Subphthalocyanines as Efficient Photosensitizers with Nanomolar Photodynamic Activity against Cancer Cells

Abstract

Because cancer is the second leading cause of death globally, investigation of new photosensitizers for photodynamic therapy is highly desirable. In this work, different peripherally substituted subphthalocyanines (SubPcs) with either a benzocrown moiety (CE-) or a tyrosine methyl ester (Tyr-) as the axial ligand have been prepared. Target SubPcs showed high Φ Δ values, >0.50 in EtOH. Both CE-and Tyr-moieties increased substantially the hydrophilicity of the compounds (log P = 1.79−2.63, noctanol/PBS). Uptake to cells, subcellular localization, and monitoring of the progression of cell death over time are described. Improved spectroscopic behavior of the CE-series in cell culture medium resulted in higher photodynamic activity versus that of the Tyr-series. In particular, the peripherally triethylsulfanyl SubPc-CE exhibited extraordinarily low EC 50 values of 2.3 and 4.4 nM after light activation and high TC 50 values of 14.49 and 5.25 μM (i.e., dark toxicity without activation) on SK-MEL-28 and HeLa cells, respectively, which rank it among the best photosensitizers ever.

Recent advances in subphthalocyanines and related subporphyrinoids

“…Very recently, Novakova, Martínez-Díaz and Torres reported an insightfully study exploring the impact of axial and peripheral substitution on the optical properties and photodynamic activity of SubPcs. 479 In this work, the authors prepared SubPcs axially functionalized with tyrosine methyl ester (Tyr) or benzo-18-crown-6 (CE), and peripherally functionalized with alkylsulfanyl groups or halogen atoms, such as fluorine or iodine. Importantly, these axial ligands were found to improve the hydrophilic properties of SubPcs.…”

Glycosylated BODIPY- Incorporated Pt(II) Metallacycles for Targeted and Synergistic Chemo-Photodynamic Therapy

“…These BODIPY building blocks were then used to prepare the metallacycles 1 and 2 according to the previously described procedure for the preparation of related metallacycles. 27 Compound 3 or 4 was treated with a stoichiometric amount of Pt(PEt 3 ) 2 (OTf) 2 (11) in CH 2 Cl 2 /MeCN (4:1 v/v) in a sealed tube at 60 °C for 24 h. The resulting supramolecular complexes were isolated by the addition of diethyl ether to induce precipitation, followed by filtration, and drying in vacuo. The successful formation of the metallacycles was confirmed by a combination of spectroscopic techniques.…”

“…Owing to their singular photochemical and structural characteristics, porphyrinoid-based derivatives − have been extensively studied as PS for PDT in clinical and preclinical studies, and some of them (e.g., Visudyne and Photofrin) have already been approved by the U.S. Food and Drug Administration (FDA) for their use in cancer therapy . Several synthetic porphyrinoids (commonly called second-generation PS), which include synthetic porphyrins, , phthalocyanines, − and boron dipyrromethene (BODIPY) derivatives , have been developed as PS over the years. Some of them have already been approved for the treatment of certain cancers or clinical trials.…”

Synthesis, Optical Properties, and Fluorescence Cell Imaging of Novel Mixed Fluorinated Subphthalocyanines

“…After incubation for 4 h, the cells were washed three times with PBS; the lysosomes and nuclei were then stained with LysoTracker Green DNA-26 (1 μg/mL) (Thermo Fisher Scientific) and Hoechst 33342 (1 μg/mL) for 30 min (Thermo Fisher Scientific). The staining was removed by washing with PBS buffer, and the solutions were then magnified using the 100× objective of an inverted fluorescence microscope and captured using the corresponding fluorescence channel [ 8 , 40 , 41 ].…”

“…In contrast to Pcs, the smaller central cavity of SubPcs is occupied by a tetrahedral boron atom and has an axial substituent, making them more polar and less aggregative [ 2 , 3 , 4 ]. In addition, a smaller π-electron conjugated system and cone structure make SubPcs possess excellent optical and electrochemical properties, which have been explored and applied in various fields, such as organic photovoltaics (OPVs) [ 5 , 6 ], photodynamic therapy (PDT) photosensitizers [ 7 , 8 , 9 ], and fluorescent ion probes [ 10 , 11 , 12 ]. Based on these structure–property relationships, the properties of SubPcs can be easily modified by peripheral substitution, axial replacement [ 13 , 14 ], or inner core modification [ 15 , 16 ].…”