Influence of substitutions on asymmetric dihydroxychlorins with regard to intracellular uptake, subcellular localization and photosensitization of Jurkat cells.
The search for new efficient sensitizers for photodynamic therapy (PDT) points to improve photophysical properties like absorption in the red region and singlet oxygen quantum yield as well as to control the localization of the sensitizer within the tumour cell. Depending on their physicochemical properties and their uptake mechanism, sensitizers can reach different intracellular concentrations and localize in different subcellular compartments. Moreover, the preferential localization of a sensitizer in target organelles, like mitochondria or lysosomes, could determine the cell death mechanism after PDT. This study aimed to investigate the influence of substitutions on dihydroxychlorins with regard to intracellular uptake, subcellular localization and cell death pathway. Moreover, the effect of a liposome-based delivery system was tested. The intracellular uptake was found to be strictly dependent on the sensitizer molecular structure and the means of its delivery. The most polar sensitizer in this study (compound 3) had, depending on incubation time, an intracellular concentration 2-8 times higher than the unsubstituted chlorin 1. All investigated photosensitizers localize predominantly in lysosomes but after longer incubation times weak fluorescence intensity was also detected in mitochondria and Golgi apparatus. The cell death pathway was found to be influenced by the sensitizer intracellular concentration and the applied light doses. In general, the increasing amphiphilicity of the sensitizer molecules is correlated with an increased sensitizer uptake and an increased rate of necrotic cells after irradiation.
Rancan
Fiorenza
F
Institut für Physik, Photobiophysik, Humboldt Universität, Newtonstr. 15, D-12489 Berlin, Germany.
Wiehe
Arno
A
Nöbel
Maria
M
Senge
Mathias O
MO
Omari
Saleh Al
SA
Böhm
Fritz
F
John
Matthias
M
Röder
Beate
B
D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport; D006801:Humans; D006878:Hydroxides / Q000737:chemistry*; D019169:Jurkat Cells; D015394:Molecular Structure; D009336:Necrosis; D010743:Phospholipids / Q000378:metabolism; D017319:Photosensitizing Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D011166:Porphyrins / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity; D013237:Stereoisomerism
D006878:Hydroxides; D010743:Phospholipids; D017319:Photosensitizing Agents; D011166:Porphyrins; C006969:chlorin; C031356:hydroxide ion