Novel Bioinspired Quercetin-Based Polymers for the Sustained Release of Donepezil in Alzheimer’s Disease Therapy

This work was inspired by quercetin, a natural bioflavonoid with well-known neuroprotective properties. We synthesized a new functional monomer, 3-acryloxy-3',4',5,7-tetramethylquercetin <b>1</b>, and used it to prepare, for the first time, a molecularly imprinted polymer (MIP) selective for donepezil, the main drug used in Alzheimer's disease therapy. The polymer was designed to be fluorescent and responsive to pH changes, aiming for controlled drug release. The optimized <b>MIP-4</b>, produced from a 1:1 mixture of the monomer <b>1</b> and acrylic acid, was characterized by FTIR-ATR, fluorescence spectroscopy, SEM, and DLS, confirming its chemical composition, morphology, particle size distribution and zeta potential. Adsorption studies showed higher donepezil binding capacity for MIP than for NIP, highlighting the polymer's selective recognition. In vitro release experiments at pH 3, 5.5, and 7 revealed a pH-dependent behaviour, with nearly 98% cumulative donepezil release at pH 7. The polymer was non-cytotoxic and successfully released donepezil in <i>in vitro</i> assays, enabling effective inhibition of <i>ee</i>AChE. These results provide a proof of concept supporting the potential of quercetin-derived fluorescent molecularly imprinted polymers as selective and stimuli-responsive platforms for donepezil delivery.