Thiophene BODIPY-substituted cyclotriphosphazene-derived photosensitizers for photodynamic therapy applications

Abstract

Cancer is one of the most important health problems that people are facing today. Photodynamic therapy (PDT) is regarded as a promising approach for cancer treatment based on the interaction of a photosensitizer and laser light of appropriate wavelength in the presence of molecular oxygen to generate reactive oxygen species which ultimately leads to cancer cell death. Numerous studies have been conducted to design novel PDT agents with improved photophysical and photochemical parameters including stability, absorption in the therapeutic window, high purity and singlet oxygen quantum yields, and minimal or no dark cytotoxicity. However, some of these photosensitizers suffer from a number of drawbacks such as low purity and toxicity. Thus, the present study aims to design, synthesize and characterize novel cyclotriphosphazene-based PDT agents branched with hydrophilic units for biocompatibility and decorated with BODIPY units for singlet oxygen generation for the first time. For this aim, halogenated and halogen-free BODIPY precursors (6–8) and their cyclotriphosphazene derivatives (11–13) were synthesized and then their structural characterization was performed using spectroscopic techniques. The maximum absorption of halogenated derivatives showed a redshift of about 20 nm compared with halogen-free derivatives; and furthermore, the halogenated derivatives exhibited weaker fluorescence characteristics. The singlet oxygen generation ability of the molecules was determined using the photobleaching technique of 1,3-diphenylisobenzofuran (DPBF) and (methylene)dimalonic acid (ABDA) under light illumination. The introduction of halogen atoms into the molecules promoted the intersystem crossing (ISC) process resulting in increased singlet oxygen generation. Importantly, preliminary PDT evaluation on cell lines proved the success of PDT agents for light-dependent cell death in vitro although the agents cannot be internalized by the cells, proposing these compounds for further clinical studies.