Activatable optical and magnetic resonance contrast agents have been devised to sense and visualize molecular activity in vivo. However, though highly sensitive, nuclear imaging has been limited considerably in sensing biological activities by the physical inability to switch radioactivity """"""""on"""""""" or """"""""off"""""""". To fill this gap, we hypothesize that Cerenkov luminescence imaging in conjunction with nanoparticles can be utilized to create activatable nanosensors based on radioactive decay. Blue Cerenkov light is generated by the passage of particulate radioactive emissions (such as positrons or electrons) through tissues. Cerenkov light allows for optical imaging of radiotracers with highly sensitive cameras. Based on the results of our previously demonstrated in vivo Cerenkov luminescence imaging from radiotracers, the overall objective of this application is to sense enzymatic activities associated with cancer in vivo using radiometals and modified nanoparticles In this new R01 application, cancer-related endoproteases modulate the physical interaction between different nanoparticles and a radiometals as Cerenkov emitters. Our hypothesis will be tested in three specific aims on the basis of strong preliminary data from our lab:
in Specific Aim (1), we will explore different design principles of the nanoparticles in evaluating the efect of diferent coatings and radiometals onto the Cerenkov emission;
in Specific Aim (2), we will sense the enzymatic activity of specific endoproteases (matrix metalloproteinase-2, cathepsin B and urokinase-type plasminogen activator) in vivo using Cerenkov imaging;
in Specific Aim (3), the objective is to implement a process to quantify the nanosensor's activation and thus the enzymatic activity. This is based on a combination of Cerenkov imaging with positron emission tomography (PET) imaging. PET imaging allows for an independent quantification of the nanosensors in the tumor (using the Specific Uptake Value (SUV)) irrespective of their current activation state. We propose an inherent method to correct for the tissue attenuation and to perform a relative quantification of the signal and thus enzymatic activity. We believe that the proposed research constitutes an innovative direction and a paradigm shift in molecular imaging as it allows for sensing of enzymatic activity with radiotracers with an optical read-out, combining the unique sensitivity of PET and optical imaging together. The contribution of the proposed research is significant as it expands the potential application for nuclear imaging. It provides an entire new path for radiotracers to detect relevant biological signals. These nanosensors could ultimately find their way into the clinical realm, for example in intraoperative imaging.

Public Health Relevance

In this research, we develop a new type of self-powered light emitting nanoparticle that is switched on only when specific biological events occur, such as when cells die or initiate replication. By using a sensitive camera system to detect the light, it s posible to monitor these events non-invasively in live animals and thereby gain new knowledge about both diseased and normal cell functions.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SBIB-X (03))
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Sastre, Antonio
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Sloan-Kettering Institute for Cancer Research
New York
United States
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Pratt, Edwin C; Shaffer, Travis M; Grimm, Jan (2016) Nanoparticles and radiotracers: advances toward radionanomedicine. Wiley Interdiscip Rev Nanomed Nanobiotechnol :
Büchel, Gabriel E; Carney, Brandon; Shaffer, Travis M et al. (2016) Near-Infrared Intraoperative Chemiluminescence Imaging. ChemMedChem 11:1978-82
Shaffer, Travis M; Drain, Charles Michael; Grimm, Jan (2016) Optical Imaging of Ionizing Radiation from Clinical Sources. J Nucl Med 57:1661-1666
Shaffer, Travis M; Harmsen, Stefan; Khwaja, Emaad et al. (2016) Stable Radiolabeling of Sulfur-Functionalized Silica Nanoparticles with Copper-64. Nano Lett 16:5601-4
Neuschmelting, Volker; Lockau, Hannah; Ntziachristos, Vasilis et al. (2016) Lymph Node Micrometastases and In-Transit Metastases from Melanoma: In Vivo Detection with Multispectral Optoacoustic Imaging in a Mouse Model. Radiology 280:137-50
Kaittanis, Charalambos; Shaffer, Travis M; Bolaender, Alexander et al. (2015) Multifunctional MRI/PET Nanobeacons Derived from the in Situ Self-Assembly of Translational Polymers and Clinical Cargo through Coalescent Intermolecular Forces. Nano Lett 15:8032-43
Lohrmann, Christian; Zhang, Hanwen; Thorek, Daniel L J et al. (2015) Cerenkov Luminescence Imaging for Radiation Dose Calculation of a ⁹⁰Y-Labeled Gastrin-Releasing Peptide Receptor Antagonist. J Nucl Med 56:805-11
Shaffer, Travis M; Wall, Matthew A; Harmsen, Stefan et al. (2015) Silica nanoparticles as substrates for chelator-free labeling of oxophilic radioisotopes. Nano Lett 15:864-8
Kiessling, Fabian; Mertens, Marianne E; Grimm, Jan et al. (2014) Nanoparticles for imaging: top or flop? Radiology 273:10-28
Penet, Marie-France; Krishnamachary, Balaji; Chen, Zhihang et al. (2014) Molecular imaging of the tumor microenvironment for precision medicine and theranostics. Adv Cancer Res 124:235-56

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