Photodynamic activity of substituted zinc trisulfophthalocyanines: role of plasma membrane damage.
We recently reported that variations in cellular phototoxicity among a series of alkynyl-substituted zinc trisulfophthalocyanines (ZnPcS3Cn) correlates with their hydrophobicity, with the most amphiphilic derivatives showing the highest cell uptake and phototoxicity. In this study we address the role of the plasma membrane in the photodynamic response as it relates to the overall hydrophobicity of the photosensitizer. The membrane tracker dye 1-[4(trimethylamino)phenyl]-6-phenylhexa-1,3,5-triene (TMA-DPH), which is incorporated into plasma membranes by endocytosis, was used to establish plasma membrane uptake by EMT-6 cells of the ZnPcS3C, by colocalization, and TMA-DPH membrane uptake rates after photodynamic therapy were used to quantify membrane damage. TMA-DPH colocalization patterns show plasma membrane uptake of the photosensitizers after short 1 h incubation periods. TMA-DPH plasma membrane uptake rates after illumination of the photosensitizer-treated cells show a parabolic relationship with photosensitizer hydrophobicity that correlates well with the phototoxicity of the ZnPcS3C,. After a 1 h incubation period, overall phototoxicity correlates closely with the postillumination rate of TMA-DPH incorporation into the cell membrane, suggesting a major role of plasma membrane damage in the overall PDT effect. In contrast, after a 24 h incubation, phototoxicity shows a stronger but imperfect correlation with total cellular photosensitizer uptake rather than TMA-DPH membrane uptake, suggesting a partial shift in the cellular damage responsible for photosensitization from the plasma membrane to intracellular targets. We conclude that plasma membrane localization of the amphiphilic ZnPcS3C6-C9 is a major factor in their overall photodynamic activity.
Cauchon
Nicole
N
Department of Nuclear Medicine and Radiobiology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada.
Nader
Moni
M
Bkaily
Ghassan
G
van Lier
Johan E
JE
Hunting
Darel
D
D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005708:Gallium / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D007211:Indoles / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008958:Models, Molecular; D009942:Organometallic Compounds / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D010778:Photochemotherapy
D007211:Indoles; D009942:Organometallic Compounds; C065939:gallium trisulfophthalocyanine; D005708:Gallium