The general goal of this research is to develop positron emission tomography (PET) and magnetic resonance imaging (MRI) based molecular imaging systems to image cancer-specific enzymatic acfivity of proteases in vivo. To date the imaging of protease activity has primarily involved the development of fluorescent probes which exploit quenching and acfivation mechanisms offered by fiuorescence resonance energy transfer (FRET). Opfical imaging unfortunately has a serious limitafion, especially for clinical translation, which is the limited tissue penetrafion of light photons and high tissue autofluorescence background, hindering its ability to image deep tissues. To address this challenge, we propose a new platform for imaging protease activity in vivo. Here we outline developments to make this new platform compatible with modalities that have deep tissue penetrafion, specifically: PET and MRI. We propose to establish and validate a general platform for imaging specific protease activity in cancer cells. The platform is based on the protease activity triggered polymerization between two chemical moieties (the amino and thiol groups of cysteine and 2-cyanobenzothiazole) incorporated into a small-molecule imaging probe. This polymerization process will convert the small-molecule probe into larger molecules (or even nanoparticles) to achieve probe concentration and retention at the target site and to generate amplified readout signals. In particular, we will exploit the highly specific condensation reaction between 1,2-aminomercapto and 2-cyanobenzothlazole groups as the base mechanism for polymerization, adding other functionalities to impart specificity to different enzymes or to enhance the effectiveness of our approach. Probes for two clinical imaging modalities, PET and MRI, will be designed, prepared and evaluated. The nature of the small-molecule PET and MRI probes, combined with the amplified activation signal, should maximize the likelihood of moving these probes into the clinic. In this project, we have chosen furin as the target enzyme because of its important role as a """"""""master switch"""""""" at different levels or stages during the process of cancer development and progression. The approach, however, should be generally applicable to other cancer- and disease-specific proteases, in particular, any endoproteases that perform C-terminal cleavage. This again may greatly improve the prospects for eventual clinical translafion of this platform technology.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA114747-06
Application #
7990890
Study Section
Special Emphasis Panel (ZCA1-SRLB-9 (M1))
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2010-07-01
Budget End
2011-08-31
Support Year
6
Fiscal Year
2010
Total Cost
$147,125
Indirect Cost
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Natarajan, Arutselvan; Patel, Chirag B; Ramakrishnan, Sindhuja et al. (2018) A Novel Engineered Small Protein for Positron Emission Tomography Imaging of Human Programmed Death Ligand-1 : Validation in Mouse Models and Human Cancer Tissues. Clin Cancer Res :
Sun, Yao; Zeng, Xiaodong; Xiao, Yuling et al. (2018) Novel dual-function near-infrared II fluorescence and PET probe for tumor delineation and image-guided surgery. Chem Sci 9:2092-2097
Natarajan, Arutselvan; Patel, Chirag B; Habte, Frezghi et al. (2018) Dosimetry Prediction for Clinical Translation of 64Cu-Pembrolizumab ImmunoPET Targeting Human PD-1 Expression. Sci Rep 8:633
Habte, Frezghi; Natarajan, Arutselvan; Paik, David S et al. (2018) Quantification of Cerenkov Luminescence Imaging (CLI) Comparable With 3-D PET Standard Measurements. Mol Imaging 17:1536012118788637
Hong, Su Hyun; Sun, Yao; Tang, Chu et al. (2017) Chelator-Free and Biocompatible Melanin Nanoplatform with Facile-Loading Gadolinium and Copper-64 for Bioimaging. Bioconjug Chem 28:1925-1930
Shen, Bin; Behera, Deepak; James, Michelle L et al. (2017) Visualizing Nerve Injury in a Neuropathic Pain Model with [18F]FTC-146 PET/MRI. Theranostics 7:2794-2805
Loft, Mathias Dyrberg; Sun, Yao; Liu, Changhao et al. (2017) Improved positron emission tomography imaging of glioblastoma cancer using novel 68Ga-labeled peptides targeting the urokinase-type plasminogen activator receptor (uPAR). Amino Acids 49:1089-1100
Natarajan, Arutselvan; Mayer, Aaron T; Reeves, Robert E et al. (2017) Development of Novel ImmunoPET Tracers to Image Human PD-1 Checkpoint Expression on Tumor-Infiltrating Lymphocytes in a Humanized Mouse Model. Mol Imaging Biol 19:903-914
Hori, Sharon Seiko; Lutz, Amelie M; Paulmurugan, Ramasamy et al. (2017) A Model-Based Personalized Cancer Screening Strategy for Detecting Early-Stage Tumors Using Blood-Borne Biomarkers. Cancer Res 77:2570-2584
Ronald, John A; Kim, Byung-Su; Gowrishankar, Gayatri et al. (2017) A PET Imaging Strategy to Visualize Activated T Cells in Acute Graft-versus-Host Disease Elicited by Allogenic Hematopoietic Cell Transplant. Cancer Res 77:2893-2902

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