Newly synthesized zinc phthalocyanine bearing sixteen quaternized imidazolyl moieties on the periphery displays high water-solubility, lack of aggregation and high singlet oxygen quantum yield in water (ΦΔ > 0.33). The in vitro tests indicated excellent anticancer photodynamic activity (EC50 = 36.7 nM) and low dark toxicity to non-cancerous cells (TC50 = 395 μM).

Novel zinc, magnesium, and metal-free octasubstituted phthalocyanine photosensitizers bearing [(triethylammonio)ethyl]sulfanyl substituents in the peripheral or nonperipheral positions were synthesized and investigated for their photophysical properties (ΦΔ value up to 0.91, λmax up to 750 nm) and photodynamic anticancer activity. The photodynamic treatment of 3T3, HeLa, SK-MEL-28, and HCT 116 cancer cells revealed that the magnesium complexes were not active (IC50 > 100 μM), whereas the IC50 values of the zinc complexes typically reached values in the submicromolar range with low toxicity in the dark (TC50 ≈ 1500 μM). The subcellular changes upon photodynamic treatment of the HeLa cells indicated that the studied photosensitizers induced damage primarily to the lysosomes, which was followed by a relocalization and damage to other organelles. The time-lapse morphological changes along with the flow cytometry and caspase activity measurements indicated a predominant involvement of necrosis-like cell death.

Anthracyclines (such as doxorubicin or daunorubicin) are among the most effective anticancer drugs, but their usefulness is hampered by the risk of irreversible cardiotoxicity. Dexrazoxane (ICRF-187) is the only clinically approved cardioprotective agent against anthracycline cardiotoxicity. Its activity has traditionally been attributed to the iron-chelating effects of its metabolite with subsequent protection from oxidative stress. However, dexrazoxane is also a catalytic inhibitor of topoisomerase II (TOP2). Therefore, we examined whether dexrazoxane and two other TOP2 catalytic inhibitors, namely sobuzoxane (MST-16) and merbarone, protect cardiomyocytes from anthracycline toxicity and assessed their effects on anthracycline antineoplastic efficacy. Dexrazoxane and two other TOP2 inhibitors protected isolated neonatal rat cardiomyocytes against toxicity induced by both doxorubicin and daunorubicin. However, none of the TOP2 inhibitors significantly protected cardiomyocytes in a model of hydrogen peroxide-induced oxidative injury. In contrast, the catalytic inhibitors did not compromise the antiproliferative effects of the anthracyclines in the HL-60 leukemic cell line; instead, synergistic interactions were mostly observed. Additionally, anthracycline-induced caspase activation was differentially modulated by the TOP2 inhibitors in cardiac and cancer cells. Whereas dexrazoxane was upon hydrolysis able to significantly chelate intracellular labile iron ions, no such effect was noted for either sobuzoxane or merbarone. In conclusion, our data indicate that dexrazoxane may protect cardiomyocytes via its catalytic TOP2 inhibitory activity rather than iron-chelation activity. The differential expression and/or regulation of TOP2 isoforms in cardiac and cancer cells by catalytic inhibitors may be responsible for the selective modulation of anthracycline action observed.

The literature reports on cationic and anionic phthalocyanines (Pcs) for photodynamic therapy suggest systematically significant differences in activity. In this work, ten different zinc(II) Pcs with carboxylate functions or quaternary nitrogens (hydrophilic anionic, hydrophilic cationic, amphiphilic anionic, and amphiphilic cationic) were investigated, with the aim of revealing reasons for such differences. In vitro assays on HeLa, MCF-7, and HCT-116 cells confirmed higher photoactivity for cationic Pcs (EC 50 ∼ 3−50 nM) than for anionic Pcs (EC 50 ∼ 0.3−10 μM), the latter being additionally significantly more active in serum-free medium. The environmental pH, binding to serum proteins, interaction with biomembranes, differences in subcellular localization, and relocalization after irradiation were found to be the main factors contributing to the generally lower photoactivity of anionic Pcs than that of the cationic derivatives. This result is not limited only to the presented derivatives and should be considered in the design of novel photosensitizers.