Rational Design of a Dual-Mode Optical and Chemical Prodrug

Purpose The purpose of this study is to demonstrate the rational design and behaviour of the first dual-mode optical and chemical prodrug, exemplified by an acetyl salicylic acid-based system.Methods A cyclic 1,4-benzodioxinone prodrug was synthesised by reaction of 3,5-dimethoxybenzoin and acetyl salicoyl chloride with pyridine. After purification by column chromatography and recrystallization, characterization was achieved using infrared and NMR spectroscopies, mass spectrometry, elemental analysis and single crystal X-ray diffraction. Light-triggered drug liberation was characterised via UV-visible spectroscopy following low-power 365 nm irradiation for controlled times. Chemical drug liberation was characterised via UV-visible spectroscopy in pH 5.5 solution.Results The synthetic method yielded pure prodrug, with full supporting characterisation. Light-triggered drug liberation proceeded at a rate of 8.30 × 10⁻² s⁻¹, while chemical, hydrolytic liberation proceeded independently at 1.89 × 10⁻³ s⁻¹. The photochemical and hydrolytic reactions were both quantitative.Conclusions This study demonstrates the first rational dual-mode optical and chemical prodrug, using acetyl salicylic acid as a model, acting as a paradigm for future dual-mode systems. Photochemical drug liberation proceeds 44 times faster than chemical liberation, suggesting potential use in drug-eluting medical devices where an additional burst of drug is required at the onset of infection.