TARGETED PHOTODYNAMIC ACTION

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"Photoradiation therapy is therapy requiring the use of a photosensitizer to elicit a therapeutic effect when the sensitizer is activated by photons in the visible region of the spectrum." Its recent use was pioneered by Dougherty who reported that fluorescein derivatives could be activated by 488 nm light to reduce the growth rate of mammary in mice1 and that hematoporphyrin derivative could be activated with red light to cause complete eradication of mammary tumors in mice and rats. Rose bengal is a xanthene dye whose properties have been studied in detail by Neckers. It is a useful sensitizer for singlet oxygen formation in many different solvents and molecular forms, including polymeric ones. Its structure can be modified easily and structural changes cause little change in photochemical or photophysical characteristics. It is a purpose of this proposal to further develop the chemistry of this dye, which like most dyes, is very complicated. We intend to make it the prototypical dye system on which future dye modifications and chemistries for phototherapeutic applications can be based. It is our intention to demonstrate that by proper structural modification this sensitizer can be directed to specific oxidizable substrates to increase the selectivity of oxidation of a specific partner molecule, and use this targeted photosensitizer concept to alter the rate of, and products obtained from, these oxidation processes. We call this the principle of targeted photodynamic action. Rose bengal, 4, will be functionalized to react with enzymes and antibodies and these will be used to attract selectively other molecular entities such as substrates, inhibitors, or antigens. This should attract these latter entities to the site of the sensitizer functionalized enzyme, or antibody, and hence to the source of singlet oxygen. It should enhance the local concentration of the potential singlet oxygen acceptor in the vicinity of the source - the sensitizer. We intend to apply this principle, Targeted Photodynamic Action, in tumor phototherapy. Collaborations are arranged with 1. Dougherty (photodynamic therapy), C. W. Lin (bladder cancer phototherapy), and J. Spikes (xanthene dye incorporation into liposomes), and A. Oseroff (functionalized monoclonal antibodies).