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A smartphone-based, calibration-free Nafion-modified SPCE electrochemical sensor for clinical validation of 6-thioguanine in erythrocyte lysate and serum
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DOI：10.1016/j.bios.2026.119014.png)
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Abstract
En 中文
The immunosuppressive prodrugs azathioprine and 6-mercaptopurine necessitate therapeutic drug monitoring of their active metabolite, 6-thioguanine (6-TG), due to their narrow therapeutic window and substantial risk of severe adverse effects. Conventional chromatographic techniques are accurate but impractical for point-of-care (POC) applications. Conversely, existing electrochemical sensors, despite their widespread use, suffer from an over-reliance on nanomaterial modifications to enhance analytical performance and face persistent challenges associated with calibration. This work resolves a long-standing knowledge gap by providing the first experimental validation of the 6-TG redox mechanism on a Nafion-modified screen-printed carbon electrode (SPCE). Through dithiothreitol intervention and electrochemical kinetic analysis, we confirm that 6-TG oxidation proceeds via a disulfide bond-mediated, four-electron, four-proton multi-step pathway. Critically, elucidation of this mechanism reveals a consistent kinetic framework, which directly inspires a universal-slope (US) calibration-free strategy wherein the calibration slope becomes a stable parameter, obviating frequent recalibration for POC applications. Leveraging this mechanistic insight, we constructed a smartphone-assisted electrochemical sensor on the same Nafion/SPCE platform for on-site detection of 6-TG in erythrocyte lysate and serum. The sensor exhibits a linear response from 0.1 to 15 μM in erythrocyte lysate, effectively covering the clinically relevant therapeutic window, alongside excellent selectivity and reproducibility. Clinical validation using 50 patient samples demonstrates strong agreement with high-performance liquid chromatography results, and the US method yields outcomes statistically equivalent to those obtained via the standard addition approach. By resolving the redox mechanism and translating this insight into a calibration-free POC sensor, this work offers a clinically deployable solution for personalized thiopurine therapy.
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