Structure-activity relationships of three differently substituted 2,7,12,17-tetrakis-(�-methoxyethyl) porphycene derivatives in vitro

Abstract

The subcellular localization, efficacy and photooxidative mechanism of three new photosensitizing porphycenes (HexoTMPn, PeloTMPn, CpoTMPn) for photodynamic therapy with different substituents at position 9 of the tetrapyrrole macrocycle were investigated in vitro using different human skin-derived cell lines (HaCaT, SCL I, SCL II) with the aim of customizing the side-chain chemistry to accelerate cellular uptake and so enhance photodynamic activity. Cells were incubated with a porphycene and costained with organelle-specific markers. Subcellular localization was determined by fluorescence microscopy. Also, cells were incubated with different sensitizer concentrations (0-1000 nmol/l) and irradiated by an incoherent light source (lambda(em) = 600-750 nm, 40 mW/cm(2), 24 J/cm(2)) with/without quenchers or enhancers (NaN(3), histidine, mannitol or D(2)O). Cell viability was assessed. All porphycenes were localized in perinuclear lysosomes and induced a decrease in mitochondrial activity following irradiation. HexoTMPn was the most efficient in all three cell lines (EC(50) in HaCaT cells: HexoTMPn 14 nmol/l, CpoTMPn 62 nmol/l, PeloTMPn 89 nmol/l). Addition of either NaN(3) or histidine reduced the phototoxicity significantly. Due to the short lifetime of singlet oxygen, the sites of sensitizer localization are the initial subcellular targets. The cytotoxicity of each sensitizer varied depending on singlet oxygen quantum yield and cell line. Despite the different chemical structures, the biological effects were not very distinct, since they seemed to be mostly determined by the tetrapyrrole ring and only slightly modified by the substituent at position 9. Also, there was only a narrow margin between biological compatibility and efficacy.

Symposium‐in‐Print: Singlet Oxygen Invited Review

“…Consequently, the diffusion distance during the lifetime of 1 O 2 under these conditions would be around 100 nm, much longer than estimates arising from the studies using cell populations described above. These results on single cells are in agreement with results of studies where isotope effects were found for of 1 O 2 photosensitization in cells when H 2 O was replaced by D 2 O in the media (44–49). Such effects would not be expected if the 1 O 2 lifetime was limited by reaction rather than solvent‐induced deactivation.…”

Porphycenes: Facts and Prospects in Photodynamic Therapy of Cancer

“…chemical design and prediction of biological activity, only few QSAR studies on pharmacokinetics, subcellular localization, and tumor photosensitization of new PSs have been published [42, [227][228][229][230][231][232][233], and also very limited information about QSAR of porphycene PSs is available [234][235][236].…”

Current Developments in Using MESO-(TETRA) Substituted Porphyrins for PDT

“…We reported recently on a series of porphyrin and chlorin based bile acid conjugates (123)(124)(125)(126) to impart greater selectivity and specificity on the photosensitizer for the treatment of esophageal cancer. 93 Chronic esophageal exposure to bile acids in patients with gastro-esophageal reflux disease is associated with the development of Barrett's metaplasia and associated molecular markers of inflammation which have been shown to support transformation, initiation and progression of tumor development.…”

“…41). 126 HexoTMPn 187 127 The triplet (Φ T = 0.33) and singlet oxygen (Φ Δ = 0.23) quantum yields of the former are comparable to that of other porphycenes, but much lower in comparison to the porphyrin isomer TPP (Φ Δ = 0.68). In the case of 191, fluorescence is inhibited by the internal heavy-atom effect and the triplet and singlet oxygen quantum yields are enhanced (Φ T = Φ Δ = 0.78).…”