Influence of the substitution of 3-vinyl by 3-formyl group on the photodynamic properties of chlorin P6: molecular, cellular and in vivo studies.
Molecular in vitro and in vivo properties of 3-devinyl-3-formylchlorin p6 (FCp6) were examined in order to characterize this derivative as a new prospective photosensitizer. The long-wavelength absorption maximum of FCp6 was 690-696 nm (depending on environment). FCp6 was found to bind readily to membranous structures and form complexes with some proteins. The dye was associated with the plasmalemma and distributed rather diffusely along the cytoplasm with ca a three-fold higher accumulation within mitochondria in A549 human adenocarcinoma cells. The spectral analysis revealed that the major part of FCp6 was bound to membranes within cells. The membrane-bound FCp6 was shown to generate singlet oxygen efficiently. The average cytoplasmic concentration of FCp6 in A549 cells achieved ca 80% of its extracellular concentration in complete medium. The dye was characterized by a very fast efflux (16-fold decrease in 2 h). The ex vivo analysis of FCp6 fluorescence in mice revealed that the maximal dye content in blood, tissues, organs and tumor was achieved in less than 1 h after injection, followed by a considerable (ca six-fold) decrease during the next 23 h and a long-term persistence at low level. A preferential accumulation of FCp6 in subcutaneously implanted Ehrlich carcinoma along with its higher retention level comparing to the surrounding skin and muscles were observed in mice treated with different dye doses. In vitro cytotoxic assays with A549 and Raji B-cell lymphoma cells as well as in vivo analyses using Ehrlich carcinoma in mice revealed the very low toxicity of FCp6 without light irradiation and the significant photodynamic activity of this compound.
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, 117871 Moscow, Russia. alexei@nmr.ru
A
A
Grichine
A
A
Feofanov
T
T
Karmakova
N
N
Kazachkina
E
E
Pecherskih
R
R
Yakubovskaya
A
A
Mironov
M
M
Egret-Charlier
P
P
Vigny
D006801:Humans; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology*; D011166:Porphyrins / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D017319:Photosensitizing Agents; D011166:Porphyrins; C072905:chlorin p6