title: Structure-photodynamic activity relationships of substituted zinc trisulfophthalocyanines.
abstract: To identify optimal features of metalated sulfophthalocyanine dyes for their use as photosensitizers in the photodynamic therapy of cancer, we synthesized a series of alkynyl-substituted trisulfonated phthalocyanines and compared their amphiphilic properties to a number of parameters related to their photodynamic potency. Varying the length of the substituted alkynyl side-chain modulates the hydrophobic/hydrophilic properties of the dyes providing a linear relationship between their n-octanol/water partition coefficients and retention times on reversed-phase HPLC. Aggregate formation of the dyes in aqueous solution increased with increasing hydrophobicity while monomer formation was favored by the addition of serum proteins or organic solvent. Trisulfonated zinc phthalocyanines bearing hexynyl and nonynyl substituents exhibited high cellular uptake with strong localization at the mitochondrial membranes, which coincided with effective photocytotoxicity toward EMT-6 murine mammary tumor cells. Further increase in the length of the alkynyl chains (dodecynyl, hexadecynyl) did not improve their phototoxicity, likely resulting from extensive aggregation of the dyes in aqueous medium and reduced cell uptake. Aggregation was evident from shifts in the electronic spectra and reduced capacity to generate singlet oxygen. When monomerized through the addition of Cremophor EL all sulfonated zinc phthalocyanines gave similar singlet oxygen yields. Accordingly, differences in the tendency of the dyes to aggregate do not appear to be a determining factor in their photodynamic potency. Our results confirm that the latter in particular relates to their amphiphilic properties, which facilitate cell uptake and intracellular localization at photosensitive sites such as the mitochondria. Combined, these factors play a significant role in the overall photodynamic potency of the dyes.
authors.affiliation: Department of Nuclear Medicine and Radiobiology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: Cauchon
authors.forename: Hongjian
authors.initials: H
authors.lastname: Tian
authors.forename: Réjean
authors.initials: R
authors.lastname: Langlois
authors.forename: Carole
authors.initials: C
authors.lastname: La Madeleine
authors.forename: Stephane
authors.initials: S
authors.lastname: Martin
authors.forename: Hasrat
authors.initials: H
authors.lastname: Ali
authors.forename: Darel
authors.initials: D
authors.lastname: Hunting
authors.forename: Johan E
authors.initials: JE
authors.lastname: van Lier
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004396:Coloring Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use; D017484:Dermatitis, Phototoxic; D005990:Glycerol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use; D054833:Isoindoles; D015674:Mammary Neoplasms, Animal; D051379:Mice; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use; D010084:Oxidation-Reduction; D010778:Photochemotherapy; D010782:Photolysis; D017319:Photosensitizing Agents / Q000737:chemistry* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013411:Sulfadiazine / Q000737:chemistry*; D013416:Sulfamerazine / Q000737:chemistry*; D013432:Sulfathiazoles / Q000737:chemistry*; D014364:Tryptophan / Q000737:chemistry / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014867:Water / Q000737:chemistry; D017967:Zinc Compounds; D000096926:Benzenesulfonamides
chemical_list: D004396:Coloring Agents; D005990:Glycerol; D007211:Indoles; D054833:Isoindoles; D009942:Organometallic Compounds; D017319:Photosensitizing Agents; D013411:Sulfadiazine; D013416:Sulfamerazine; D013432:Sulfathiazoles; D014364:Tryptophan; D014867:Water; D017967:Zinc Compounds; C052159:Zn(II)-phthalocyanine; C011376:trisulfon; D000096926:Benzenesulfonamides; C000515:cremophor EL