The goal of this proposal is to advance an optical imaging system for longitudinal, high throughput small animal cancer imaging using fluorescence lifetime contrast. We will specifically advance and validate a novel time domain (TD) lifetime- based tomography technique for whole-body imaging of two important and related phenomena, namely tumor metastasis and angiogenesis. We will first enable whole animal imaging of metastasis using fluorescent proteins (FPs) in the visible spectrum (450nm - 650nm). Lifetime imaging of FPs will be applied to track metastasis in a small animal model of human breast cancer. This will allow longitudinal quantification of metastatic foci in living mice at earlier stages than currently possible with other non- invasive techniques. We will next employ near infra-red (NIR) (650nm - 850nm) fluorophores with distinct lifetimes to study angiogenesis and drug delivery during therapy. Optical imaging can enable rapid, deep tissue (>1 cm) imaging of the entire tumor volume with mm-scale resolution, which can allow global quantitative readouts of tumor physiology under therapeutic intervention. Optical imaging also allows a unique opportunity for simultaneously tracking multiple processes within the tumor volume using multiple fluorophores with distinct lifetimes (lifetime """"""""multiplexing""""""""). We will validate lifetime multiplexing to track angiogenesis and drug delivery to tumors simultaneously. In order to achieve this, we will use a NIR fluorophore that targets vasculature and a second NIR fluorophore with distinct lifetime that is tagged to herceptin. Herceptin is an anti-angiogenic and therapeutic agent that targets the human epidermal growth factor receptor 2 (HER2/neu), which is over-expressed in human breast cancers. Additionally, NIR spectroscopy of intrinsic tissue optical contrast will reveal changes in tumor blood volume and oxygenation due to therapy, and FP expressing cancer cells will reveal tumor growth. By enabling simultaneous monitoring of multiple physiological markers in the entire volume of tumor, this technology will provide new insights into the interplay between angiogenesis and drug delivery during herceptin treatment, and will allow the validation and optimization of developmental cancer drugs.

Public Health Relevance

Early detection and prevention using novel molecularly targeted cancer diagnostics and therapeutics is a key strategy to reduce cancer deaths. This proposal will advance a non-invasive, pre-clinical time domain fluorescence system exploiting lifetime contrast that will accelerate the discovery of cancer therapeutics.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
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Biomedical Imaging Technology Study Section (BMIT)
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Conroy, Richard
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Massachusetts General Hospital
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Hou, Steven S; Bacskai, Brian J; Kumar, Anand T N (2016) Optimal estimator for tomographic fluorescence lifetime multiplexing. Opt Lett 41:1352-5
Rice, William L; Shcherbakova, Daria M; Verkhusha, Vladislav V et al. (2015) In vivo tomographic imaging of deep-seated cancer using fluorescence lifetime contrast. Cancer Res 75:1236-43
Hou, Steven S; Rice, William L; Bacskai, Brian J et al. (2014) Tomographic lifetime imaging using combined early- and late-arriving photons. Opt Lett 39:1165-8
Rice, William L; Kumar, Anand T N (2014) Preclinical whole body time domain fluorescence lifetime multiplexing of fluorescent proteins. J Biomed Opt 19:046005
Kumar, Anand T N (2013) Fluorescence lifetime detection in turbid media using spatial frequency domain filtering of time domain measurements. Opt Lett 38:1440-2
Rice, William L; Hou, Steven; Kumar, Anand T N (2013) Resolution below the point spread function for diffuse optical imaging using fluorescence lifetime multiplexing. Opt Lett 38:2038-40
Metelev, Valeri; Zhang, Surong; Tabatadze, David et al. (2013) The three-dimensional context of a double helix determines the fluorescence of the internucleoside-tethered pair of fluorophores. Mol Biosyst 9:2447-53
Goergen, Craig J; Chen, Howard H; Bogdanov, Alexei et al. (2012) In vivo fluorescence lifetime detection of an activatable probe in infarcted myocardium. J Biomed Opt 17:056001
Bogdanov Jr, Alexei A; Metelev, Valeriy; Zhang, Surong et al. (2012) Sensing of transcription factor binding via cyanine dye pair fluorescence lifetime changes. Mol Biosyst 8:2166-73
Guo, Yanyan; Yuan, Hushan; Rice, William L et al. (2012) The PEG-fluorochrome shielding approach for targeted probe design. J Am Chem Soc 134:19338-41

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