The recent approvals of Photofrin-sensitized photodynamic therapy (PDT) in Canada and the Netherlands are significant events in the history of this relatively new cancer therapy. These developments will encourage further research in the design, synthesis, and evaluation of new photo- sensitizing agents, which seek to overcome certain limitations of the first generation prophyrins. Among these generally recognized limitations are weak absorption at wavelengths where optical penetration in tissue is optimal, relatively poor specificity with respect to tumor and normal tissue uptake and retention, and prolonged skin photosensitivity. A number of candidate 'second generation' compounds have been proposed and studied. The focus of these proposed studies is a family of cationic dyes that show particular promise as sensitizers of direct tumor cell destruction for PDT. Initial experience with the use of these compounds, described as Nile Blue derivatives, raises interesting and challenging research problems that are critical to resolve in order to optimize the effectiveness of these photosensitizers. Furthermore, these questions are likely to be of general importance in the search for optimum PDT methods of targeting tumor cells directly. On the basis of a body of experimental and theoretical work carries out in our laboratory over the past several years, we hypothesize that problems associated with photochemical oxygen consumption and diffusion will be critical aspects of optimizing the use of the Nile Blue derivatives for PDT. These issues are particularly important for these dyes in that they are bleached through enzymatic and photoreduction mechanisms under conditions of low oxygen concentration. Careful attention to the details of these processes can create significant opportunities for improved therapeutic efficacy. Towards this end, the application poses fives specific aims: (1) direct microelectrode measurements of PDT-induced oxygen consumption in Nile blue-sensitized multicell tumor spheroids and determination of photodynamic rates of oxygen consumption; (2) determination of the threshold dose for these dyes in the multicell tumor spheroid system; (3) optical sectioning (confocal) fluorescence microscopy of Nile blue-sensitized spheroids under various incubation conditions and during irradiation to determine bleaching rates and mechanisms; (4 optical reflectance spectroscopy of tumor oxygenation during Nile blue-sensitized PDT with emphasis on hemoglobin O2 saturation and cytochrome redox status; and (5) optimization of Nile blue-sensitized PDT irradiation protocols in three rodent tumor systems.

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National Cancer Institute (NCI)
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Radiation Study Section (RAD)
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University of Rochester
Schools of Dentistry
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Baran, Timothy M (2015) Cylindrical diffuser axial detection profile is dependent on fiber design. J Biomed Opt 20:040502
Wojtovich, Andrew P; Foster, Thomas H (2014) Optogenetic control of ROS production. Redox Biol 2:368-76
Baran, Timothy M; Foster, Thomas H (2014) Comparison of flat cleaved and cylindrical diffusing fibers as treatment sources for interstitial photodynamic therapy. Med Phys 41:022701
Haidaris, Constantine G; Foster, Thomas H; Waldman, David L et al. (2013) Effective photodynamic therapy against microbial populations in human deep tissue abscess aspirates. Lasers Surg Med 45:509-16
Baran, Timothy M; Fenn, Michael C; Foster, Thomas H (2013) Determination of optical properties by interstitial white light spectroscopy using a custom fiber optic probe. J Biomed Opt 18:107007
Mitra, Soumya; Modi, Kshitij D; Foster, Thomas H (2013) Enzyme-activatable imaging probe reveals enhanced neutrophil elastase activity in tumors following photodynamic therapy. J Biomed Opt 18:101314
Baran, Timothy M; Foster, Thomas H (2013) Recovery of intrinsic fluorescence from single-point interstitial measurements for quantification of doxorubicin concentration. Lasers Surg Med 45:542-50
Baran, Timothy M; Foster, Thomas H (2012) Fluence rate-dependent photobleaching of intratumorally administered Pc 4 does not predict tumor growth delay. Photochem Photobiol 88:1273-9
Snell, Sara B; Foster, Thomas H; Haidaris, Constantine G (2012) Miconazole induces fungistasis and increases killing of Candida albicans subjected to photodynamic therapy. Photochem Photobiol 88:596-603
Baran, Timothy M; Wilson, Jeremy D; Mitra, Soumya et al. (2012) Optical property measurements establish the feasibility of photodynamic therapy as a minimally invasive intervention for tumors of the kidney. J Biomed Opt 17:98002-1

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