Photodynamic therapy (PDT) is an extremely promising anticancer protocol used for the treatment of a wide variety of human tumors. A hematoporphyrin derivative (HpD) photosensitizer is selectively retained by neoplastic tissue. Photoirradiation of HpD-embedded tumors leads to tumor necrosis via the intermediacy of highly destructive oxygen-derived species. However, HpD is a chemically ill-defined photosensitizer that can only weakly absorb long wavelength light. Many photosensitizers possess photophysical properties that are more ideal for PDT than HpD, yet these sensitizers do not have a special affinity for tumor cells. We are currently investigating the synthesis of a series of alkyllysophospholipid-photosensitizers (ALP-photosensitizers) where the ALP component will serve as a vehicle for the selective delivery of the sensitizer moiety to the cellular target. This design feature provides the flexibility to choose photosensitizers that possess photophysical properties more ideal for phototherapy than HpD. Certain alkyllysophospholipids posses a strong affinity for tumor cells. The corresponding ALP-photosensitizers should retain the tumor cell selectivity displayed by the parent lipid. This strategy is similar to the use of a monoclonal antibody delivery system with the exception that the lipid vehicle delivers the photosensitizer internally to the cell where the greatest photodamage occurs. Two enzymes that have been implicated in the retention of ALPs by tumors are an alkyl ether cleavage monooxygenase and a 2- LPC-acyltransferase. Both enzymes will be isolated and assayed with the appropriate ALP-photosensitizers. At present, the assays available for the alkyl ether cleavage monooxygenase and the 2-LPC-acyltransferase are tedious and involve the use of radiolabelled substrates. Indeed, both enzymes are enigmatic in large part due to the extremely tedious nature of these assays. We are currently investigating the development of a convenient assay for these enzymes that does not require the use of radioisotopes.
| Dick, D; Pluskey, S; Sukumaran, D K et al. (1992) NMR spectral analysis of cytotoxic ether lipids. J Lipid Res 33:605-9 |
| Dick, D L; Lawrence, D S (1992) Physicochemical behavior of cytotoxic ether lipids. Biochemistry 31:8252-7 |
