MedicalResearch.com Interview with:
Greg Thurber, PhD
Department of Chemical Engineering
Department of Biomedical Engineering
University of Michigan
MedicalResearch.com: What is the background for this study?
Response: Most current disease screening strategies rely on either blood tests, where the physician can obtain information on specific disease molecules but has no idea where they originated in the body, or anatomical imaging, where the physician can see changes in the structure of tissues but doesn’t have any molecular information. We wanted to develop a method that could provide both molecular information and an image of where these molecules were located. We know from decades of research in cancer that this is a molecular disease, so providing molecular information to the physician will help improve detection and diagnosis. Breast cancer screening provides an excellent opportunity to apply this approach to improve detection. Currently, estimates indicate that we are overspending $4 billion per year on the overdiagnosis and overtreatment of breast cancer because we cannot accurately determine which patients need treatment and which can be safely monitored with no intervention. Despite this problem with overdiagnosis, however, screening saves lives…we simply need a better way.
Molecular imaging has the capability of providing both molecular information and the location within the body. However, most of these techniques are expensive and use ionizing radiation, meaning there is a small risk of actually causing cancer. This is not acceptable for screening large numbers of otherwise healthy patients. To avoid this risk and provide a safe, inexpensive, and relatively easy method for patients to undergo screening, we decided to develop near-infrared fluorescent imaging agents that can be taken as a pill. The goal is for the patient to simply take a pill a day or two before their visit, and then the physician shines near-infrared light on the breast tissue to detect tumors where they ‘light up’ by giving off a different color of light.
MedicalResearch.com: What are the main findings? What should readers take away from your report?
Response: The most important result from this report is that this technique is possible. Prior to this study, no one had ever reported this type of approach. In fact, there are many reasons it could have failed, and based on the current scientific literature, one could argue that it should not have worked. The types of molecules that can be absorbed when taken orally have very different properties than molecules that are being developed as imaging agents. Our lab specializes in using computer simulations to predict how the molecular properties of molecules impact their distribution in the body, so we decided to take this as a challenge to develop an agent that could be used for this type of screening.
Our main finding surprised us. Molecules that are orally absorbed are typically small and lipophilic (greasy) while imaging agents are larger and hydrophilic (they like water). We initially thought that the best agents would have a balance of these properties – they would be halfway in between these two extremes. However, our results showed us that the best agents were actually at the far end of the spectrum – the hydrophilic molecules performed the best. The amount absorbed is not extremely high (better than some current drugs, but lower than average). However, while this can be problematic for drugs, it actually isn’t an issue with imaging. The near-infrared light is so sensitive, that very little imaging agent is needed, and the agents are very safe, so even if a patient absorbed a large amount, it wouldn’t be a problem. This provides a very large ‘window’ to dose patients.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Now that we know this approach can work, we are developing other imaging agents to go after additional targets in cancer. Every patient’s tumor is different, so we’d like to add a second imaging agent to the pill so the physician has even more information to make an informed decision. This second agent would use a different ‘color’ of near-infrared light to help differentiate different types of tumors. Once the necessary agents are developed, then these need to be tested for safety before starting a clinical trial. We’ve chosen molecules that have a good track record for safety (similar agents have gone into humans at high doses with no problems), but the FDA requires testing of every new agent (even if it is a combination of two previous agents) to make sure it is safe for use in humans. Once this has been demonstrated, it would be ready for clinical trials.
MedicalResearch.com: Is there anything else you would like to add?
Response: An exciting part of this research has been to go after other diseases, now that we know it works. This approach cannot be used for all diseases, since near-infrared light can only penetrate a few centimeters of tissue. This means that the imaging agent has to be accessible from the body surface. It works for breast cancer since imaging instruments can scan from multiple angles around the breast tissue to detect tumors (known as tomography). Another method we are developing would aid in the early diagnosis and treatment of rheumatoid arthritis.
Rheumatoid arthritis (RA) is an autoimmune disease, meaning the body’s immune system starts attacking the joints. The damage is largely irreversible, but there are effective treatments available. Therefore, there is lots of interest in early diagnosis. The use of a disease-screening pill for RA would allow patients who are at high-risk of developing the disease (or those that have some early symptoms but it’s too early to tell if it is RA) to take the pill and have their hands scanned for inflammatory markers of the disease. The goal is to allow physicians to more accurately diagnose and treat these patients at an early stage to improve their outcomes. There’s even early evidence that some patients may be cured if the disease is caught early enough. We think this is another exciting application for this approach.
Sumit Bhatnagar, Kirti Dhingra Verma, Yongjun Hu, Eshita Khera, Aaron Priluck, David E. Smith, Greg M. Thurber. Oral Administration and Detection of a Near-Infrared Molecular Imaging Agent in an Orthotopic Mouse Model for Breast Cancer Screening. Molecular Pharmaceutics, 2018; 15 (5): 1746 DOI: 10.1021/acs.molpharmaceut.7b00994
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