Synthesis and characterization of mono-, di-, and tri-poly(ethylene glycol) chlorin e6 conjugates for the photokilling of human ovarian cancer cells.

Abstract

PEGylated chlorin e(6) photosensitizers were synthesized with tri(ethylene glycol) attached at the ester bond(s) for a 1:1 conjugate at the 17(3)-position, a 2:1 conjugate at the 15(2)- and 17(3)-positions, and a 3:1 conjugate at the 13(1)-, 15(2)-, and 17(3)-positions. These chlorin sensitizers were studied for hydrolytic stability and solubility, as well as ovarian OVCAR-5 cancer cell uptake, localization, and phototoxicity. Increasing numbers of the PEG groups in the mono-, di-, and tri-PEG chlorin conjugates increased the water solubility and sensitivity to hydrolysis and uptake into the ovarian cancer cells. The PEG chlorin conjugates accumulated in the cytoplasm and mitrochondria, but not in lysosomes. Higher phototoxicity was roughly correlated with higher numbers of PEG groups, with the tri-PEG chlorin conjugate showing the best overall ovarian cancer cell photokilling of the series. Singlet oxygen lifetimes, solvent deuteration, and the effects of additives azide ion and d-mannitol were examined to help clarify the photokilling mechanisms. A Type-II (singlet oxygen) photosensitized mechanism is suggested for the di- and tri-PEG chlorin conjugates; however, a more complicated process based in part on a Type-I (radicals or radical ions) mechanism is suggested for the parent chlorin e(6) and the mono-PEG chlorin conjugate.

• Authors: Stanley Kimani, Goutam Ghosh, Ashwini Ghogare, Benjamin Rudshteyn, Dorota Bartusik, Tayyaba Hasan, Alexander Greer
• Journal: The Journal of organic chemistry (J Org Chem) Vol. 77 Issue 23 Pg. 10638-47 (Dec 07 2012) ISSN: 1520-6904 [Electronic] United States
• PMID: 23126407 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chlorophyllides
• Porphyrins
• Radiation-Sensitizing Agents
• Polyethylene Glycols
• phytochlorin

Topics

• Chlorophyllides
• Female
• Humans
• Ovarian Neoplasms (drug therapy)
• Photochemotherapy (methods)
• Polyethylene Glycols (pharmacology, therapeutic use)
• Porphyrins (pharmacology, therapeutic use)
• Radiation-Sensitizing Agents (pharmacology, therapeutic use)