enclosed by a lipid membrane. Peptide or antibody-based coatings can be incorporated on the surface, providing the opportunity for molecular imaging of vascular targets. Ultrasonic molecular imaging is unique in that the effective application of these agents depends not only on the surface chemistry, but also on the applied ultrasound field. An ultrasound .radiation. force can deflect these particles to the surface, increasing adhesion efficiency, and the agents can then be fragmented, effectively erasing the image and facilitating independent image acquisitions at later time periods.
Perhaps more intriguing, however, is the impact of ultrasound in multi-modality imaging and drug delivery. Through thermal and mechanical mechanisms, ultrasound can increase vascular permeability. Local fragmentation of vehicles can deposit imaging probes or drugs within a small region. Insonation of lipid-shelled nanoparticles after extravasation enhances the cellular internalization of such particles.
June 12, 2006
Amy Wagers, PhD
Assist Professor, Pathology
Harvard Medical School
Regulation and Function of Blood and Muscle Stem Cells
Stem cells are rare and unique precursor cells that in many adult tissues mediate both homeostatic and regenerative replacement of specific types of differentiated cells. Our work focuses particularly on understanding the mechanisms that regulate the function of blood-forming and muscle-forming stem cells. In the blood system, we are working to identify regulators of hematopoietic stem cell migration, self-renewal and differentiation, and to understand the mechanisms underlying apparent stem cell lineage plasticity. In the skeletal muscle, we are studying a novel population of myogenic stem cells to elucidate the signaling pathways that maintain and activate these cells during normal muscle turnover and in particular disease states.
July 10, 2006
Robert Balaban, PhD
Division of Intramural Research
National Heart, Lung, and Blood Institute
The domestication of the mitochondrion: tissue specific spatial and protein programming of function
The existence of the mitochondrion in eukaryotic cell is believed to be the result of an ancient symbiotic relationship. How the mitochondrion has been domesticated in different cells to perform specific tasks such as ATP production in most tissues, urea metabolism in the liver and GABA metabolism in the brain is relatively unknown and will be the topic of this discussion. In this presentation, I will address three basic problems in working out the details of the regulation of mitochondrial function utilizing several new technological and theoretical approaches. The first topic will involve the spatial distribution and in vivo function of mitochondria using a variety of imaging techniques. I will highlight a technical discussion of monitoring of mitochondrial function as well as other intracellular process using non-linear optical imaging techniques that provide spatial resolution on the order of microns, relatively deep inside tissues. This exciting approach permits the visualization of intracellular events, in vivo, bring together the fields of cell biology and physiology. The second approach will be the generation of a 'system' model of mitochondrial function based on a quantitative consensus view of mitochondrial function. This model has provided specific insights with regard to where gaps in knowledge and understanding exist even in this extensively studied organelle. Towards filling in these knowledge gaps, extensive cross tissue proteomic screens of mitochondrial proteins have been conducted to evaluate how the nuclear proteins are used to program mitochondria in different tissues to perform different tasks. This approach permits a unique view of metabolic control and regulation by examining naturally occurring modifications of a given organelles function. A basic conclusion of the quantitative modeling was that the mitochondrial metabolic control network is highly distributed. To begin to work out the control mechanisms within the mitochondria proteome, screening methods for dynamically following protein phosphorylation within the mitochondria proteome have been developed. These studies reveal that protein phosphorylation in the mitochondria is much more extensive and dynamic than previously believed with novel kinase-phosphatase systems. The role of these phosphorylations in the distributed control of mitochondrial function is currently being systematically evaluated. In summary, what will be presented in a systems approach to understanding the domestication of the mitochondria, from its spatial deposition in the cell, to its "programming" with nuclear proteins, to finally the post-translational modifications that direct metabolic flow through this remarkable organelle.
July 17, 2006
Treating Minimal Residual Disease After Cancer Therapy
Christopher Contag, PhD, Stanford University
July 24, 2006
Function Study of Hath6 in Escs Derived Endothelium
Xiaoyan Xie, MD, PhD, Wu Lab
Indirect Imaging of Caspase-3 Activation Using a Novel Multi-modality Caspase Sensor Vector by Reporter Gene Expression
Pritha Ray, PhD, Gambhir Lab
July 31, 2006
Emerging Trends in MR Based Molecular Imaging
Michael Moseley, PhD, Stanford University
August 7, 2006
Focused Ultrasound, Proteomics and Biomarkers
Samira Guccione, PhD, Stanford University
August 14, 2006
Michael Garwood, PhD
Associate Director, Center for Magnetic Resonance Research, Cancer Center
University of Minnesota Medical School
Magnetic resonance techniques and contrasts for molecular imaging
Contrast for tracking molecular probes with MRI derives from difference in nuclear spin relaxation. The most commonly exploited contrast mechanisms are based on longitudinal and transverse relaxation, as described by time constants T1 and T2*, respectively. A paramagnetic contrast agent that shortens T1 of water, such as the Gd-DTPA molecule commonly exploited in clinical MRI scanning, leads to a signal increase at sites where it accumulates when images are acquired using a T1-weighted pulse sequence. Several successful examples of Gd-labeled probes that enhance T1 relaxation at molecular targets have been demonstrated. However the majority of the probes developed for MR molecular imaging are T2*-based. Typically, T2* shortening is achieved by using highly paramagnetic molecules, such as iron-oxide labeled nanoparticles, which reduce image intensity in and around cells and tissues where the probe accumulates. Although iron-oxide molecules induce some T1 shortening, image contrast generally remains dominated by the stronger T2* effect, since gradient- and spin-echo sequences with a finite time interval (TE) between the excitation and detection periods are used. A significant disadvantage of T2*-based contrast is the lack of specificity in heterogeneous populations of cells and tissues where low intensity signals can naturally occur. Ideally, to attain optimal sensitivity and specificity in molecular imaging, selective signal enhancement is preferred over signal loss. In addition, due to the competing effects of longitudinal and transverse relaxation, some level of diminished contrast is unavoidable with conventional MRI pulse sequences. These issues have motivated our efforts to develop a new MRI method that performs image acquisition without an echo delay (i.e., TE=0). In this talk, the principles of this novel MRI technique called SWIFT will be described along with experimental results demonstrating the ability to image nuclear spins with extremely short T2*, such as those in cortical bone and teeth. This novel technique is expected to have tremendous advantages for molecular imaging with magnetic resonance approaches. This talk will also present an overview of MRI and spectroscopy, with specific examples of applications having relevance to molecular imaging.
August 21, 2006
From Mouse to Man: The Journey of a PET Tracer
Sanjiv Sam Gambhir, MD, PhD, Stanford University
August 28, 2006
Extensive Cell Fusion Limited to the Marrow Space in Stress Hematopoiesis
Qian Wang, PhD, Contag Lab
VEGFR Targeted Imaging and Therapy
Kai Chen, PhD, Chen Lab
September 11, 2006
Robert W. Hamm, PhD
Co-founder, CEO, President & Technical Leader, AccSys Technology, Inc.
The PULSAR Linac - Proven Technology for PET Radionuclide Production
As molecular imaging moves into more clinical applications using new radiolabeled compounds, there will be an increasing demand for hospital-based radionuclide production systems. The PULSAR isotope production system is a unique proton linac developed by AccSys Technology, Inc. for the cost-effective production of positron emitting radionuclides in such an environment. The combination of its 7 MeV proton energy, high beam current, high production yield targets and minimal shielding requirements make it a proven alternative to small cyclotrons for clinical applications. It has a much lighter weight, lower power consumption and smaller overall footprint, making it attractive for use in a hospital environment. Used in routine proton therapy for more than a decade, these compact linacs have been proven to be extremely robust, reliable and easy to operate and maintain. These features also make it possible to place a PULSAR PL-7 system in a trailer, making it the only PET radionuclide production system available as a mobile unit. This seminar will trace the development of the PULSAR linac technology as well as provide the details of its features and performance.
September 18, 2006
Molecular Imaging of Hypoxia
Edward (Ted) Graves, PhD, Stanford University
September 25, 2006
Role of HO-1 in Stem Cell Engraftment and Proliferation
Yuan Cao, MD, PhD, Contag Lab
Enhanced Drug Delivery Using Focused Ultrasound
Yi-Shan Yang, PhD, Guccione Lab
October 2, 2006
General Synthetic Strategies for Carbon-11 PET Tracers
Frederick Chin, PhD, Stanford University
October 9, 2006
Kit S. Lam, MD, PhD
Professor and Chief
Division of Hematology/Oncology
Department of Internal Medicine
From Combinatorial Chemistry to Cancer Targeting
Using the "one-bead one-compound" (OBOC) combinatorial library method to directly screen intact cancer cells and normal cells, we were able to discover ligands that bind specifically to the cancer cell surface. Highly focused OBOC combinatorial libraries were then used to further optimized these lead compounds into high-affinity and high-specificity cancer targeting agents. When conjugated to appropriate reporters, these ligands can be used as effective imaging and therapeutic agents for cancers. The cyclic peptide that targets alpha3 beta1 integrin of ovarian cancer was labeled with Cu-64 and the PET study showed that the peptide was able to localize a small tumor nodule in a nude mouse. The high-affinity peptidomimetic ligand that targets activated alpha4 beta1 of lymphoid malignancies, when conjugated to near infra-red dye or In-111 was able to detect lymphoma xenograft with high specificity. Work is currently undergoing in our laboratory to develop these ligands into effective therapeutic agents against cancers. These include the use of the high affinity ligands to deliver liposomal and nanoparticle drug to the cancer.
October 16, 2006
Integrin Targeted Cancer Imaging and Therapy
Xiaoyuan (Shawn) Chen, PhD, Stanford University
October 23, 2006
Molecular Imaging of Protein-Protein Interactions in Living Subjects for Drug Development
Carmel Chan, PhD, Gambhir Lab
Novel Peptides for Detecting Colon Cancer
Pei-Lin Hsiung, PhD, Contag Lab
October 30, 2006
Imaging Things Painful
Sandip Biswal, MD, Stanford University
November 6, 2006
Jianghong Rao, PhD, Stanford University
November 13, 2006
Brian Ross, PhD
Professo, Radiology & Biochemistry
University of Michigan
Optical and MR Molecular Imaging
Molecular diffusion of water molecules within a tissue can be quantified in terms of an apparent diffusion coefficient (ADC) using a technique known as diffusion MRI. This measurable value is strongly affected by molecular viscosity, membrane permeability between intra- and extra-cellular compartments, active transport/flow and directionality of a tissue/cellular structure that impedes water mobility. Water mobility is reduced in a restricted environment of cellular-dense tissue regions relative to cellular-sparse regions. If the cellular regions under investigation are neoplastic in origin, then a therapeutic intervention which results in a regional loss of cellular density within a tumor resulting in a net increase in the measured ADC value. The hypothesis is that the diffusion or Brownian motion of water molecules within a tumor can serve as a biomarker for cell density and, when a loss of cell membrane integrity occurs, alterations in this biomarker will be observable. This lecture will evaluate the concept that alterations in tumor cell density occur early in the treatment process thereby providing information related to future clinical outcome measures.
November 20, 2006
Leaving the Lights on: Luciferin Regenerating-Enzyme Expression in Mammalian Cells
Timothy Doyle, PhD, Stanford University
November 27, 2006
Fluorescent Imaging of Matrix Metalloproteinase Activity of Specific Bone Tissue
Tiffany Chung, PhD, Rao Lab
Fluorescence Signal Activation by Bioluminescent Light: A Strategy for Monitoring In Vivo Protein Functions
Abhijit De, PhD, Gambhir Lab
December 4, 2006
Jagat Narula, MD, PhD, FACC, FAHA, FRCP (Edin, Hon.)
Professor of Medicine
Chief, Division of Cardiology
Assoc Dean for Research
Imaging Unstable Coronary Lesions
Not the extent of luminal stenosis but the vessel wall lesional characteristics, determine prognostic outcomes in coronary disease. The atherosclerotic lesions that are sizably large to expansively remodel the vessel, carry large necrotic cores, and are covered by thin and inflammed fibrous caps are vulnerable to rupture. These lesions are profusely neovascularized and almost always demonstrate intraplaque hemorrhage. The morphological extent and characteristics are best defined noninvasively by multislice CT, lesional hemorrhage by MR imaging and the inflammation is best amenable to molecular imaging. Targeting of macrophages with FDG and annexin A5 has been demonstrated clinically. On the other hand, imaging for metalloproteinase production, and neovascularization have shown promising data in experimental studies.
January 3, 2006
Update on Stem Cell Imaging
Joseph Wu, MD, PhD, Stanford University