title: Photosensitizers derived from 132-oxo-methyl pyropheophorbide-a: enhanced effect of indium(III) as a central metal in in vitro and in vivo photosensitizing efficacy.
abstract: The effects of an additional keto group on absorption wavelength and the corresponding metal complexes Zn(II), Cu(II) In(III) on singlet oxygen production and photodynamic efficacy were examined among the alkyl ether analogs of pyropheophorbide-a. For the preparation of the desired photosensitizers, the methyl 13(2)-oxo-pyropheophorbide-a obtained by reacting methyl pyropheophorbide-a with aqueous LiOH-THF was converted into a series of alkyl ether analogs. These compounds were evaluated for photophysical properties and in vitro (by means of the MTT assay and intracellular localization in RIF cells) and in vivo (in C3H mice implanted with RIF tumors) photosensitizing efficacy. Among the alkyl ether derivatives, the methyl 3-decyloxyethyl-3-devinyl-13(2)-oxo-pyropheophorbide-a was found to be most effective and the insertion of In(III) into this analog further enhanced its in vitro and in vivo photosensitizing efficacy. Fluorescence microscopy showed that, in contrast to the hexyl and dodecyl ether derivatives of HPPH (which localize in mitochondria and lysosomes, respectively), the diketo-analogs and their In(III) complexes localized in Golgi bodies. The preliminary in vitro and in vivo results suggest that, in both free-base and metalated analogs, the introduction of an additional keto group at the five-member exocyclic ring in pyropheophorbide-a diminishes its photosensitizing efficacy. This may be due to a shift in subcellular localization from mitochondria to the Golgi bodies. The further introduction of In(III) enhances photoactivity, but not by shifting the localization of the photosensitizer.
authors.affiliation: Photodynamic Therapy Center, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rosenfeld
authors.forename: Janet
authors.initials: J
authors.lastname: Morgan
authors.forename: Lalit N
authors.initials: LN
authors.lastname: Goswami
authors.forename: Tymish
authors.initials: T
authors.lastname: Ohulchanskyy
authors.forename: Xiang
authors.initials: X
authors.lastname: Zheng
authors.forename: Paras N
authors.initials: PN
authors.lastname: Prasad
authors.forename: Allan
authors.initials: A
authors.lastname: Oseroff
authors.forename: Ravindra K
authors.initials: RK
authors.lastname: Pandey
mesh_terms: D000818:Animals; D002734:Chlorophyll / Q000031:analogs & derivatives; D006056:Golgi Apparatus / Q000378:metabolism; D007204:Indium; D008670:Metals; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000378:metabolism; D017319:Photosensitizing Agents / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008670:Metals; D017319:Photosensitizing Agents; D007204:Indium; D002734:Chlorophyll; C040298:pyropheophorbide a