[Photobiological properties of 13,15-N-(carboxymethyl)- and 13,15-N-(2-carboxyethyl)cycloimide derivatives of chlorin p6].
Lipophilic derivatives of chlorin p6, 13,15-N-(carboxymethyl)cycloimide methyl ester (CIC1) and 13,15-N-(2-carboxyethyl)cycloimide methyl ester (CIC2), were shown to absorb light in 710 nm region and to be efficient IR photosensitizers. They exhibit similar phototoxicities on the cells of A549 human lung adenocarcinoma, which are 40- and 100-fold higher than those of chlorin p6 and the clinically used Photogem, respectively, and are not toxic in the absence of light irradiation. The confocal spectral imaging technique allowed us to demonstrate that the high phototoxicity of CIC1 and CIC2 is due to their ability to readily penetrate to cells and to be bound to the cell membranes and lipid-containing structures in the monomeric photoactive form. Under the irradiation, the membrane-bound CIC1 and CIC2 are characterized by high quantum yields of singlet oxygen generation (0.6 and 0.65, respectively) and the inability to produce hydroxyl radicals. A 1.5-microM content of CIC1 and CIC2 in the incubation medium provides for their average cytoplasmic concentrations of 21 and 16.5 microM, respectively. The incubation times to achieve 50% level of maximum accumulation for CIC1 and CIC2 in A549 cells are 30 +/- 6 and 24 +/- 12 min, and the times for 50% release of the dyes from the cells are 17 +/- 4 and 50 +/- 10 min, respectively. A diffuse distribution with the predominant accumulation in the membranes of the Golgi apparatus and mitochondria is characteristic of both CIC2 and CIC1, whereas, in addition, CIC1 is considerably accumulated in lipid droplets (cellular organelles responsible for the storage and metabolism of neutral lipids and steryl esters). Our results demonstrate that changes in the structure of the imide substituent could affect the intracellular localization and the rate of release of chlorin p6 cycloimide derivatives from cells while preserving their high photodynamic activity.
A V
AV
Feofanov
A I
AI
Nazarova
T A
TA
Karmakova
A D
AD
Pliutinskaia
A I
AI
Grishin
R I
RI
Iakubovskaia
V S
VS
Lebedeva
R D
RD
Ruziev
A F
AF
Mironov
J C
JC
Maurizot
P
P
Vigny
D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D005609:Free Radicals / Q000378:metabolism; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008027:Light; D050356:Lipid Metabolism; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017319:Photosensitizing Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D011166:Porphyrins / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship
D005609:Free Radicals; D017319:Photosensitizing Agents; D011166:Porphyrins; D017382:Reactive Oxygen Species; C502409:chlorin p6 13,15-N-(2-carboxyethyl)cycloimide methyl ester; C502408:chlorin p6 13,15-N-(carboxymethyl)cycloimide methyl ester