ECSE-4963 Introduction to Subsurface Sensing and Imaging Systems Lecture 23:  Molecular Imaging Kai Thomenius 1  & Badri R...
Recap <ul><li>Last time we discussed: </li></ul><ul><ul><li>Broad characteristics of molecular imaging. </li></ul></ul><ul...
Cost of Cancer <ul><li>Only late symptoms of cancer are diagnosed and treated. </li></ul><ul><li>Annual expenditures on ca...
What is Molecular Imaging? <ul><li>Molecular imaging (MI) is: </li></ul><ul><ul><li>the remote sensing of  cellular proces...
Vision for Molecular Imaging If successful, the following will be true: <ul><li>a life-threatening disease is detected bef...
Molecular Imaging <ul><li>Rationale: </li></ul><ul><ul><li>Changes at cellular level occur well before anatomic changes </...
Molecular Imaging <ul><li>Practical Goals: </li></ul><ul><ul><li>To image gene delivery & expression </li></ul></ul><ul><u...
 
Two More Terms <ul><li>Angiogenesis :  </li></ul><ul><ul><li>growth of new blood vessels on demand, e.g. to sustain or est...
3D Imaging of Tumor Microvasculature Injected contrast agent Multi-photon Microscope Normal Abnormal
Anti-angiogenesis <ul><li>New anti-angiogenesis drugs are being developed. </li></ul><ul><li>The images below show ultraso...
Two More Terms <ul><li>Apoptosis :  </li></ul><ul><ul><li>Programmed cell death </li></ul></ul><ul><ul><li>Destruction cel...
Nuclear Medicine-based MI Example <ul><li>Apomate is a kit (Tc-99m) based probe specific for apoptosis. </li></ul><ul><ul>...
Molecular Imaging of Apoptosis <ul><li>The left hand image shows a typical nuclear study </li></ul><ul><ul><li>The appeara...
Molecular Imaging <ul><li>Key enablers: </li></ul><ul><ul><li>Highly specific imaging probes (i.e. MI agents injected into...
Gene Expression:  DNA to mRNA to Protein
Design for a MRI Probe <ul><li>Yet some more new terminology: </li></ul><ul><ul><li>Ligand :  Part of the MI probe that is...
Optical Imaging & MI <ul><li>Optical Imaging is gaining popularity rapidly in MI. </li></ul><ul><li>Various imaging method...
Fluorescence in-situ Hybridization (FISH)
<ul><li>FISH Imaging of Immediate Early Gene “Arc”  </li></ul><ul><li>(Quick Acting) </li></ul><ul><li>Nuclear FISH Signal...
Imaging Targets for MI Genetic Imaging Genetic Defects Molecular Biology Molecular Imaging Modified gene expression, angio...
MI & Cardiovascular Disease Diagnosis & Staging Screening Treatment & Monitoring Follow-up <ul><li>Ultrasound </li></ul><u...
Targeted Agent for Ultrasound <ul><li>Work by Wickline & Lanza at Wash. U. </li></ul><ul><li>Nanoparticle agent </li></ul>...
Intravascular study w. u/s agent <ul><li>Pig carotid arteries were overstretched w. balloon catheters. </li></ul><ul><ul><...
Therapy Agents <ul><li>Thrombus-targeted agent, MRX-408  </li></ul><ul><ul><li>Agent:  small white bubbles, IV injection <...
Summary <ul><li>Molecular Imaging has tremendous potential. </li></ul><ul><ul><li>MI is the result from a tight coupling o...
Homework:  Lecture 20 <ul><li>All the examples of molecular imaging dealt with medical applications. </li></ul><ul><li>Pro...
Instructor Contact Information <ul><li>Badri Roysam </li></ul><ul><li>Professor of Electrical, Computer, & Systems Enginee...
Instructor Contact Information <ul><li>Kai E Thomenius </li></ul><ul><li>Chief Technologist, Ultrasound & Biomedical </li>...
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  1. 1. ECSE-4963 Introduction to Subsurface Sensing and Imaging Systems Lecture 23: Molecular Imaging Kai Thomenius 1 & Badri Roysam 2 1 Chief Technologist, Imaging Technologies, General Electric Global Research Center 2 Professor, Rensselaer Polytechnic Institute Center for Sub-Surface Imaging & Sensing
  2. 2. Recap <ul><li>Last time we discussed: </li></ul><ul><ul><li>Broad characteristics of molecular imaging. </li></ul></ul><ul><ul><li>Review of cellular biology </li></ul></ul><ul><ul><ul><li>Components of a cell </li></ul></ul></ul><ul><ul><ul><li>DNA </li></ul></ul></ul><ul><ul><ul><li>RNA </li></ul></ul></ul><ul><ul><ul><li>Transcription </li></ul></ul></ul><ul><li>Today </li></ul><ul><ul><li>Future of Molecular Imaging </li></ul></ul>
  3. 3. Cost of Cancer <ul><li>Only late symptoms of cancer are diagnosed and treated. </li></ul><ul><li>Annual expenditures on cancer treatment in the US exceeded $156B in 2001 </li></ul><ul><li>Similar numbers hold true for cardiovascular disease. </li></ul><ul><li>Hence, a major shift in health care is needed to realize prevention and cure </li></ul><ul><li>This is where molecular imaging comes in. </li></ul>
  4. 4. What is Molecular Imaging? <ul><li>Molecular imaging (MI) is: </li></ul><ul><ul><li>the remote sensing of cellular processes at the molecular level in vivo . </li></ul></ul><ul><ul><ul><li>So far, this has involved animals, typically mice, but humans are the longer term target. </li></ul></ul></ul><ul><ul><li>This remote sensing is being done with: </li></ul></ul><ul><ul><ul><li>Conventional or modified imaging methods (e.g. MRI, PET scanners, optical methods) </li></ul></ul></ul><ul><ul><ul><li>Exogenous agents (called probes) which interact with the cellular processes, often involve protein creation </li></ul></ul></ul><ul><ul><li>Except for nuclear medicine and PET, the focus today is on technique development on experimental animals </li></ul></ul>
  5. 5. Vision for Molecular Imaging If successful, the following will be true: <ul><li>a life-threatening disease is detected before symptoms appear </li></ul><ul><li>therapeutic drugs are seen hitting their target, instantaneously </li></ul><ul><li>therapeutic efficacy is measured in hours instead of months </li></ul><ul><li>life saving drugs tailored to your genetic make-up and disease variant get to market years faster than possible today. </li></ul>
  6. 6. Molecular Imaging <ul><li>Rationale: </li></ul><ul><ul><li>Changes at cellular level occur well before anatomic changes </li></ul></ul><ul><ul><ul><li>Hence promise of earlier diagnosis. </li></ul></ul></ul><ul><ul><ul><li>Functional changes may occur as much as a decade before anatomical changes. </li></ul></ul></ul><ul><ul><li>Redefinition of diseases such as cancer </li></ul></ul><ul><ul><ul><li>from </li></ul></ul></ul><ul><ul><ul><ul><li>organ system-based diseases </li></ul></ul></ul></ul><ul><ul><ul><li>to </li></ul></ul></ul><ul><ul><ul><ul><li>aberrations in molecular structure & function traceable to the genetic (DNA) level. </li></ul></ul></ul></ul>Breast Carcinoma We may be able to identify genetic pre-disposition to a disease.
  7. 7. Molecular Imaging <ul><li>Practical Goals: </li></ul><ul><ul><li>To image gene delivery & expression </li></ul></ul><ul><ul><ul><li>MI identifies specific gene products & intracellular processes </li></ul></ul></ul><ul><ul><li>To understand cellular processes in their intact microenvironments </li></ul></ul><ul><ul><li>To develop new imaging technologies to realize such goals </li></ul></ul><ul><ul><li>To facilitate new drug development and methods for therapeutic monitoring, and </li></ul></ul><ul><ul><li>To promote an interdisciplinary approach to biomedical imaging issues. </li></ul></ul>Most of these goals involve action at the cellular level.
  8. 9. Two More Terms <ul><li>Angiogenesis : </li></ul><ul><ul><li>growth of new blood vessels on demand, e.g. to sustain or establish tumor growth. </li></ul></ul><ul><ul><li>Occurs both in health and in disease. </li></ul></ul>http://www.angio.org/understanding/understanding.html <ul><li>Desirable angiogenesis </li></ul><ul><ul><li>Restores blood flow after injuries </li></ul></ul><ul><ul><li>Placenta growth </li></ul></ul><ul><li>Undesirable angiogenesis </li></ul><ul><ul><li>Tumor growth </li></ul></ul><ul><ul><li>Macular degeneration </li></ul></ul><ul><li>Angiogenesis & MI </li></ul><ul><ul><li>Can we image formation of new blood vessels? </li></ul></ul><ul><ul><li>Can we image reduction in angiogenesis? </li></ul></ul>
  9. 10. 3D Imaging of Tumor Microvasculature Injected contrast agent Multi-photon Microscope Normal Abnormal
  10. 11. Anti-angiogenesis <ul><li>New anti-angiogenesis drugs are being developed. </li></ul><ul><li>The images below show ultrasound Doppler results demonstrating the impact of such drugs. </li></ul><ul><li>Unfortunately, this doesn’t mean the problem has been solved. </li></ul>
  11. 12. Two More Terms <ul><li>Apoptosis : </li></ul><ul><ul><li>Programmed cell death </li></ul></ul><ul><ul><li>Destruction cells by an organized plan </li></ul></ul><ul><li>Why should cells commit suicide? </li></ul><ul><ul><li>Resorption of the tadpole tail at the time of its metamorphosis into a frog </li></ul></ul><ul><ul><li>Formation of the fingers and toes of the fetus requires the removal, by apoptosis, of the tissue between them. </li></ul></ul><ul><ul><li>Sloughing off of the inner lining of the uterus (the endometrium) at the start of menstruation. </li></ul></ul><ul><li>Apoptosis & MI </li></ul><ul><ul><li>Apoptosis occurs in response to certain drugs, e.g. chemotherapy agents. </li></ul></ul><ul><ul><li>Can we image the onset of this process and thereby determine the utility of the therapy? </li></ul></ul>http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/Apoptosis.html
  12. 13. Nuclear Medicine-based MI Example <ul><li>Apomate is a kit (Tc-99m) based probe specific for apoptosis. </li></ul><ul><ul><li>In apoptosis, an intracellular chemical, PS, can be translocated to the extracellular membrane </li></ul></ul><ul><ul><li>Apomate has strong affinity to PS & will attach to it. </li></ul></ul><ul><ul><li>Nuclear medicine imagers are great at Tc-99m imaging </li></ul></ul><ul><li>Proposed Uses: </li></ul><ul><ul><li>Apoptosis occurs in response to radio- or chemotherapy agents. </li></ul></ul><ul><ul><ul><li>Taxol effect. </li></ul></ul></ul><ul><ul><li>Apoptosis occurs in infarcted tissues. </li></ul></ul><ul><li>First clinical trials to assess utility of chemotherapy. </li></ul><ul><ul><li>Currently in Phase II clinical trials. </li></ul></ul>Apomate, product of North American Scientific, Inc.
  13. 14. Molecular Imaging of Apoptosis <ul><li>The left hand image shows a typical nuclear study </li></ul><ul><ul><li>The appearance is nearly normal </li></ul></ul><ul><li>The right hand image show the same heart after an Apomate injection </li></ul><ul><ul><li>Clearly the apex of the heart is severely ischemic with cell death occurring. </li></ul></ul>
  14. 15. Molecular Imaging <ul><li>Key enablers: </li></ul><ul><ul><li>Highly specific imaging probes (i.e. MI agents injected into a lab animal to study cellular processes). </li></ul></ul><ul><ul><li>Suitable amplification strategies for signal starved modalities such as MR </li></ul></ul><ul><ul><li>More sensitive imaging methods </li></ul></ul><ul><li>Imaging Probes: </li></ul><ul><ul><li>probes can be single-stranded DNA or RNA molecules of specific base sequence. </li></ul></ul><ul><ul><li>Must clear from all irrelevant sites within the time frame of an imaging study. </li></ul></ul><ul><ul><li>Must traverse physiologic barriers to get to their target sites of action. </li></ul></ul>
  15. 16. Gene Expression: DNA to mRNA to Protein
  16. 17. Design for a MRI Probe <ul><li>Yet some more new terminology: </li></ul><ul><ul><li>Ligand : Part of the MI probe that is target specific, i.e. has special affinity to a site on a cell. </li></ul></ul><ul><ul><li>Moiety : specific chemical component of a probe </li></ul></ul><ul><li>Key components of probe: </li></ul><ul><ul><li>Targeting ligand </li></ul></ul><ul><ul><ul><li>Attachment of the ligand to the receptor site releases enzymes </li></ul></ul></ul><ul><ul><ul><li>These enzymes activate contrast agent </li></ul></ul></ul><ul><ul><li>Polymer based backbone for signal amplification </li></ul></ul><ul><ul><li>Enzyme (or pH) activatable contrast capability </li></ul></ul>(Patents Pending) http://www.science.uwaterloo.ca/course_notes/biology/biol473/lecture7.pdf
  17. 18. Optical Imaging & MI <ul><li>Optical Imaging is gaining popularity rapidly in MI. </li></ul><ul><li>Various imaging methods: </li></ul><ul><ul><li>Fluorescence </li></ul></ul><ul><ul><li>Bioluminescence </li></ul></ul><ul><ul><li>Absorption </li></ul></ul><ul><ul><li>Diffuse optical tomography </li></ul></ul><ul><ul><li>Confocal imaging </li></ul></ul><ul><ul><li>Multi-photon imaging </li></ul></ul><ul><li>Almost all of these are limited to small animals. </li></ul><ul><li>Translation to imaging of humans will be a challenge. </li></ul>
  18. 19. Fluorescence in-situ Hybridization (FISH)
  19. 20. <ul><li>FISH Imaging of Immediate Early Gene “Arc” </li></ul><ul><li>(Quick Acting) </li></ul><ul><li>Nuclear FISH Signal 2 – 15 min </li></ul><ul><li>Cytoplasmic FISH Signal 20 – 60 min </li></ul>Double labeling showing Arc (green) & zif268 (red) foci
  20. 21. Imaging Targets for MI Genetic Imaging Genetic Defects Molecular Biology Molecular Imaging Modified gene expression, angiogenesis, receptors Molecular Biochemistry Dynamic Imaging Hypoxia, angiogenesis Physiology Imaging Abnormal mass Anatomy
  21. 22. MI & Cardiovascular Disease Diagnosis & Staging Screening Treatment & Monitoring Follow-up <ul><li>Ultrasound </li></ul><ul><li>Cardiac Cath </li></ul><ul><li>Nuclear Cardiology </li></ul><ul><li>ECG </li></ul><ul><li>Ultrasound </li></ul><ul><li>Nonspecific markers </li></ul><ul><li>Surgery </li></ul><ul><li>PTCA/Stent </li></ul><ul><li>Nuclear Cardiology </li></ul><ul><li>Nuclear Card </li></ul><ul><li>Cardiac Cath </li></ul><ul><li>Nonspecific Markers </li></ul>The Future w. Molecular Imaging: <ul><li>Molecular Imaging </li></ul><ul><ul><li>AMI </li></ul></ul><ul><ul><li>Ischemia </li></ul></ul><ul><li>CT or MRI </li></ul><ul><li>Genetic Predisposition </li></ul><ul><li>Specific Markers </li></ul><ul><li>Minimally invasive surgery </li></ul><ul><li>Local drug delivery </li></ul><ul><li>Tissue Analysis </li></ul><ul><li>Molecular Imaging </li></ul><ul><li>Molecular Dx </li></ul>
  22. 23. Targeted Agent for Ultrasound <ul><li>Work by Wickline & Lanza at Wash. U. </li></ul><ul><li>Nanoparticle agent </li></ul><ul><ul><li>About 250 nm in diameter. </li></ul></ul><ul><li>Targeting a three-step process: </li></ul><ul><ul><li>Antibody attached to clot </li></ul></ul><ul><ul><li>Avidin attaches to the antibody </li></ul></ul><ul><ul><li>Contrast agent attaches to avidin. </li></ul></ul><ul><li>Successful ultrasound images of fibrin have been made </li></ul>
  23. 24. Intravascular study w. u/s agent <ul><li>Pig carotid arteries were overstretched w. balloon catheters. </li></ul><ul><ul><li>Damage introduced to observe healing process. </li></ul></ul><ul><li>Tissue factor is a glycoprotein that initiates healing process. </li></ul><ul><li>Arteries were imaged w. tissue factor targeted agent and control agent. </li></ul><ul><li>Enhancement due to targeted agent is obvious. </li></ul>
  24. 25. Therapy Agents <ul><li>Thrombus-targeted agent, MRX-408 </li></ul><ul><ul><li>Agent: small white bubbles, IV injection </li></ul></ul><ul><ul><li>Contains ligands which bind to platelets in clot. </li></ul></ul><ul><ul><li>Agents make clots more visible </li></ul></ul><ul><ul><li>Ultrasound can be used to destroy agent via cavitation </li></ul></ul><ul><ul><li>Helps in dissolving clot </li></ul></ul><ul><li>Drug delivery </li></ul><ul><ul><li>Therapeutic microbubbles circulate </li></ul></ul><ul><ul><li>They are selectively destroyed by ultrasound when passing through pathology. </li></ul></ul>
  25. 26. Summary <ul><li>Molecular Imaging has tremendous potential. </li></ul><ul><ul><li>MI is the result from a tight coupling of biology & subsurface imaging technologies. </li></ul></ul><ul><ul><ul><li>Pursuit of activities in this area will require a good grounding in cell biology, biochemistry. </li></ul></ul></ul><ul><ul><li>PET, nuclear will be most likely the first modalities esp. in human imaging. </li></ul></ul><ul><ul><li>Optical imaging, MRI are receiving much attention in animal studies. </li></ul></ul><ul><ul><li>There is a very exciting potential for a fundamental change in diagnostic & therapeutic medicine. </li></ul></ul>
  26. 27. Homework: Lecture 20 <ul><li>All the examples of molecular imaging dealt with medical applications. </li></ul><ul><li>Propose a non-medical application of “molecular imaging”, i.e. an imaging situation where: </li></ul><ul><ul><li>an external agent is introduced </li></ul></ul><ul><ul><li>that agent alters the imaged site </li></ul></ul><ul><ul><li>that alteration is imaged by an SSI probe. </li></ul></ul>
  27. 28. Instructor Contact Information <ul><li>Badri Roysam </li></ul><ul><li>Professor of Electrical, Computer, & Systems Engineering </li></ul><ul><li>Office: JEC 7010 </li></ul><ul><li>Rensselaer Polytechnic Institute </li></ul><ul><li>110, 8 th Street, Troy, New York 12180 </li></ul><ul><li>Phone : (518) 276-8067 </li></ul><ul><li>Fax : (518) 276-6261/2433 </li></ul><ul><li>Email : [email_address] </li></ul><ul><li>Website : http://www.rpi.edu/~roysab </li></ul><ul><li>NetMeeting ID (for off-campus students) : 128.113.61.80 </li></ul><ul><li>Secretary : Laraine Michaelides ( [email_address] ), 518-276-8525 </li></ul>
  28. 29. Instructor Contact Information <ul><li>Kai E Thomenius </li></ul><ul><li>Chief Technologist, Ultrasound & Biomedical </li></ul><ul><li>Office: KW-C300A </li></ul><ul><li>GE Global Research </li></ul><ul><li>Imaging Technologies </li></ul><ul><li>Niskayuna, New York 12309 </li></ul><ul><li>Phone : (518) 387-7233 </li></ul><ul><li>Fax : (518) 387-6170 </li></ul><ul><li>Email : [email_address] , [email_address] </li></ul><ul><li>Secretary : Laraine Michaelides ( michal @ rpi . edu ), 518-276-8525 </li></ul>

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