[Applications of molecularly imprinted solid-phase microextraction coupled with chromatography/mass spectrometry for determination of drug residues].

Drugs play an indispensable role in the fields of medicine， agriculture， and animal husbandry. However， their long-term and improper use may lead to drug residues in food， the environment and organisms， posing a potentially serious threat to human health and the ecological environment. For instance， antibiotic residues may induce bacterial resistance， pesticide residues may cause neurotoxicity， and hormone drugs may interfere with the endocrine system. Therefore， developing sensitive and accurate detection methods for drug residues has become an important prerequisite and current hot topic in drug research. Meanwhile， the complicated matrices and low contents of the residues make it necessary for the widely used chromatography/mass spectrometry （MS） determination technologies to be coupled with efficient sample pretreatment procedures. Molecularly imprinted solid-phase microextraction （MI-SPME） technology combines the rapidity， high efficiency and solvent-free characteristics of SPME， and the specific recognition and selective adsorption capabilities of molecularly imprinted polymers （MIPs）， and shows significant advantages in the highly selective separation and enrichment of drug residues in complex samples. In recent years， the MI-SPME technology has become a research hotspot in the field of drug residue detection.This work systematically reviews the research progress since 2019 on the application of MI-SPME coupled with chromatography/MS in drug residue detection across food safety， environmental monitoring and biomedical fields. First， this work introduces in detail on the working principle and operation process of SPME technology. SPME achieves efficient enrichment of target analytes through the selective adsorption of the stationary phase-coated fibers， offering simplicity， speed， minimal solvent use， and compatibility with analytical instruments such as chromatography/MS.Next， the review focuses on elaborating the preparation methods and new technologies and strategies of MIPs. The traditional methods for preparing MIPs mainly include free radical polymerization， in-situ polymerization and sol-gel methods. However， traditional MIPs have defects such as template leakage risk， limited binding ability， and irregular material morphology， which restrict the application range. To this end， researchers have developed a series of novel preparation technologies and strategies， such as surface imprinting， nanoimprinting， dummy template imprinting， multi-template imprinting， multifunctional monomer imprinting and stimulus-response imprinting. These technologies and strategies have significantly enhanced the recognition and enrichment ability of MIPs for trace drug residues in complex samples by optimizing their structures and performances.To meet the requirements of different sample types and analytical instruments， MI-SPME media need to be designed into specific technical configurations through chemical or physical methods. This review summarizes six different MI-SPME device modes： MIPs-coated fiber SPME， MIPs in-tube SPME （IT-SPME）， MIPs stir bar sorptive extraction （SBSE）， MIPs dispersive SPME （DSPME）， MIPs thin-film SPME （TFME）， and MIPs in-tip SPME. Each mode offers unique advantages for the separation， enrichment and determination of drug residues in real samples. For example， the coated fiber SPME is simple to operate and suitable for direct immersion or headspace extraction of liquid samples； IT-SPME features miniaturization and automation， with excellent compatibility with chromatographic and mass spectrometric systems； DSPME achieves efficient separation and enrichment by dispersing adsorbents directly into sample solutions.Then， the applications of MI-SPME in the fields of food safety， environmental monitoring and biological medicine are summarized， highlighting typical research examples. In the field of food safety， MI-SPME can be used to detect pesticide residues， veterinary drug residues， and drugs for human use in fruits， vegetables， animal meats and dairy products. In environmental monitoring， it can be used for the detection of drug residues in aqueous environments and soil. In the field of biological medicine， it can be used for the analysis of drug residues in biological samples such as plasma， urine， and serum.Although the MI-SPME technology has shown great potential in drug residue detection， it still faces some challenges. For example， the preparation process of MIPs needs to be further optimized to improve their selectivity and stability； the development and application of new materials （such as graphene， metal-organic frameworks） for composite MIPs still need to solve problems such as high cost and complex processes； the integration of MI-SPME technology and automated equipment is also a bottleneck and important direction for future development. Looking ahead， with the advancement of green chemistry principles and point-of-care testing technologies， MI-SPME is expected to play an even greater role in drug residue detection. It will provide more efficient and precise technical support for food safety， environmental monitoring， and biomedical research.