Ultrasensitive Breath Analysis of Lung Cancer Biomarkers Using a Carboxyl-Functionalized Hyper-cross-linked Polymer–Based SPME Coupled with GC─MS

Vollständiger Abstract

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Abstract Exhaled breath analysis offers a noninvasive route for disease screening, yet its practical implementation is constrained by ultratrace analyte levels, high humidity, and limited selectivity of existing enrichment materials. Herein, we report the rational design of a carboxyl-functionalized hyper-cross-linked polymer (HCPs-COOH) as a high-performance solid-phase microextraction (SPME) coating and its integration into a two-step preconcentration workflow for breath analysis. The HCPs-COOH exhibits an ultrahigh specific surface area (1916 m2 g–1) and hierarchical micromesoporosity, enabling high-capacity uptake and rapid mass transfer. Surface carboxyl (−COOH) groups introduce specific interactions (hydrogen bonding and dipole–dipole), while the hydrophobic framework mitigates water interference, collectively enhancing affinity and selectivity toward diverse volatile organic compounds (VOCs) classes. Coupling Tenax-TA adsorption tube sampling with solvent elution and headspace HCPs–COOH–SPME, followed by GC–MS detection, affords a sensitive and robust method for the simultaneous determination of five lung cancer-related biomarkers. The method achieved limits of quantification of 0.10–0.21 pg mL–1, excellent precision, and high enrichment factors up to 5304. Compared with commercial fibers and reported approaches, the HCPs-COOH coating provides faster equilibration, higher enrichment efficiency, and improved tolerance to humid matrices. Application to exhaled breath samples from lung cancer patients and healthy volunteers reveals consistently elevated levels of all five biomarkers in the patient group, demonstrating clear discriminative capability. This work establishes a versatile, cost-effective platform that integrates high-capacity adsorption with selective SPME enrichment, providing a powerful strategy for ultrasensitive breathomics and advancing the clinical translation of noninvasive cancer screening.