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.

An amphiphilic ruthenium(II)–polypyridyl appended porphyrin as potential bifunctional two-photon tumor-imaging and photodynamic therapeutic agent

“…4a). The rapid uptake by the cells can be explained by the amphiphilic properties of Ru-P which facilitate its cell membrane penetration [27][28][29][30][31]. The results are in consonant with the recent observation that adjusting the hydrophobic/hydrophilic balance of the Ru(II)-polypyridyl complex can enhance its cellular uptake [48][49][50].…”

“…Currently, most research work focused on the design of water-soluble photosensitizers with large intrinsic 2PA cross-sections for in vitro studies [21][22][23][24]. However, the contributions of other crucial properties, including high cellular uptake by tumor cells, high singlet oxygen quantum yield, subcellular localization and good luminescent properties for tumor-imaging in a ''see and treat" approach to PDT [17][18][19][20], have not been adequately explored in 2PA-PDT as in one-photon PDT (1PA-PDT) [27][28][29][30][31]. Recently, Anderson and coworkers has synthesized a series of ionic conjugated porphyrin dimers with 2PA crosssections up to 17,000 GM and exhibiting substantial 2PA-PDT and cell imaging properties [32][33][34].…”

“…To accomplish this goal, an amphiphilic porphyrin with an appropriate hydrophobic/hydrophilic balance, shown to be crucial for cellular uptake [20,[27][28][29][30][31], was designed ( Fig. 1) with the tetraphenylporphyrin (H 2 TPP) and its cationic Ru(II)-polypyridyl appendage acts, respectively, as the hydrophobic and the hydrophilic ends.…”

Cyclic voltammetry and spectroelectrochemistry of a novel manganese phthalocyanine substituted with hexynyl groups

“…The presence of electron donating groups results in the shift of the Q band to longer wavelengths. Alkynyl substituted MPc complexes are known [6][7][8][9]; they were found to be more soluble in common organic solvents (such as dichloromethane, chloroform and tetrahydrofuran) when compared with alkylthiophthalocyanines [7]. MPc complexes containing Mn as a central metal show a highly red-shifted Q band [10].…”

“…MPc complexes containing Mn as a central metal show a highly red-shifted Q band [10]. The alkyne substituted MPc complexes reported in the literature so far are either unmetallated or contain electrochemically inactive central metals such as Cu or Zn [6][7][8][9]. Also alkyne substituted MPc complexes containing a long alkyl chain and which terminate with a triple bond carbon are unknown.…”