Molecularly imprinted polymer nanoparticles-based electrochemical chemosensors for selective determination of cilostazol and its pharmacologically active primary metabolite in human plasma.

Molecularly imprinted polymer (MIP) nanoparticles-based differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS) chemosensors for antiplatelet drug substance, cilostazol (CIL), and its pharmacologically active primary metabolite, 3,4-dehydrocilostazol (dhCIL), selective determination in human plasma were devised, prepared, and tested. Molecular mechanics (MM), molecular dynamics (MD), and density functional theory (DFT) simulations provided the optimum structure and predicted the stability of the pre-polymerization complex of the CIL template with the chosen functional acrylic monomers. Moreover, they accounted for the MIP selectivity manifested by the molecularly imprinted cavity with the CIL molecule complex stability higher than that for each interference. On this basis, a fast and reliable method for determining both compounds was developed to meet an essential requirement concerning the personalized drug dosage adjustment. The limit of detection (LOD) at the signal-to-noise ratio of S/N = 3 in DPV and EIS determinations using the ferrocene redox probe in a "gate effect" mode was 93.5 (±2.2) and 86.5 (±4.6) nM CIL, respectively, and the linear dynamic concentration range extended from 134 nM to 2.58 µM in both techniques. The chemosensor was highly selective to common biological interferences, including cholesterol and glucose, and less selective to structurally similar dehydroaripiprazole. Advantageously, it responded to dhCIL, thus allowing for the determination of CIL and dhCIL together. The EIS chemosensor appeared slightly superior to the DPV chemosensor concerning its selectivity to interferences. The CIL DPV sorption data were fitted with Langmuir, Freundlich, and Langmuir-Freundlich isotherms. The determined sorption parameters indicated that the imprinted cavities were relatively homogeneous and efficiently interacted with the CIL molecule.