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Clinical Research: NIH group using Intera 3.0T system in molecular imaging research studies

Best Practice
Li, King, M.D. National Institutes of Health USA
Pettigrew, Roderic, Ph.D., M.D. National Institutes of Health USA

NIH group using Intera 3.0T system in molecular imaging research studies

 

Historically, diagnostic imaging's role has been the visualization of disease, typically at a point at which symptoms of a suspected illness have triggered a visit to the physician. However, new research at the U.S. National Institutes of Health (NIH) joins a burgeoning effort worldwide to detect and study the molecular basis of disease - long before illness has the ability to cause symptoms. A cornerstone of this growing field of molecular medicine, molecular imaging, exploits specific molecules for image contrast, enabling invivo measurement and characterization of cellular and molecular level processes. NIH researchers King Li, M.D. and Roderic I. Pettigrew, Ph.D., M.D. are spearheading a multi-faceted molecular imaging research project that uses the center's Intera 3.0T system to explore atherosclerosis origins.

King Li, M.D. Roderic I. Pettigrew, Ph.D., M.D. NIH campus
King Li, M.D.
Roderic I. Pettigrew, Ph.D., M.D.
NIH campus

 

Numbering between 500,000 and a million different protein types, the human body is literally seething with proteins, the genetic expression of DNA. Responsible for cellular structure and function, these proteins are the focus of proteomics, the study of proteins' structure, roles and interactions. The aim of proteomics is to understand the relationships between genes, proteins, disease causes and effects of drugs. If intracellular processes cause the expression of a defective protein, disease may result. Molecular imaging is used to visualize the composition of such proteins, targeting the biochemical changes of diseases, which often take place long before the morphological expressions.

Major research effort to focus on molecular basis of atherosclerosis

Dr. Pettigrew's laboratory, housed in the National Health, Lung and Blood Institute (NHLBI), in collaboration with the NIH Clinical Center, is working toward a cooperative research and development agreement (CRADA) emphasizing molecular medicine strategies that focus on the visualization and treatment of atherosclerotic plaques through the development of 3.0T MRI methods, targeted contrast agents, targeted therapies and proteomic analysis.

 

"Specifically, we will continue to develop coronary artery imaging and vessel wall imaging and analysis methods at 3.0T, building on past work on 1.5T systems. The goal is to remove obstacles to realize the full potential of higher field MRI as applied to this problem," says Roderic I. Pettigrew, Ph.D., M.D., who also is the NIBIB director. "In particular, we will develop and evaluate intravascular devices and targeted contrast agents that will help visualize atherosclerotic plaques and molecular markers of vascular growth and disease. This should help realize molecular therapies, using these new contrast agents and imaging methods to evaluate specificity and effectiveness in targeted drug delivery. Another aim is to identify protein markers of disease and disease burden."

 

A key component of this work will be proteomic analysis of atherosclerotic disease, in which investigators will work to identify the protein constituents of, for example, an unstable plaque and then compare this finding with that of imaging studies. The goal is to determine the ability of these methods to detect the presence of current disease, predict future diseases and/or provide information of the effectiveness of a current treatment. Using proteomic profiles as surrogate markers of disease that might be employed for early detection and initiating pre-emptive treatment is particularly exciting, Dr. Pettigrew adds.

 

Researchers will progress concurrently on all aspects of this CRADA. Molecular analysis, targeting, development of targeted therapies and therapy monitoring via molecular imaging are all necessary to satisfy the requirements for the emerging paradigm of "personalized medicine," in which a patient's unique genetic profile informs treatment decisions.

 

"Personalized medicine requires the development of many diverse clinical tools, including risk algorithms, molecular therapeutics and surrogate biomarkers for monitoring treatment efficacy," says King Li, M.D., Chair, Imaging Sciences Program, and co-investigator with Dr. Pettigrew and 15 other scientists representing many different disciplines. "To succeed, we must simultaneously develop all the required links in the chain right from the start."

Investigating the genetic fingerprint of disease

The emergence of high throughput technology for proteomic analysis, the global study of large numbers of proteins contained in a cell or organism, will make personalized medicine infinitely more practical, Dr. Li says.

 

"The mass spectrometry that most companies use today for high throughput proteomic analysis is called surfaceenhanced laser desorption/ionization [SELDI] mass spectrometry, which can identify 50,000 proteins per test, instead of just one at a time," he notes. "Each of the 50,000 spectral peaks represents a signal from each of the different proteins. Once you identify a strong peak, you can then use high resolution mass spectrometry to determine exactly what the peptide is."

 

Dr. Li envisions a personalized medicine practice that encompasses all of the CRADA's goals. Each goal is in varying stages of reaching clinical practicality and, indeed, the proteomic aspects are being tested in animal models now. Explorations of targeted MR contrast agents had been done using human subjects for some time.

 



Presymptomatic disease detection and treatment  - a hypothetical case

 

In a hypothetical personalized medicine case, Dr. Li imagines an asymptomatic patient visiting a doctor because he is concerned about a family history of atherosclerosis. A tiny drop (i.e. 30 ┴l) of blood from a routine draw is subjected to proteomic analysis, which shows a combination of protein peaks indicating a high risk of dying from a heart attack in six months.The serum protein profile not only identifies the culprit as a plaque, but based on a unique protein signature, one that is in peril of rupturing soon. Subsequently, clinicians select an appropriate targeted MR contrast agent that speeds to receptor proteins on the unstable plaque, precisely pinpointing its location.

 

Physicians then discuss optimal treatment options. One alternative could be to attach drug molecules to the same carrier (e.g. liposomes, synthetic nanoparticles) on which the contrast agent and targeting agent (i.e. antibody or ligand) were attached. Similarly, doctors could attach biodegradable polymers to the carrier that can imitate the ability of white blood cells to target inflamed blood vessel walls. Either way, an MR-safe intravascular imaging and drug delivery device ensures the therapy payload is delivered on target.The result of the chosen therapy is the same: an imminent crisis averted by intercepting disease at an early stage.



MRI in molecular imaging

A variety of diagnostic imaging modalities can be used in molecular imaging, including PET, PET/CT, MRI and ultrasound. According to the research team, MRI offers exceptional spatial resolution and soft tissue visualization and has the potential to image proteins and other molecular markers at concentration levels as low as picomols (10^-12 mol).

 

In the case of atherosclerosis, 1.5T MRI is making significant inroads in the depiction of vessel wall disease - atherosclerotic plaques in carotids to larger size vessels in particular. "In this lab, we will be using the Intera 3.0T to continue these developments. We think the greater SNR of 3.0T will afford better spatial resolution for vessel wall and molecular imaging of the burden of disease," says Dr. Pettigrew."

 

Coronary artery imaging and vessel wall Imaging at 3.0T.

Courtesy M. Stuber, Johns Hopkins University and A. Gharib, NIH.

 

 

 

To enable detection of peptides and molecular markers that may exist at low concentrations, investigators will develop and evaluate targeted contrast agents to improve visualization of atherosclerotic plaques and other markers of vascular growth and disease, Dr. Li says. The strategy will employ the use of polymerized nanoparticles, upon which targeting agents, such as antibodies, ligands, contrast ions and therapeutic agents for imaging and therapy can be attached.

 

While MRI provides superb anatomical detail, it is relatively insensitive. "Since we can attach anywhere from 100,000 to one million contrast ions to each nanoparticle, the contrast amplification by the particle should be enough to enable in vivo MRI detection of endothelial receptors - protein markers of a vulnerable plaque, for example," he adds.

 

In MRI, contrast agents such as gadolinium can provide the imaging signal. The necessary specificity is accomplished by using the specific binding properties of antibodies or other proteins. The antibody against the adhesion receptor integrin av»3, for example, has been shown to have potential due to its upregulation in plaques. Another targeting mechanism with numerous potential applications is the use of contrast agents based on ultrasmall superparamagnetic iron oxide (USPIO) particles. These particles are swept from the bloodstream by macrophages.

 


Principle of molecular imaging and treatment. A delivery agent is loaded with a targeting system (orange diamonds) that will bind to specific receptors (blue "Y"s) on the site of interest. A diagnostic "signal giver" (red particles) enables identification of the bound site via imaging. A therapeutic agent (green blocks) may be added to treat disease locally.


 

 

MRI provides an excellent modality for monitoring treatment, as well, Dr. Li says. "If you give the patient an individualized treatment, tailor-made for the specific protein profile of his or her disease and targeted directly at protein receptors at the disease site, then when the MRI scan fails to light up the disease because the receptors have disappeared, there is no reason to continue with the treatment, because the treatment has either succeeded or the receptor expression is changing, implying the disease is entering a new stage," he says. "So the actual response of the disease via specific treatment can be monitored using MR and the right contrast agent."

Cornerstone in new paradigm of healthcare

The increasing insight into the molecular origins of disease will undoubtedly reshape healthcare. Molecular diagnostics and therapy are already reaching the clinic, and many therapies are now in phase III trials. Molecular imaging, admittedly, is new and gradually working its way into the clinical routine. While substantial research will be required before this goal is reached, molecular imaging will certainly be a cornerstone in this new paradigm of healthcare.


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