13,15-N-Cycloimide derivatives of chlorin p6 with isonicotinyl substituent are photosensitizers targeted to lysosomes

Abstract

Four monocationic cycloimide derivatives of chlorin p(6) (CICD) were studied as photosensitizers and compared to a structurally similar neutral derivative. Cationic CICD are highly photostable (quantum yield of photobleaching is about 1 x 10(-5), generate singlet oxygen under irradiation (quantum yields are 0.3-0.45), can be involved in a photo-induced substrate-dependent generation of superoxide radicals, but do not produce OH . 17,18-delta-lacton 13(2)-(N-methylisonicotinylamido)-13,15-cycloimide mesochlorin p(6) () and 13(2)-(N-methylisonicotinylamido)-13,15-cycloimide mesochlorin p(6) methyl ester () possess high cancer cell killing photodynamic activity, but they provide no photoinduced bactericidal effect. Substitution of an ethyl group with a hydroxyethyl or acetyl group at position 3 of the macrocycle results in a decrease in extinction and intracellular accumulation that finally leads to the reduced photocytotoxicity. Cationic CICD are targeted to lysosomes, and their intracellular penetration occurs most probably via caveolae-dependent endocytosis. Photodynamic treatment with cationic CICD results in the cell death via necrosis at both sub-phototoxic (40-70% of dead cells) and phototoxic (90-100% of dead cells) regimes of cell treatment. Irradiation induces lysosome damage, leakage of CICD from lysosomes and development of protease activity in cytoplasm, whereas mitochondria are not affected with irradiation. A positive charge of cationic CICD modified drastically an internalization pathway, sites of intracellular localization and mechanisms of photoinduced cytotoxicity as compared to previously studied neutral and anionic CICD. Our experiments with different CICD show that varying charge and structure of substituents it is possible to modulate many cellular properties of CICD in order to find the best molecular template of the advanced near-IR photosensitizer for photodynamic therapy.

Ionic Liquid-Based Chlorins and Type III Mechanism of Photodynamic Therapy (PDT)

“…Four monocationic cycloimide derivatives of chlorin p 6 (CICD) 31-34 ( Figure 11) having λ max in 699-734 nm range were developed by Nazarova et al in 2007 as PSs and their photodynamic efficacies were compared to a structurally similar neutral derivative. 168 The authors found that the cationic CICD are highly photostable, generate singlet oxygen under irradiation, and can be involved in a photo-induced substrate-dependent generation of superoxide radicals, but do not produce OH • . Two of them possess high cancer cell killing photodynamic activity, but provide no photo-induced bactericidal effect.…”

Erythrocytes Membrane Photodestruction Sensitized Chlorophyll a Derivatives: Some Structure-Activity Regularities

“…It was shown that chlorins without exo-cycle (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) cause an active photosensitized lysis of erythrocytes regardless of the substituent's nature. The presence of exocycle (compounds 1-19) in the most cases leads to decrease in photohemolysis power and increase in its induction period.…”

Confocal fluorescence spectral imaging technique and its applications to drug development

“…These photosensitizers absorb in the 705-745 nm range, where human tissues are relatively transparent for the exciting light. Varying different substituents the CIC derivatives were found, which accumulated intensely (distribution ratio of 5-11) in cytoplasm of cancer cells in a lipid-bound monomeric photoactive form [12][13][14][15][16]. Hydrophobic substituents provided predominant accumulation of CICD in lipid droplets.…”

“…The CSI technique was successfully used in the studies of sulfonated phthalocyanines [9][10][11], cycloimide derivatives of chlorin p 6 (CIC) [12][13][14][15][16][17][18] and bacteriochlorin p (CIBC) [19]. It helped to clarify the fact that chelating with a metal atom was not essential for the efficiency of phthalocyanines in anticancer PDT [9].…”