Targeted Molecular Imaging Agents – Lighting up Cancer Cells
The philosophy in the Schmitthenner lab is to apply fundamental aspects of chemistry and imaging science to practical applications in medical imaging and cancer research. Our research involvers a mix of peptide, dye and organometallic chemistry combined with fluorescence, photoacoustic, MRI and PET imaging.
Our goal is to transform screening and early diagnosis of cancer by creating novel imaging agents that specifically target cancer cells. Our strategy incorporates new synthetic methods which we developed at RIT for preparing single and multi-modal imaging agents. These agents are built on a modular peptide scaffold with features that facilitate their gentle conjugation to biomolecules that target cancer cells. This conjugation is performed in the last step which broadens the utility of imaging agents for a wide variety of cancers and other diseases by simply changing the targeting agent.
In collaboration with Dr. Irene Evans (SOLS) we were able to evaluate our TMIA’s by staining and imaging human lung cancer A549 cells and prostate cancer C4-2B cells by confocal fluorescence microscopy (CFM). Utilizing the near infrared (NIR) fluorescence we were able to selectively light up the cancer cells by the use of selective targeted imaging agents (TMIA’s) and show an important utility for the new CFM within the College of Science.
In collaboration with Dr. Joseph Hornak (CIS and SCMS) a method was also developed to measure of T1 relaxation times in NMR. This is a measure of the efficacy of gadolinium containing agents in magnetic resonance imaging. We have made dual modal agents containing a dye for CFM and gadolinium for MRI using our modular method.
We have further developed a practical method for transmetalation of imaging agents for PET imaging based on the exchange of a placeholder metal which serves as a protecting group during synthesis. This includes the preparation of targeted agent with targeting group and place-holder metal which may be exchanged in the clinic or facility that can exchange the placeholder for a radioactive metal for PET imaging. This is significant as it affords a rapid and safe method to prepare radioactive PET agents.
Two US patent application which includes students as inventors have been filed. The first is based on the truly modular approach which can be used to place multiple imaging agents of one type (single modal) or more than one type (dual or multi-modal) on a single template. The second is a method to synthesize radioactive PET agents from non-radioactive single or dual-modal imaging agents for PET-NIR or PET-MRI using the transmetalation method.
With a third collaborator, Dr. Navalgund Rao (Center for Imaging Science our group recently received an NIH R15 area grant that builds on these advances coupled with advances made in instrumentation for photoacoustic imaging (PAI) of prostate cancer (PrCa). A research collaboration was then forged between researchers at the Rochester Institute of Technology (RIT) and a team of cancer biologists and radiologists at Roswell Park Cancer Institute with the goal of developing a new screen for prostate cancer.
R15 grant activity: Transform screening and diagnosis for prostate cancer (PrCa) by using new methods for photoacoustic imaging (PAI) coupled with novel near infrared (NIR) imaging agents that specifically target PrCa tissue. The binding efficacy to PrCa cells will be evaluated by in-vitro confocal fluorescence microscopy (CFM) using TMIAs containing NIRF dyes. In-vitro evaluation of TMIAs in PAI will be performed at URMC. This collaboration highlights expertise in imaging agent synthesis and evaluation by CFM at RIT and expertise in cancer biology and PAI at URMC. These provide a vibrant learning environment in cancer imaging research for undergraduates with the achievable goal of transforming screening and diagnosis of PrCa, and directing biopsies by PAI.
Develop the methods we patented for agents for MRI and demonstrate the utility of targeted TMIA’s for MIR and NIR-MRI, and PET_MRI. The goal of this work is to publish at least two papers in the short term and utilize our patented work to develop a collaboration with medical imaging companies. We are in discussion with Bruker Biospin who awaits the development of each of these types of agents
Develop the methods we patented for agents for PET and demonstrate the utility of targeted TMIA’s for PET-NIR, and PET-MRI. Recently a graduate student completed the development of the preparation of PET agents. Our next goal is to publish that work in a paper and continue this work in the preparation of PET-NIR agents and PET-MRI agents. A second goal of this work is to develop a collaboration with medical imaging companies. We are in discussion with Bruker Biospin who awaits the development of each of these types of agents along with the above agents.
Develop method for the conjugation of targeting agents for other cancers to our imaging peptides in aim 1 above containing dyes for photoacoustic imaging (PAI). One of our top priorities is to create imaging agents for the early diagnostic imaging of breast cancer by PAI. This would be the first.
The potential value of targeted molecular imaging is very large. Scientific papers in this field are growing in number at an exponential rate. A large international organization called the World Molecular Imaging Society (WMIS) has formed and now meets each year for a large conference in this rapidly growing field.
Developing collaboration with researchers at the URMC as well as researchers at RIT who complement the chemistry effort is important to the success of this research. Collaborations are vital to success in NIH funding and funding from other agencies. Researchers at URMC are applying for large grants in which we will also participate.
This research is increasing research activity within the SCMS, SOLS and CIS in health related research. This new area provides RIT students in all three areas with impactful, meaningful research specifically to areas of biomedicine and cancer research.
The possibility of obtaining sponsored research is within grasp. Dual modal agents are rapidly becoming valued for the definitive diagnoses of cancer but there are precious few methods to prepare these. Imaging agent companies such as Bruker have manufactured instruments for the pre-clinical imaging for NIR-PET and for PET-MRI and MRI-PET. These technique are all in need of TMIA’s.
The impact on human health will be large. Our initial focus is:
Prostate cancer: The advice of urologists and other medical specialists have been solicited. A urologist told me last week “There is no other way to diagnose prostate cancer apart from painful and unreliable biopsies….so get going!”
Breast cancer: A group at the University of Twente in the Netherlands has a prototype of a PAI imaging system to diagnose breast cancer in humans. The imaging is by a robotic arm which digitally scans the breast without contact. Photoacoustic involves a pulsed laser beam that excites the cells which produce sound, and detection is by ultra-sound. The advantages are no ionization radiation, no discomfort during the screening, and more accurate imaging.
Schmitthenner, H., Chinni, B, Singh, S, Heese, L, Akporji, N, Le Tourneau, R, Embong, A K, Evans, I, Nastiuk, K., Krolewski, J, Rao, N, Dogra, V, PSMA-Targeted Near Infrared Dye Imaging Agents for Photoacoustic Imaging of Prostate Cancer, World Molecular Imaging Conference, abs.131, 2016, New York, NY.
Schmitthenner, H, Sweeney, AM, Williams, S. Transmetalation Methods for the Synthesis of PET and SPECT Imaging Agents, (US Appl. 15/055,203 A1), (Rochester Institute of Technology 2016)
Schmitthenner, H., Beach, Stephanie., Weidman, Chelsea, Barrett Taylor M, Modular Imaging Agents Containing Amino Acids and Peptides, (US Appl. 2015/0038672 A1), (Rochester Institute of Technology 2015)
Schmitthenner, H., Barrett, T., Beach, S., Heese. L., Weidman, C., Sweeny-Jones, A.M, Becker, A, Hornak, J., Ophardt, H., Evans, I., Modular Synthesis of Peptide-based Single and Multimodal targeted Molecular Imaging Agents, World Molecular Imaging Conference, 537, Honolulu, HI 2015
Tao Ji, Schmitthenner, Hans F, Yonghong Yang, Harder John W, Leon Jeffrey W, Harrison William J, Kelley Brian J, Bennett James R, Stegman David A, Ruizheng Wang, "Loaded latex optical molecular imaging probes containing lipophilic large stokes shift dyes", U.S. Patent 8,905, 354 B2, Bruker Biospin Corp. December, 2014.
Schmitthenner, Hans F. (PI), Evans, Irene, Rao, Navalgund, Targeted Molecular agents for the Photoacoustic Imaging of Prostate Cancer”, NIH grant 1R15CA192148-01, Sept. 2014
Orton, Sean P.; Van Praagh, Andrew D.G.; Potenza, Joan C.; Schmitthenner, Hans F.; Mclaughlin, William E.; Leevy, W. Matthew Broad Based Tissue Uptake of Polycationic Near-Infrared Polymeric Nanoparticles in Living Mice, Journal of Biomedical Nanotechnology, Volume 9, Number 1, January 2013 , pp. 77-85
Loaded Latex Optical Molecular Imaging Probes Containing Lipophilic Large Stokes Shift Dyes (US Appl 2012/0058050 A1,) , Toa Ji, Schmitthenner, Hans F., Yang Yonghong, Harder, John W., (Carestream Health, Bruker Biospin 2013)
Wang, Ruizheng; Harder, John W., Stegman, D.A., Harrison, Wm. J, Schmitthenner, Hans F, Large Stokes Shift Dyes used for Optical Imaging, U.S. Patent 8,017,104, Carestream Health, September 2011.
Evans, I.M., Aronow, S.D., Wang, S.M., Lee, Y.P, Schmitthenner, H., F. Targeted Molecular Imaging Agents for Imaging of Cancer Cells. Mol. Biol. Cell 24 (Suppl.), Abstract No. 2453 (2013).