Investigation of Sonosensitizers Based on Phenothiazinium Photosensitizers

The main advantage of sonodynamic therapy (SDT), the combining of ultrasound with a sonosensitizer, over photodynamic therapy (PDT) is that ultrasound penetrates deeper into tissues to activate the sonosensitizer, which offers noninvasive therapy for tumors in a site-oriented approach. In this study, we synthesized two symmetrical phenothiazine derivatives in which the methyl groups of MB (methylene blue) have been replaced by a hexyl and hydroxyethyl chains, named 3,7-bis(dihexylamino)-phenothiazin-5-ium iodide (MB6C) and 3,7-bis(di(2-hydroxyethyl)amino)-phenothiazin-5-ium iodide (MBOH), respectively. We explore the efficiency differences between PDT and SDT induced by these phenothiazine derivatives based on the standard of methylene blue (MB). Spectral studies indicate that these MB analogs exhibit sonosensitization ability with a similar tendency to the photosensitization ability. This means that MB, MBOH, and MB6C can be potential photosensitizers and sonosensitizers. After biological evaluation, we conclude that compound MB6C is a potential PDT and SDT candidate because it exhibits higher uptake, efficient intracellular phototoxicity and sonotoxicity over MB and MBOH, with IC50 values of ~2.5 µM and ~5 µM, respectively.