Glycol Porphyrin Derivatives as Potent Photodynamic Inducers of Apoptosis in Tumor Cells

Abstract

The design and synthesis of glycol-functionalized porphyrins that contain one to four low molecular weight glycol chains that are linked via ether bonds to the meta-phenyl positions of meso-tetraphenylporphyrin and the comparison of fluorinated and nonfluorinated para derivatives are reported. The cellular uptake and photodynamic activity significantly depend on terminal groups of the glycol substituent. Hydroxy glycol porphyrins, in contrast with methoxy glycol porphyrins, show efficient intracellular transport and a high induction of apoptosis in tumor cell lines in vitro . Furthermore, the ethylene glycol chain at the meta position exhibits a superior efficacy that leads to the permanent ablation of human breast carcinoma (MDA-MB-231) in nude mice. In addition, fluorination enhanced the photosensitizing potential of para-phenyl derivatives. The analysis of the cell-death mechanism revealed that glycol-functionalized porphyrins represent novel nonmitochondrially localized photosensitizers that have a profound ability to induce apoptosis in tumor cells that act upstream of caspase activation. The strong interaction with a tumor marker (sialic acid) indicates the preferential association of these compounds with tumor cells.

Glycol porphyrin derivatives and temoporfin elicit resistance to photodynamic therapy by different mechanisms

“…In some cases, aggregation merely diminishes the activity of the PS, whereas with others it may change its mechanisms of action38. The tetra-ethylene glycol derivatives were originally prepared in our laboratory to improve solubility1819. The improvement in solubility might be the reason for their higher PDT efficacy in comparison to temoporfin.…”

“…Synthesis and elemental analysis of the porphyrin derivatives KP1 (meta-ethyleneglycol-tetraphenyl porphyrin), KP6 (para-ethyleneglycol-tetraperfluorophenyl porphyrin) and temoporfin (meta-hydroxy-tetraphenyl chlorin) was performed at the University of Chemistry and Technology, Prague and have been described elsewhere18. Photofrin (Axcan Pharma International, Sittard, NL) was used as a control.…”

“…The structure of PS, a feature assumed to be related to its particular subcellular localization2, is believed to be a key factor in the development of resistance. To investigate this issue, we selected two glycol porphyrin derivatives with diverse intracellular localization, KP1 and KP6, which were prepared in our laboratory as compound 2 and compound 6, respectively18. These two particular derivatives were specifically chosen for the study of PDT resistance mechanisms because as neutral and highly water-soluble glycol porphyrin derivatives are known to be very potent inducers of apoptosis in tumor cells and exhibit a high potential for in vivo PDT applications.…”

“…These two particular derivatives were specifically chosen for the study of PDT resistance mechanisms because as neutral and highly water-soluble glycol porphyrin derivatives are known to be very potent inducers of apoptosis in tumor cells and exhibit a high potential for in vivo PDT applications. Moreover, in spite of their chemical structural similarity, they are varied in both intracellular localization and apoptosis-triggering mechanism1819. The differences between the KP1 and KP6 derivatives can be found in the position of their ethylene glycol chains which are linked via ether bonds to either meta- or para-phenyl positions of meso-tetraphenylporphyrin, respectively.…”

Fluorinated porphyrinoids as efficient platforms for new photonic materials, sensors, and therapeutics

“…7). 45 In their study they substituted O -glycols and aminoethanol on the TPPF 20 . The DMF solvent and the NaH base were used to substitute the O -glycols.…”