Reduction of non-specific binding in molecularly imprinted polymers via covalent surface functionalization: Smartphone-assisted colorimetric biosensor for sulfamethoxazole detection as case study

Non-specific adsorption remains one of the main challenges limiting the specificity of molecularly imprinted polymers (MIPs). It arises from unintended interactions between the polymer matrix and non-target molecules, often due to surface functional groups located outside cavities. Achieving high selectivity in MIPs requires both rational monomer selection and effective strategies to reduce non-specific adsorption. In this study, density functional theory (DFT) calculations were used to select methacrylic acid (MAA) as the optimal monomer for sulfamethoxazole (SMX), based on favorable binding energy. While DFT ensured strong monomer-template interactions, two covalent hydrophobic surface modification strategies, using octadecylamine (OD) and oleic acid (OA), were explored to reduce non-specific binding. The OD modification, which acts through the covalent coupling with the monomer functional groups, effectively reduced the non-specific binding but exhibited limited versatility, as its performance depends on the chemical functionality of the chosen monomer. In contrast, the OA modification, involving the reaction of the vinyl moiety of the monomer, present in most monomers used for radical polymerization, proved to be more general and stable, yielding the MIP@OA material with improved performance. The OA-modified MIP exhibited significantly higher selectivity and adsorption capacity toward SMX, while minimal binding was observed for NIP@OA and for structurally related analogs of SMX. A linear range between 0.1 and 5 μg mL-1, with a low detection limit of 0.03 μg mL−1, was achieved. This combined DFT-guided monomer selection and OA-based surface modification offer a robust, versatile strategy to reduce non-specific binding and create MIPs with enhanced recognition and stability.