Acetaminophen (ACP), as an antipyretic and analgesic drug, can cause hepatotoxicity and nephrotoxicity when it is used with alcohol or other medications, and its metabolites can accumulate in aquatic environments and result in aquatic toxicity, so it is necessary to address the need for rapid, selective, and sensitive detection of ACP to mitigate its ecological impact. A novel molecularly imprinted silica modified-CdTe QDs composite (Si-CdTe@MIPs) was synthesized via the sol-gel technique for ultraselective detection of ACP for the first time. Under optimized conditions, the Si-CdTe@MIPs nanoprobe showed excellent linear behavior in the ACP concentration range of 0.21–10 μM (R2 = 0.998) with high sensitivity (LOD 62.5 nM) and the imprinting factor reached (IF = 8.1). The response time was 5 min, and the fluorescence detection mechanism of Si-CdTe@MIPs was proposed to be electron/charge transfer and static process. The sensor demonstrated good reproducibility (RSD of 2.61%) and exceptional stability. The bonding of ACP and its analogs with the Si-CdTe@MIPs sensor was optimized, respectively, by employing DFT simulations, and the developed Si-CdTe@MIPs sensor showed excellent selectivity and anti-interference ability in the presence of analogs. The satisfactory recoveries of 95.18 to 107.18% were achieved with precision below 2.70% for ACP analysis in aqueous media. The resultant Si-CdTe@MIPs offered a facile approach for the rapid and sensitive analysis of ACP in complex water matrices.
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