Dicyanomethylene Substituted Benzothiazole Squaraines: The Efficiency of Photodynamic Therapy In Vitro and In Vivo

Abstract

The lack of ideal photosensitizers limits the clinicalapplication of photodynamic therapy (PDT). Here we report the PDT efficiency of dicyanomethylene substituted benzothiazole squaraine derivatives. This class of squaraine derivatives possess strong absorption and long excitation and emission wavelengths (ex/em, 685/720 nm). They show negligible dark toxicity, but can generate singlet oxygen under irradiation resulting in the apoptosis and necrosis of cells (phototoxicity). Changing the side chains of these compounds greatly influences their albumin-binding rate, cellular uptake and their phototoxicity. One of the squaraine derivatives with two methyl butyrate side chains shows high PDT efficiency in a mouse subcutaneous xenograft model under the irradiation of a 690 nm laser. These results show the great potential of dicyanomethylene substituted benzothiazole squaraines to be the leading compound of near-infrared photosensitizers in PDT.

Red and Near-Infrared Absorbing Dicyanomethylene Squaraine Cyanine Dyes: Photophysicochemical Properties and Anti-Tumor Photosensitizing Effects

“…Regarding the dicyanomethylene squaraine cyanine dyes shown in Figure 1, their experimental details and spectroscopic characterization were recently published by us, as fluorescent probes for protein detection [16]. However, and as far as we know, the in vitro phototherapeutic effects presented by these dyes have never been tested, nevertheless, this study is assumed to be quite pertinent, given the encouraging results of some in vitro and in vivo works already reported [24] and the scantiness of photodynamic therapy studies related to this scaffold of compounds. The fact that these dyes have shown good interaction with serum albumin [16], according to some studies [28][29][30], also makes these compounds potential photodynamic therapy photosensitizers with increased phototherapeutic efficiency.…”

“…Moreover, the diversity of possible changes in the molecular structure of this group of dyes allows the research groups to shape and control this core of compounds to exhibit different properties according to the desired application [22]. The photosensitizing potential of squaraine dyes has already been proved, both in in vitro [7,21] and in vivo studies [23,24], showing that with the appropriate substituents, the ideal properties can be obtained to act as photodynamic therapy photosensitizers.…”

“…Although the synthesis of dicyanomethylene-substituted dyes is already known [25], reports on the preparation of novel dyes from this core of compounds are still ongoing, and the results of the studies of their potential application in technological [26] and biomedical areas [16,24,27] are very encouraging. Regarding its possible use as photosensitizers, Wei et al [24] reported an in vitro and in vivo study in which this dye's scaffold presents an intense phototherapeutic activity. The squaraines bearing the dicyanomethylene functional group exhibit inherent characteristics with those of an ideal photodynamic therapy photosensitizer, since when introduced in the four-membered central ring, it is the promotor that is responsible for their phototherapeutic activity [24].…”

“…Regarding its possible use as photosensitizers, Wei et al [24] reported an in vitro and in vivo study in which this dye's scaffold presents an intense phototherapeutic activity. The squaraines bearing the dicyanomethylene functional group exhibit inherent characteristics with those of an ideal photodynamic therapy photosensitizer, since when introduced in the four-membered central ring, it is the promotor that is responsible for their phototherapeutic activity [24].…”

Synthesis, photochemical and in vitro cytotoxic evaluation of benzoselenazole-based aminosquaraines

“…Even though a significant number of different squaraine compounds have been tailored to be used as PDT photosensitizers, both the in vitro and in vivo assessment of their photodynamic action have been poorly explored. [24][25][26][27][28][29][30][31][32][33][34][35][36][37] Aminosquaraines, a particular class of cationic squaraine dyes bearing an amino group replacing one of the oxygen atoms of the central squaric ring, have previously shown to be able to produce singlet oxygen in variable quantum yields depending on the nature of the amino substituents and the degree of halogenation of both the terminal nuclei and the amino group. 21,23,38,39 The ability of aminosquaraines to generate singlet oxygen is generally much superior to that of the non-functionalized zwiterionic analogues 39 and is thought to arise from a higher degree of rigidification of the dye's structure due to the presence of a bulkier group and to possible intramolecular hydrogen bonding.…”