Synthesis and Characterization of Mono?, Di?, and Tri-Poly(ethylene glycol) Chlorin e6 Conjugates for the Photokilling of Human Ovarian Cancer Cells

摘要

PEGylated chlorin e6 photosensitizers werensynthesized with tri(ethylene glycol) attached at the esternbond(s) for a 1:1 conjugate at the 173-position, a 2:1 conjugatenat the 152- and 173-positions, and a 3:1 conjugate at the 131-,n152-, and 173-positions. These chlorin sensitizers were studiednfor hydrolytic stability and solubility, as well as ovariannOVCAR-5 cancer cell uptake, localization, and phototoxicity.nIncreasing numbers of the PEG groups in the mono-, di-, andntri-PEG chlorin conjugates increased the water solubility andnsensitivity to hydrolysis and uptake into the ovarian cancerncells. The PEG chlorin conjugates accumulated in thencytoplasm and mitrochondria, but not in lysosomes. Highernphototoxicity was roughly correlated with higher numbers ofnPEG groups, with the tri-PEG chlorin conjugate showing the best overall ovarian cancer cell photokilling of the series. Singletnoxygen lifetimes, solvent deuteration, and the effects of additives azide ion and D-mannitol were examined to help clarify thenphotokilling mechanisms. A Type-II (singlet oxygen) photosensitized mechanism is suggested for the di- and tri-PEG chlorinnconjugates; however, a more complicated process based in part on a Type-I (radicals or radical ions) mechanism is suggested fornthe parent chlorin e6 and the mono-PEG chlorin conjugate.