Novel stable “sandwich” cyclodextrin inclusion of a lipophilic S-nitrosothiol for controlled delivery of nitric oxide

Nitric oxide (NO) is a versatile biological signaling molecule with applications in antimicrobial, anticancer, and cardiovascular therapies. A newly developed NO donor, S-nitroso-1-adamantane thiol (SNAT), has previously demonstrated excellent antithrombogenic and antimicrobial properties when impregnated into PVC tubing of extracorporeal circuits. However, the hydrophobicity of SNAT and its storage stability remain a major challenge for further biomedical applications. Here, we report a novel NO delivery system based on the inclusion of the highly lipophilic SNAT within hydroxypropyl-β-cyclodextrin (CD), forming a stable "sandwich" cyclodextrin inclusion complex (CD-SNAT). Spectroscopic, structural, and morphological characterization confirmed successful SNAT inclusion in the CD cavity. The CD-SNAT complex showed excellent aqueous solubility, and remarkable aqueous stability at physiological pH, even resistant to trace amounts of transition metal ions, which are detrimental to common S-nitrosothiols, like S-nitroso-N-acetyl-penicillamine. NO release could be efficiently triggered by endogenous free thiols like cysteine, or UV light. Sustained and cysteine-induced NO release from CD-SNAT was confirmed by chemiluminescence. Intracellular NO delivery from SNAT was visualized in melanoma cells in the presence of cysteine. Remarkably, the solid complex remained >90% intact after six-month storage at room temperature. Hence, CD-SNAT provides a stable, tunable, biocompatible platform for controlled NO delivery, with promising biomedical applications.