The broad spectrum tetracycline (TC) antibodies are among the most frequently used therapeutic agents. These compounds are efficient photosensitizers and two biologic consequences of this property are: (i) cutaneous phototoxicity; (ii) potential for photochemotherapy. This proposal seeks to understand the mechanisms involved in TC- photosensitization in vitro and in vivo and to correlate biologic observations with basic TC photophysics and photochemistry. Two TCs, minocycline (MC) and doxycycline (DOTC), will be used in these investigations. They were chosen because they are clinically relevant and are representative of the possible effects of chemical structure on photochemistry. The basis for the variation in phototoxic potential within the TCs will be investigated and the action spectrum will be determined in guinea pig skin. Limited investigations establishing sub-cellular targets will be undertaken. Selective depletion of Class II antigen-expressing cells using TC-monoclonal antibody conjugates will be attempted. Investigations of biologic responses to a range of peak irradiances, pulse durations and repetition rates are planned. Biologic effects will be correlated with basic photophysical parameters to fully understand the mechanisms underlying these photosensitizations. Characterization of photophysical parameters will include determination of excited state lifetimes, yields, absorption spectra of transients and the potential for resonant and non-resonant biphotonic processes. The techniques used will be of the excite-probe type and time-dependent decay of fluorescence or absorption will be followed. Such information will aid in understanding the basics photophysics of 2 well-known photosensitizers and may prove important in applications of pulsed lasers in photosensitization schemes. The fluorescence induced by non-resonant two photon absorption using long wavelength irradiation with good tissue penetration properties might therefore have potential in diagnostic schemes. The proposed comprehensive investigations will lead not only to a clearer understanding of phototoxicity mechanisms of TCs in particular, but will provide fundamental improvements in the understanding of phototoxic mechanisms in general. This improved understanding could be significant in the design of photosensitizers and phototherapy regimens.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
First Independent Research Support & Transition (FIRST) Awards (R29)
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General Medicine A Subcommittee 2 (GMA)
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Massachusetts General Hospital
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