Ethanol-responsive fluorene-based fluorescent nanoprobes for photodynamic cancer therapy

Abstract

Ethanol-responsive fluorophores represent a promising tool for the early diagnosis of selected cancers owing to ethanol accumulation within cancer cells due to the 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 an environment-friendly ultrasonication method. Schiff bases containing electron-donating groups, like methoxy, and heterocyclic moieties, like benzothiazole, showed prominent fluorescence responses, with almost 3000-fold increase in emission intensity in the presence of ethanol, a low detection limit (10.6 µL) and extraordinary selectivity compared with other competitive alcohols. The nanoprobes afforded higher singlet oxygen quantum yields than the bulk compounds. Density functional theory calculations corroborated the substituent effect on the electronic properties of fluorene-Schiff base derivatives. The ground-state optimization of fluorene derivatives in different solvents using the polarizable continuum model (PCM) established the ethanol-selective fluorescence response. In vitro studies in colon cancer cells (CT-26) revealed 20% cell viability in the presence of 100 µM of the fluorene nanoprobe under irradiation for 10 min at ≥410 nm.