Many physiological processes function efficiently within a well-controlled pH range and significant deviations from this range typically are indicative of pathologic conditions. Within cells, maintenance of a pH gradient in different organelles allows for differential activation of certain enzymes or generation of active conformations of proteins for transient or prolonged activity. Globally, the sum of cellular events can reflect on the pH of tissues and organ systems. A common strategy to monitor the pH of biochemical events relies on the use of pH-sensitive fluorescent molecular probes to monitor diverse physiological and pathological processes, including studies related to cancer, cell proliferation, endocytotic and other physiological processes. Currently, there is a major disconnection between the use of pH-sensitive fluorescent dyes in molecular cell biology and for imaging diseases in vivo. This is because most of these dyes fluoresce in the visible wavelengths where absorption of light by native fluorophores and autofluorescence limits their use in both tissue and cell imaging. To overcome these problems, we propose to develop new classes of pH-sensitive near infrared fluorescent molecular probes that are useful for imaging molecular processes by microscopy and whole-body animal imaging by diffuse optical tomography. Advantages of this approach include high detection sensitivity because of low autofluorescence, low phototoxicity because of the use of low energy radiation, and the extension of the spectral window to the 900 nm which allows the use of multiple fluorophores between 400 and 900 nm wavelengths. More importantly, information gleaned from the molecular cell biology studies can be translated to small animals, and eventually to humans with the same pHsensitive NIR molecular probe because NIR light can penetrate into deep tissues. We will accomplish these goals by (1) designing and developing two new classes of pHsensitive NIR dyes;(2) demonstrating their utility to image pH-dependent molecular processes in cells;and (3) imaging the onset of acidosis in solid tumors in vivo. The products generated from this project will be distributed to other investigators for research purposes. Project Narrative The goals of this project are to (1) design and develop two new classes of pH-sensitive NIR dyes;(2) demonstrate their utility to image pH-dependent molecular processes in cells by microscopy;and (3) image the onset of acidosis in solid tumors in vivo. The technology platform developed will be useful for diverse pH-based biological applications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB007276-03
Application #
7796634
Study Section
Special Emphasis Panel (ZRG1-BST-Q (03))
Program Officer
Zhang, Yantian
Project Start
2008-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
3
Fiscal Year
2010
Total Cost
$320,047
Indirect Cost
Name
Washington University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Miller, Jessica P; Habimana-Griffin, LeMoyne; Edwards, Tracy S et al. (2017) Multimodal fluorescence molecular imaging for in vivo characterization of skin cancer using endogenous and exogenous fluorophores. J Biomed Opt 22:66007
Mondal, Suman B; Gao, Shengkui; Zhu, Nan et al. (2017) Optical See-Through Cancer Vision Goggles Enable Direct Patient Visualization and Real-Time Fluorescence-Guided Oncologic Surgery. Ann Surg Oncol 24:1897-1903
Som, Avik; Raliya, Ramesh; Tian, Limei et al. (2016) Monodispersed calcium carbonate nanoparticles modulate local pH and inhibit tumor growth in vivo. Nanoscale 8:12639-47
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Gilson, Rebecca C; Tang, Rui; Som, Avik et al. (2015) Protonation and Trapping of a Small pH-Sensitive Near-Infrared Fluorescent Molecule in the Acidic Tumor Environment Delineate Diverse Tumors in Vivo. Mol Pharm 12:4237-46
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Lee, Hyeran; Berezin, Mikhail Y; Tang, Rui et al. (2013) Pyrazole-substituted near-infrared cyanine dyes exhibit pH-dependent fluorescence lifetime properties. Photochem Photobiol 89:326-31
Akers, Walter J; Edwards, W Barry; Kim, Chulhong et al. (2012) Multimodal sentinel lymph node mapping with single-photon emission computed tomography (SPECT)/computed tomography (CT) and photoacoustic tomography. Transl Res 159:175-81

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