Ethanol-Responsive Fluorene-based Fluorescent Nanoprobes for Photodynamic Cancer Therapy

Abstract

Ethanol-responsive fluorophores represent a promising tool for early diagnosis of selected cancers owing to ethanol accumulation within cancer cells due to Warburg effect. Herein, we report a series of fluorene-based nanoprobes containing imine bonds for facile hydrogen bond interactions with ethanol. Fluorenes with small S₁-T₁ gaps can generate singlet oxygen with high quantum yields upon suitable substitution, facilitating ethanol-responsive synergic diagnosis and photodynamic therapy of cancers. In this study, fluorene-Schiff bases with versatile substituents are synthesized following the environment-friendly ultrasonication method. Schiff-bases containing electron-donating groups like methoxy and heterocyclic moieties like benzothiazole showed prominent fluorescence response with almost 3000-fold increase in emission intensity in the presence of ethanol with a low detection limit (10.6 µL) and extraordinary selectivity compared to other competitive alcohols. The nanoprobes afforded higher singlet oxygen quantum yield than the bulk compounds. Density functional theory calculations corroborated the substituent effect on the electronic properties of fluorene-Schiff base derivatives. Ground-state optimization of fluorene derivatives in different solvents using the polarizable continuum model (PCM) establishes the ethanol-selective fluorescence response. In vitro studies in colon cancer cell (CT-26) revealed 20% cell viability in the presence of 100 µM of fluorene nanoprobe under irradiation for 10 min at ≥410 nm.