Dr. Jean R. Starkey Profile

KEYWORDS: Tumors, Photodynamic therapy, Chlorine, Lung cancer, Absorption, Laser tissue interaction, Tumor growth modeling, Skin, Receptors, Breast cancer

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Proceedings Article | 11 February 2008 Paper

Histopathological and expression profiling studies of early tumor responses to near-infrared PDT treatment in SCID mice

Jean Starkey, Aleksander Rebane, Mikhail Drobizhev, Fanqin Meng, Aijun Gong, Aleisha Elliott, Kate McInnerney, Elizabeth Pascucci, Charles Spangler

Proceedings Volume 6845, 68450U (2008) https://doi.org/10.1117/12.761273

KEYWORDS: Tumors, Photodynamic therapy, Tissues, Lung, Profiling, Oxygen, Receptors, Spleen, Near infrared, Blood circulation

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Proceedings Article | 6 March 2006 Paper

Synthesis, characterization, and preclinical studies of two-photon-activated targeted PDT therapeutic triads

C. Spangler, J. Starkey, A. Rebane, F. Meng, A. Gong, M. Drobizhev

Proceedings Volume 6139, 61390X (2006) https://doi.org/10.1117/12.646312

KEYWORDS: Tumors, Photodynamic therapy, Receptors, Skin, Tissues, Near infrared, Breast cancer, Molecules, Bioluminescence, Collagen

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Photodynamic therapy (PDT) continues to evolve into a mature clinical treatment of a variety of cancer types as well as age-related macular degeneration of the eye. However, there are still aspects of PDT that need to be improved in order for greater clinical acceptance. While a number of new PDT photo-sensitizers, sometimes referred to as second- or third- generation therapeutic agents, are currently under clinical investigation, the direct treatment through the skin of subcutaneous tumors deeper than 5 mm remains problematic. Currently approved PDT porphyrin photo-sensitizers, as well as several modified porphyrins (e.g. chlorins, bacteriochlorins, etc.) that are under clinical investigation can be activated at 630-730 nm, but none above 800 nm. It would be highly desirable if new PDT paradigms could be developed that would allow photo-activation deep in the tissue transparency window in the Near-infrared (NIR) above 800 nm to reduce scattering and absorption phenomena that reduce deep tissue PDT efficacy. Rasiris and MPA Technologies have developed new porphyrins that have greatly enhanced two-photon absorption ( P A ) cross-sections and can be activated deep in the NIR (ca. 780-850 nm). These porphyrins can be incorporated into a therapeutic triad that also employs an small molecule targeting agent that directs the triad to over-expressed tumor receptor sites, and a NIR onephoton imaging agent that allows tracking the delivery of the triad to the tumor site, as well as clearance of excess triad from healthy tissue prior to the start of PDT treatment. We are currently using these new triads in efficacy studies with a breast cancer cell line that has been transfected with luciferase genes that allow implanted tumor growth and post- PDT treatment efficacy studies in SCID mouse models by following the rise and decay of the bioluminescence signal. We have also designed highly absorbing and scattering collagen breast cancer phantoms in which we have demonstrated dramatic cell kill to a depth of at least 4 cm. We have also demonstrated that at the wavelength and laser fluences used in the treatment of implanted tumors in the mouse mammary fat pads, there is little, if any, damage to the skin or internal mouse organs. In addition, we have also demonstrated that the implanted tumors can be treated to a depth of more than 1 cm by direct radiation through the dorsal side of the mouse.

Proceedings Article | 8 April 2005 Paper

Targeted two-photon photodynamic therapy for the treatment of subcutaneous tumors

Charles Spangler, Jean Starkey, Fanqing Meng, Aijun Gong, Mikhail Drobizhev, Aleksander Rebane, B. Moss

Proceedings Volume 5689, (2005) https://doi.org/10.1117/12.589210

KEYWORDS: Tumors, Photodynamic therapy, Tissues, Receptors, Near infrared, Breast cancer, Transparency, In vivo imaging, Molecules, Skin

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Photodynamic therapy (PDT) has developed into a mature technology over the past several years, and is currently being exploited for the treatment of a variety of cancerous tumors, and more recently for age-related wet macular degeneration of the eye. However, there are still some unresolved problems with PDT that are retarding a more general acceptance in clinical settings, and thus, for the most part, the treatment of most cancerous rumors still involves some combination of invasive surgery, chemotherapy and radiation treatment, particularly subcutaneous tumors. Currently approved PDT agents are activated in the Visible portion of the spectrum below 700 nm, Laser light in this spectral region cannot penetrate the skin more than a few millimeters, and it would be more desirable if PDT could be initiated deep in the Near-infrared (NIR) in the tissue transparency window (700-1000 nm). MPA Technologies, Inc. and Rasiris, Inc. have been co-developing new porphyrin PDT designed to have greatly enhanced intrinsic two-photon cross-sections (>800 GM units) whose two-photon absorption maxima lie deep in the tissue transparency window (ca. 780-850 nm), and have solubility characteristics that would allow for direct IV injection into animal models. Classical PDT also suffers from the lengthy time necessary for accumulation at the tumor site, a relative lack of discrimination between healthy and diseased tissue, particularly at the tumor margins, and difficulty in clearing from the system in a reasonable amount of time post-PDT. We have recently discovered a new design paradigm for the delivery of our two-photon activated PDT agents by incorporating the porphyrins into a triad ensemble that includes a small molecule targeting agent that directs the triad to over-expressed tumor receptor sites, and a NIR one-photon imaging agent that allows the tracking of the triad in terms of accumulation and clearance rates. We are currently using these new two-photon PDT triads in efficacy studies with two breast cancer cell lines, both in vitro and in vivo. Both of these cell lines have been transfected with luciferase genes that allow implanted tumor growth and PDT efficacy to be monitored in living mouse models over time by following the rise and decay of the bioluminescence signals.

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