Assessment of Water-Soluble π-Extended Squaraines as One- and Two-Photon Singlet Oxygen Photosensitizers:  Design, Synthesis, and Characterization

Abstract

Singlet oxygen sensitization by organic molecules is a topic of major interest in the development of both efficient photodynamic therapy (PDT) and aerobic oxidations under complete green chemistry conditions. We report on the design, synthesis, biology, and complete spectroscopic characterization (vis-NIR linear and two-photon absorption spectroscopy, singlet oxygen generation efficiencies for both one- and two-photon excitation, electrochemistry, intrinsic dark toxicity, cellular uptake, and subcellular localization) of three classes of innovative singlet oxygen sensitizers pertaining to the family of symmetric squaraine derivatives originating from pi-excessive heterocycles. The main advantage of pi-extended squaraine photosensitizers over the large number of other known photosensitizers is their exceedingly strong two-photon absorption enabling, together with sizable singlet oxygen sensitization capabilities, for their use at the clinical application relevant wavelength of 806 nm. We finally show encouraging results about the dark toxicity and cellular uptake capabilities of water-soluble squaraine photosensitizers, opening the way for clinical small animal PDT trials.

A novel fluorescent molecule based on 1,8-naphthalimide: synthesis, spectral properties, and application in cell imaging

“…The water solubility of MEBN is good. It was accordingly possible to directly employ a 0.9% saline solution of the dye without use of any solubilizing agent such as CrEL (polyoxyethylene castor oil) [11]. Cells were incubated at room temperature for 2 h and were then washed with aqueous PBS solution to remove excess unbound dye.…”

Photophysical properties and intracellular imaging of water-soluble porphyrin dimers for two-photon excited photodynamic therapy

“…Photodynamic therapy (PDT) is a light-activated treatment which is 25 used in the clinic to destroy diseased tissues, 1,2 and is in trials for the eradication of localised bacterial infections. 3 PDT drugs (or photosensitisers) achieve their therapeutic effect by generating a cytotoxic species in the presence of light, by either electron-transfer (Type I) or energy-transfer (Type II) processes.…”

Pyrrolyl Squaraines–Fifty Golden Years

“…Fluorescence in the soluble pyrrole-derived polysquaraines has been useful in the investigation of these materials as molecular sensors [16,18,34,70]. Their optical properties have also lead to recommendations that they are suitable candidates for photodynamic therapy (PDT) [25,32].…”

“…Reports of large third-order susceptibilities, based on the observance of large two-photon absorption cross-sections, have continued [29]. Other studies have been undertaken that just concentrate on the large two-photon absorption cross-sections that pyrrolyl squaraine dyes exhibit [32,33,52,55,66]. Following the discovery that symmetrical bis(anilino)squaraine dyes exhibit second-order nonlinear optical effects as Langmuir-Blodget deposited monolayers on hydrophilic glass slides [93], results for a range of pyrrolyl squaraines were similarly reported [11,13,14].…”

“…In the pyrrolyl squaraine literature there appear to be no extensive studies measuring toxicity although some evidence can be inferred from the studies where the molecules have been studied with biological entities. In the second of the two studies aimed at PDT [25,32] there is mention of a simple cellular toxicity assay where no effect was reported and cellular uptake studies proceeded. Preliminary bacterial culture experiments, which preceded model porous pavement studies [27], showed that PMPS particles were non-inhibiting to bacterial growth.…”