Hydrophobicity Modulation of Rose Bengal Derivatives in Homogeneous and Biomimetic Systems: Implications for...

Rose Bengal (RB) is a highly efficient xanthene photosensitizer (PS) for photodynamic therapy (PDT). However, its high hydrophilicity and dianionic charge limit its interaction with biological membranes. To overcome these limitations, we synthesized octyl- (RBOCT) and dodecyl-substituted (RBDOD) RB esters to modulate hydrophobicity while preserving the photoactive xanthene core. Solvatochromic studies based on the ET(30) polarity scale and aggregation analyses in homogeneous media demonstrated that esterification increased lipophilicity (logK _p = 0.62, 1.65, and 2.27 for RB, RBOCT, and RBDOD, respectively), induced bathochromic shifts, enhanced fluorescence in less polar environments, and promoted aggregation in aqueous media, particularly for RBDOD, without compromising singlet oxygen generation in organic solvents. RB and its derivatives were also incorporated efficiently into biomimetic micellar systems composed of SDS, CTAB, TX-100, and SB3-14, with encapsulation efficiencies above 90%, appropriate hydrodynamic diameters (6.3-17.2 nm), and low polydispersity (0.21 < PDI < 0.46). Apparent pK _a analyses in micellar systems showed that RB predominantly exists as a dianion at physiological pH, whereas the ester derivatives remain mainly monoanionic. Micellar incorporation efficiently suppressed aggregation, restored the monomeric spectral features, significantly enhanced fluorescence quantum yields, and preserved the ability of all PSs to generate singlet oxygen. TX-100 and SB3-14 provided the most favorable microenvironments for fluorescence recovery. Stern-Volmer quenching studies demonstrated that micellar charge and polarity govern PS localization and protolytic equilibria, while increasing alkyl chain length promotes deeper insertion into less polar micellar domains. Overall, modulating molecular hydrophobicity and biomimetic microenvironments tailors the photophysical behavior of RB derivatives, providing design principles for optimized PSs and nanocarrier-based PDT formulations.