Tailoring Electrode Surface Charge to Achieve Discrimination and Quantification of Chemically Similar Small Molecules with Electrochemical Aptamers

Electrochemical biosensors based on structure‐switching aptamers offer many advantages because they can operate directly in complex samples and offer the potential to integrate with miniaturized electronics. Unfortunately, these biosensors often suffer from cross‐reactivity problems when measuring a target in samples containing other chemically similar molecules, such as precursors or metabolites. While some progress has been made in selecting highly specific aptamers, the discovery of these reagents remains slow and costly. In this work, a novel strategy is demonstrated to distinguish molecules with miniscule difference in chemical composition (such as a single hydroxyl group)—with cross reactive aptamer probes—by tuning the charge state of the surface on which the aptamer probes are immobilized. As an exemplar, it is shown that the strategy can distinguish between DOX and many structurally similar analytes, including its primary metabolite doxorubicinol (DOXol). Then the ability to accurately quantify mixtures of these two molecules based on their differential response to sensors with different surface‐charge properties is demonstrated. It is believed that this methodology is general and can be extended to a broad range of applications. A novel strategy is demonstrated to distinguish molecules with miniscule physicochemical differences by tuning the surface charge of an interface on which cross‐reactive aptamer probes are immobilized. As an exemplar, the method is applied to distinguish between doxorubicin and many structural analogs. This strategy eliminates the need for exquisitely selective aptamers by instead modulating the signal transduction to obtain specificity