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Activatable COX‐2 Probes in Optical Imaging of Cancer
Author(s) -
Uddin Md. Jashim,
Crews Brenda C,
Ghebreselasie Kebreab,
Daniel Cristina K,
Marnett Lawrence J.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.886.3
Subject(s) - fluorophore , fluorescence , nitroxide mediated radical polymerization , chemistry , quenching (fluorescence) , in vivo , magnetic resonance imaging , molecular imaging , cancer cell , cancer , biophysics , cancer research , medicine , radiology , biology , radical polymerization , optics , polymerization , physics , microbiology and biotechnology , organic chemistry , polymer
Conventional imaging methods, such as angiography, computed tomography, magnetic resonance imaging and radionuclide imaging, rely on contrast agents that are “always on”. A unique aspect of optical imaging is that fluorescent probes can be designed to be activatable, so that they are only “turned on” under certain conditions. Probes that are activatable and also accumulate in the tumor in a targeted fashion could be ideal for detection of superficial tumors or tumors that can be accessed by endoscopy. We developed fluorocoxib A, the 1 st COX‐2 targeted optical imaging probe, which displayed a high degree of selectivity of uptake in the COX‐2‐positive tumors over COX‐2‐negative tumors. Having an established proof‐of‐concept compound for COX‐2‐targeted imaging, we sought to expand the applicability of this approach by designing activatable pro‐fluorescent nitroxide probes that are capable of visualization of cancer with high signal‐to‐noise ratios. We synthesized a series of nitroxide derivatives of fluorocoxib A and B, containing a carboxy‐X‐rhodamine (ROX) fluorophore closely linked to a TEMPO or PROXYL nitroxide moiety. These probes exhibited selective COX‐2 inhibition in purified enzymes and intact cells, and showed significantly reduced fluorescence due to efficient quenching of the excited electronic state of the fluorophore by the nitroxide radical. Upon radical trapping in cancer cells, these COX‐2‐targeted probes demonstrated enhanced fluorescent emission, making them effective in detecting COX‐2 in tumors in vivo. Thus, this novel strategy allows target‐specific delivery of quenched agents into tumor cells and subsequent on‐site fluorescence activation by radical trapping allowing selective visualization of tumor in vivo. This technology can be widely adapted for background free detection of inflammatory and neoplastic diseases in preclinical and clinical settings. Support or Funding Information This work was supported by research grants from the National Institutes of Health number CA89450 (LJM).