SERS substrate based on COFs@Ag for rapid detection of pefloxacin

SERS substrate based on COFs@Ag for rapid detection of pefloxacin | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article SERS substrate based on COFs@Ag for rapid detection of pefloxacin Kun Chen, Chaoqun Ma, Guoqing Chen, Taiqun Yang, Hui Gao, Lei Li, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6055076/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 31 Mar, 2025 Read the published version in Plasmonics → Version 1 posted 11 You are reading this latest preprint version Abstract The detection of pefloxacin in milk is of significant importance for food safety. Traditional methods for detecting pefloxacin often rely on techniques such as high-performance liquid chromatography (HPLC), which are complex and time-consuming. This article introduces a surface-enhanced Raman scattering (SERS) substrate based on a composite of covalent organic frameworks (COFs) and silver nanoparticles (AgNPs) for the rapid detection of pefloxacin in milk. After testing pefloxacin (PEF) in both water and milk, the detection limits were calculated to be 6.31 µg/L for water and 82 µg/L for milk, with correlation coefficients of 0.991 and 0.998, respectively. Furthermore, the average recovery rate of pefloxacin in milk ranged from 96.25–106.17%, with a relative standard deviation (RSD) of 4.32–8.88%. This work offers a simple and rapid method for detecting pefloxacin in milk. SERS Pefloxacin COFs AgNPs Milk Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Pefloxacin is an excellent third-generation quinolone known for its broad-spectrum bactericidal properties and strong antibacterial activity, making it widely used in the livestock industry to treat bacterial infections in animals [ 1 ]. However, the extensive use of antibiotics has raised concerns about antibiotic resistance and food safety. Although pefloxacin is primarily used in veterinary medicine, humans may be exposed to excessive amounts through improper drug use or by consuming animal products containing residual pefloxacin. This can pose various health risks [ 2 , 3 ]. Numerous methods for detecting pefloxacin have been reported, including high-performance liquid chromatography (HPLC) [ 4 ], fluorescence spectrophotometry [ 5 , 6 , 7 ], enzyme-linked immunosorbent assay (ELISA) [ 8 ], and capillary electrophoresis [ 9 ]. While these techniques offer excellent accuracy and sensitivity for pefloxacin detection, they also present some flaws, such as lengthy experimental times, high equipment costs, complex sample preparation, and the need for skilled personnel [ 10 ]. Therefore, it is essential to develop a simple, cost-effective method that can reliably and quickly detect pefloxacin in milk. Surface-enhanced Raman spectroscopy is an ultra-sensitive detection technique that significantly enhances Raman scattering through physical and chemical amplification. It is characterized by high sensitivity, high selectivity, fingerprint specificity, and non-destructive testing, making it applicable in various fields such as biomedicine, environmental protection, and food safety [ 11 ]. There have been several reports on using SERS for the detection of quinolone antibiotics. For instance, Zhang and colleagues utilized a combination of SERS and thin-layer chromatography (TLC) to detect four types of quinolone antibiotics in seafood, achieving their separation [ 12 ]. Similarly, Markina and collaborators used β-cyclodextrin as a reducing agent to prepare silver nanoparticles for detecting quinolone antibiotics in human urine and plasma [ 13 ]. SERS technology holds great potential in the field of new materials. By integrating with nanotechnology, biotechnology, and other areas, SERS is poised to become a key tool in analytical chemistry, materials science, and biomedicine. Covalent organic frameworks are a class of highly ordered, porous, and designable crystalline materials linked by strong covalent bonds. Constructed from light elements such as carbon, nitrogen, boron, and oxygen using segmental polymer chemistry methods, COFs offer high structural tunability, large specific surface areas, and excellent thermal and chemical stability [ 14 , 15 , 16 ]. Their tunable pore channels and functionalized surfaces give them significant potential in various applications, including the SERS field. For example, Yuan successfully synthesized Au@Ag core-shell composites on sea urchin-like COFs for the detection of sulfonamide antibiotics and nanoplastics [ 17 ]. They found that the large surface area and high adsorption capacity of COFs greatly enhanced pollutant enrichment and detection. Similarly, Wei and colleagues used silver nanoparticle-modified COFs as SERS substrates for the adsorption and detection of fungicides [ 18 ]. Their results showed that the substrates exhibited a high enhancement factor, along with excellent reproducibility and stability. Additionally, Xie and team employed a photoreduction deposition method to generate gold nanoparticles in situ on COFs surfaces. This method produced larger gold nanoparticles compared to traditional methods, leading to improved detection performance [ 19 ]. Their study successfully detected four macrolide antibiotics, offering new insights into SERS substrate detection. In this study, we employed a relatively simple method to synthesize COFs@Ag substrates, enabling the sensitive and rapid detection of PEF in milk. The substrate is rich in hydroxyl groups, allowing for electrostatic adsorption with PEF's functional groups, thereby significantly amplifying the Raman signal of PEF molecules on the substrate. [ 20 ]. Additionally, by comparing the Raman intensity of crystal violet (CV) across different substrates, we demonstrated that the substrate possesses a high enhancement factor. The substrate's excellent anti-interference capability is demonstrated through the mixed detection of common macromolecular substances. By establishing a linear relationship between the SERS intensity at the PEF characteristic peak of 1374 cm − 1 and the concentration of PEF, we successfully achieved the detection of PEF in milk. 2. Experimental section 2.1. Reagents 2,5-Dimethyl-1,4-phenylenediamine, 2,5-dihydroxyterephthalaldehyde, 1,4-dioxane, acetic acid, and β-cyclodextrin were purchased from China National Pharmaceutical Group Corporation (Shanghai, China). Silver nitrate, sodium hydroxide, CV, and pefloxacin were sourced from Beijing InnoChem Technology Co., Ltd (Beijing, China). Galactose, maltose, glucose, and sucrose were obtained from J&K Scientific Co., Ltd (Shanghai, China). Methionine, glycine, tryptophan, aspartic acid, phenylalanine, lysine, proline, and threonine were purchased from Shanghai Aladdin Biochemical Technology Co., Ltd (Shanghai, China). Milk was procured from a local supermarket. 2.2. Experimental instruments and parameters SERS spectra were acquired utilizing a confocal Raman spectrometer (Renishaw Ltd., UK). The laser wavelength employed for all SERS measurements was 532 nm, operating at a power of 12.5 mW (10%), with sampling conducted through a capillary tube. Absorption spectra were obtained using a UV-2600 UV-Vis spectrophotometer (Shimadzu, Japan), spanning the wavelength range from 200 nm to 700 nm. Scanning electron microscopy images of covalent organic frameworks (COFs) and substrates were captured using a Zeiss-G500 (Carl Zeiss AG, Germany). Zeta potential measurements were performed with a Zetasizer Nano ZS 90 (Malvern Instruments Ltd., UK), within a range of -100 mV to 100 mV. The Fourier Transform Infrared (FTIR) spectra of COFs and substrates were recorded using a Nicolet iS5 spectrometer (Thermo Fisher Scientific, USA), featuring a wavelength resolution of 0.1 cm⁻¹ and an accuracy of 0.5 cm⁻¹. X-ray photoelectron spectroscopy (XPS) analyses were conducted on an ESCALAB 250Xi (Thermo Fisher Scientific, USA), with a binding energy range of 0–1000 eV. The pass energy was calibrated to 40 eV, and the scan step size was meticulously set at 0.1 eV per step. 2.3. Synthesis of COFs and COFs@Ag The synthesis of COFs materials begins with selecting 2,5-dimethyl-1,4-phenylenediamine and 2,5-dihydroxyterephthalaldehyde as precursors. Using 1,4-dioxane as a solvent and 3 mol/L acetic acid as a catalyst, the mixture is heated at 80°C for 24 hours, resulting in the formation of the COFs material. The COFs@Ag substrate is prepared through an in-situ synthesis method, employing β-cyclodextrin as both a binder and a reducing agent in a one-step reduction process. The synthesis procedure is as follows: Weigh 0.13 g of β-cyclodextrin and 10 mg of COFs, and mix them with 30 mL of deionized water. Incubate the mixture at 60°C for 20 minutes, then adjust the pH by adding 1 mL of 0.1 M sodium hydroxide solution. Finally, add 20 mL of 10 mM silver nitrate solution and allow the reaction to proceed at 60°C for 20 minutes to synthesize the desired composite substrate. 2.4. Sample preparation To prepare a 100 mg/L standard solution of pefloxacin, dissolve 10 mg of pefloxacin powder in 100 mL of deionized water. Subsequently, dilute this standard solution to various concentration gradients. Mix the pefloxacin solutions with the COFs@Ag substrate in a 3:1 volume ratio, and then perform SERS measurements. For testing in milk, follow these steps: Vortex 10 mL of milk with 2 mL of methanol containing 1% acetic acid for 2 minutes. Centrifuge the mixture at 5000 rpm for 10 minutes and collect the supernatant, then filter it. Dissolve pefloxacin powder in the pre-treated milk to create solutions at different concentration gradients. Mix these solutions with the substrate in a 3:1 ratio and conduct SERS measurements. 3. Results and discussion 3.1. Scheme As illustrated in Fig. 1 , the COFs materials and COFs@Ag substrate were synthesized using the method outlined in section 2.3 . The synthesized substrate features numerous hydroxyl functional groups, which can attract the pefloxacin analyte. Concurrently, COFs are capable of securely anchoring AgNPs hotspots, thereby expanding the hotspot region and enhancing both the stability of the substrate and the detection sensitivity. 3.2.Characterization of substrate The substrate and COFs were examined utilizing a scanning electron microscope. As shown in Fig. 2 a, the synthesized COFs material appears as a fibrous 2D structure. After in-situ synthesis, abundant AgNPs are encapsulated on the COFs material, as illustrated in Fig. 2 b. These immobilized AgNPs enhance the substrate’s stability, while the densely packed Raman hotspots facilitate improved Raman signal detection. Fourier Transform Infrared Spectroscopy was conducted for both COFs and COFs@Ag. The resulting FTIR spectra are shown in Fig. 3 a. The peak at 3385 cm − 1 indicates a significant presence of hydroxyl groups in the synthesized COFs@Ag. The peak at 1659 cm − 1 is typically attributed to the C = O stretching vibration of unreacted aldehyde groups on the COFs, or the C = C stretching vibration of unsaturated double bonds. The peak at 1604 cm − 1 corresponds to the C = N double bond stretching vibration, signifying the successful occurrence of the condensation reaction and thus the successful synthesis of COFs. The peak at 1035 cm − 1 may be associated with the C-O stretching vibration of the reducing agent β-cyclodextrin [ 21 ]. The abundance of hydroxyl groups not only provides more adsorption sites for AgNPs [ 22 ] but also facilitates the formation of hydrogen bonds and charge transfers with the analyte, allowing it to approach the substrate closely. Additionally, it can be observed that the peaks characteristic of COFs are generally weakened on the substrate, indicating that AgNPs are encapsulating the COFs. As shown in Fig. S3, the electrostatic potential maps of the precursor and the analyte were calculated using Gaussian and the related software Multiwfn [ 23 ]. From the potential maps, it can be seen that the hydroxyl groups on the COFs are very likely to undergo electrostatic adsorption with the aldehyde or carboxyl groups on PEF, which also corroborates the explanation provided by the infrared spectroscopy discussed above. As shown in Fig. 3 b, the increase in Zeta potential indicates that the composite substrate is more stable. X-ray photoelectron spectroscopy (XPS) analysis was conducted on the substrate, as illustrated in Fig. 3 c and Fig. 3 d. The substrate exhibits three main elemental peaks located at 531 eV, 285 eV, and 367 eV and 373 eV, corresponding to O1s, C1s, and Ag3d, respectively. High-resolution XPS spectra for Ag3d reveal two symmetric peaks at 367 eV and 373 eV, attributed to the Ag3d3/2 and Ag3d5/2 binding energies. According to the peak fitting results, the purple and green peaks correspond to Ag⁰, while the blue and yellow peaks are associated with Ag⁺. These findings suggest that silver in the substrate predominantly exists in the form of silver nanoparticles. Additionally, the UV-Vis absorption spectrum (Fig. S1 ) shows a peak for COFs at 409 nm, which shifts to 430 nm after the assembly of AgNPs, further confirming the effective synthesis of AgNPs on the COFs surface. 3.3. Spectral Characteristics of the Substrate Figure 4 a compares the detection of a 1 mg/L pefloxacin solution using AgNPs synthesized via the classic Lee-Meisel method [ 24 ] and the substrate. It is evident that the substrate exhibits a significantly stronger response to pefloxacin than the AgNPs. The main Raman characteristic peaks include: at 1050 cm⁻¹, in-plane bending vibrations of C-H single bonds and stretching vibrations of C-C and C-F single bonds; at 1130 cm⁻¹, symmetric stretching vibrations of C-N single bonds and twisting vibrations of C-H bonds; at 1325 cm⁻¹, bending vibrations of O-H and C-H single bonds; at 1374 cm⁻¹, bending vibrations of C-H single bonds; at 1542 cm⁻¹ and 1552 cm⁻¹, stretching vibrations of C-C single bonds and bending vibrations of C-H bonds; and at 1612 cm⁻¹, stretching vibrations of C = C double bonds [ 25 ]. The Raman enhancement factor (EF) of the substrate was evaluated using Crystal CV. As shown in Fig. S2, COFs@Ag, AgNPs, and CV solution were mixed, and their SERS intensity was measured, along with the Raman spectrum intensity of CV. Using the formula provided in [ 26 ], the EF of the substrate was calculated to be 4.4 × 10 4 . These results indicate that the substrate exhibits a strong Raman enhancement effect. A 2 mg/L solution of common sugars and amino acids was mixed with a 2 mg/L pefloxacin solution. This mixture was then combined with the substrate in a 3:1 ratio for SERS measurements. As shown in Fig. 4 b, using the characteristic peak at 1374 cm⁻¹ as a criterion, it is evident that while the intensity of pefloxacin fluctuates within a certain range upon the addition of interferents, the Raman spectral peak shape remains largely unchanged. This indicates that the identification of the analyte is not affected, demonstrating the substrate's strong anti-interference capability. In Fig. 4 c, the SERS spectra of the aforementioned macromolecules and pefloxacin are measured separately, with the Raman intensity at 1374 cm⁻¹ recorded. The results show that these substrates effectively resist interference from these macromolecules. 3.4. SERS measurement of PEF solutions A series of SERS spectra for PEF aqueous solutions with varying concentration gradients were measured. As shown in Fig. 5 a, the characteristic peak at 1374 cm⁻¹ remains observable even when the concentration of the PEF aqueous solution decreases to 50 µg/L. Figure 5 b illustrates the linear fit of these results, with a linear range from 50 µg/L to 200 µg/L. The fitted linear equation is y = 33458.54 x − 239.86, with a correlation coefficient of R 2 = 0.991. The limit of detection (LOD) is determined to be 6.31 µg/L. The detection results in milk are shown in Fig. 5 c and Fig. 5 d. The pretreatment method for milk has been previously described. Upon measurement, the linear range for PEF in milk was found to be 200 µg/L to 600 µg/L, with a fitted linear equation of y = 14107.09 x − 767.91 and a correlation coefficient of R 2 = 0.998. The LOD in milk was determined to be 82 µg/L. Comparing the detection results in water and milk reveals that, although the intensities of certain Raman characteristic peaks vary, the fundamental peak profile attributable to PEF remains unchanged. As the concentration increases, the Raman signal initially rises rapidly before gradually declining. This decline is hypothesized to result from an excess of target molecules covering the substrate surface, potentially blocking or covering hotspot regions, thereby reducing the substrate's enhancement effect on the analyte molecules. 3.5. Recovery rate experiment To ensure accurate recovery experiments for varying spiked concentrations of PEF in milk, results were summarized in Table 1 . The findings indicate that the average recovery rate of PEF in milk ranges from 96.25–106.17%, with a relative standard deviation (RSD) between 4.32% and 8.88%. Table 1 Results of average recovery rate and relative standard deviation (RSD) (n = 5). Spiked(mg/L) Detected(mg/L) Recovery(%) RSD(%) 0.38 0.3658 96.25 5.48 0.45 0.4778 106.17 4.32 0.55 0.5636 102.48 8.88 3.6. Comparison with other methods This work was compared with other methods for detecting PEF, as shown in Table 2 . The table lists the linear range and limit of detection (LOD) for this study alongside those of other detection methods. Table 2 Comparison of this method with other methods Detection method LOD Linear range Environment Ref. Fluorescence 5.8×10 -7 M 0 -1.5 ×10 –5 mol·L –1 Water [5] [Zn(L)0.5(NDC)] 2.1×10 -7 M 0 -4.0 ×10 –5 mol·L –1 Water [27] SERS 0.17μg/mL 1-6 μg mL -1 Blood plasma [13] Fluorescent probe 6.25 nM 0- 2.0 × 10 –6 mol·L –1 Water [6] fluorescent sensors 13.6 nM 0 - 6.50 μmol·L −1 Water [7] This work 6.31μg/L (18 nM) 1.49-5.99×10 –7 mol·L –1 Water This work 82μg/L (0.24 μM) 6.0-18.0×10 –7 mol·L –1 milk 4. Conclusions This study developed a straightforward method for determining PEF concentration using AgNPs and COFs materials combined with β-cyclodextrin as a SERS substrate. The COFs materials provide an exceptionally high surface area for the stabilization of AgNP hotspots, and their abundant hydroxyl groups facilitate the adsorption of PEF molecules into these hotspots, significantly enhancing the Raman signal. Through a series of experiments, the limits of detection (LOD) in water and milk were found to be 6.31 µg/L and 82 µg/L, respectively. The results demonstrate excellent linearity for PEF detection in milk, with a linear range of 200–600 µg/L, a correlation coefficient of 0.998, an average recovery rate between 96.25% and 106.17%, and a relative standard deviation (RSD) ranging from 4.32–8.88%. In summary, this method enables rapid detection of PEF with good sensitivity and reliability, and it also expands the application of SERS technology in food detection to some extent. Declarations Funding This work was supported by the National Natural Science Foundation of China [62375112] and the Postgraduate Research & Practice Innovation Program of Jiangsu Province [KYCX23_2554]. Author Contribution Kun Chen：Conceptualization, Methodology, Writing – original draft. Chaoqun Ma: Project administration, Funding acquisition. Guoqing Chen: Resources. Taiqun Yang: Resources. Lei Li: Supervision. Anqi Hu: Investigation. Jun Cao: Validation. Chenkai Zheng: Data curation. Longyao Ma:Writing – review & editing. Zehao Chen: Data curation. Gao Hui: Supervision. Data Availability The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. References Schwarz S, Kehrenberg C, Walsh TR (2001) Use of antimicrobial agents in veterinary medicine and food animal production. 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optoelectronic engineering and Technology","correspondingAuthor":false,"prefix":"","firstName":"Chenkai","middleName":"","lastName":"Zheng","suffix":""},{"id":417906648,"identity":"654fef84-7d3e-4b3a-a947-fb2d7c4d746b","order_by":9,"name":"Longyao Ma","email":"","orcid":"","institution":"Jiangsu Provincial Research Center of Light Industrial optoelectronic engineering and Technology","correspondingAuthor":false,"prefix":"","firstName":"Longyao","middleName":"","lastName":"Ma","suffix":""},{"id":417906650,"identity":"0a008490-a135-4363-b441-c8c30f20f4d3","order_by":10,"name":"Zehao Chen","email":"","orcid":"","institution":"Jiangnan University","correspondingAuthor":false,"prefix":"","firstName":"Zehao","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2025-02-18 10:08:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6055076/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6055076/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11468-025-02935-3","type":"published","date":"2025-03-31T15:57:27+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":76823691,"identity":"4994ddb3-42ab-40c6-bb33-538fab7780df","added_by":"auto","created_at":"2025-02-21 07:19:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":6324164,"visible":true,"origin":"","legend":"\u003cp\u003ePreparation and Detection Schematic of COFs@Ag Substrate.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6055076/v1/028ea7f8f2cee0bf137edba8.png"},{"id":76823467,"identity":"34fdaecc-d895-4275-8ada-f7ee4eb11082","added_by":"auto","created_at":"2025-02-21 07:11:44","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":8244996,"visible":true,"origin":"","legend":"\u003cp\u003e(a) SEM images of COFs, (b) SEM images of COFs@Ag.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-6055076/v1/20ac667a8db6e647fd246225.png"},{"id":76825081,"identity":"a5e16ddd-c14e-4af7-800f-81da19ca76ee","added_by":"auto","created_at":"2025-02-21 07:27:44","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":4771042,"visible":true,"origin":"","legend":"\u003cp\u003e(a) FTIR spectra of COFs and COFs@Ag. (b) Zeta potential of AgNPs and COFs@Ag. (c) XPS survey spectrum of COFs@Ag. (d) Ag3d XPS spectra of COF@Ag.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-6055076/v1/af496a77e1e10c7567cd8c7d.png"},{"id":76825082,"identity":"257ea679-43af-4700-9d27-c8a585071c57","added_by":"auto","created_at":"2025-02-21 07:27:44","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":2551576,"visible":true,"origin":"","legend":"\u003cp\u003e(a) SERS spectra of PEF solution were detected using both AgNPs and COFs@Ag. (b) SERS spectra of PEF mixed with different sugars and amino acids were analyzed (Galactose, maltose, glucose, sucrose, Methionine, glycine, tryptophan, aspartic acid, phenylalanine, lysine, proline, and threonine). (c) The intensity comparison of the Raman characteristic peak at 1374 cm⁻¹.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-6055076/v1/2d69b909ec05196053f7732b.png"},{"id":76823694,"identity":"a658e24e-37f9-42e9-a94c-f6b35cc9d9b0","added_by":"auto","created_at":"2025-02-21 07:19:44","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":6370491,"visible":true,"origin":"","legend":"\u003cp\u003e(a) SERS spectra of PEF solutions at different concentrations. (b) The curve relationship between SERS intensity at 1374 cm\u003csup\u003e-1\u003c/sup\u003e and concentrations of PEF solutions. The illustration represented the calibration curve acquired by fitting in the linear range. (c) SERS spectra of PEF at different concentrations in milk. (d) The curve relationship between SERS intensity at 1374 cm\u003csup\u003e-1\u003c/sup\u003e and concentrations of PEF in milk.\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-6055076/v1/25680c744d8c0a5d84f560e8.png"},{"id":80082247,"identity":"2e425be7-ee99-4370-9383-11866ebf3e6c","added_by":"auto","created_at":"2025-04-07 16:07:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":28862747,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6055076/v1/4a2d0ba1-4202-406a-b5a2-6648a00d9d41.pdf"},{"id":76823473,"identity":"2a37f1ff-e64d-4554-97f4-85c34e355576","added_by":"auto","created_at":"2025-02-21 07:11:44","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":6926959,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarymaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-6055076/v1/dfe673b0f266df4045f1fd6d.docx"},{"id":76823492,"identity":"8cc6d5a2-cacc-42a3-a8bc-3fc339fe3edc","added_by":"auto","created_at":"2025-02-21 07:11:50","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":21698245,"visible":true,"origin":"","legend":"","description":"","filename":"GraphicalAbstract.docx","url":"https://assets-eu.researchsquare.com/files/rs-6055076/v1/b903c7a136317e5a6b4b8fa1.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"SERS substrate based on COFs@Ag for rapid detection of pefloxacin","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003ePefloxacin is an excellent third-generation quinolone known for its broad-spectrum bactericidal properties and strong antibacterial activity, making it widely used in the livestock industry to treat bacterial infections in animals [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. However, the extensive use of antibiotics has raised concerns about antibiotic resistance and food safety. Although pefloxacin is primarily used in veterinary medicine, humans may be exposed to excessive amounts through improper drug use or by consuming animal products containing residual pefloxacin. This can pose various health risks [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNumerous methods for detecting pefloxacin have been reported, including high-performance liquid chromatography (HPLC) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], fluorescence spectrophotometry [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], enzyme-linked immunosorbent assay (ELISA) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], and capillary electrophoresis [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. While these techniques offer excellent accuracy and sensitivity for pefloxacin detection, they also present some flaws, such as lengthy experimental times, high equipment costs, complex sample preparation, and the need for skilled personnel [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Therefore, it is essential to develop a simple, cost-effective method that can reliably and quickly detect pefloxacin in milk.\u003c/p\u003e \u003cp\u003eSurface-enhanced Raman spectroscopy is an ultra-sensitive detection technique that significantly enhances Raman scattering through physical and chemical amplification. It is characterized by high sensitivity, high selectivity, fingerprint specificity, and non-destructive testing, making it applicable in various fields such as biomedicine, environmental protection, and food safety [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. There have been several reports on using SERS for the detection of quinolone antibiotics. For instance, Zhang and colleagues utilized a combination of SERS and thin-layer chromatography (TLC) to detect four types of quinolone antibiotics in seafood, achieving their separation [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Similarly, Markina and collaborators used β-cyclodextrin as a reducing agent to prepare silver nanoparticles for detecting quinolone antibiotics in human urine and plasma [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. SERS technology holds great potential in the field of new materials. By integrating with nanotechnology, biotechnology, and other areas, SERS is poised to become a key tool in analytical chemistry, materials science, and biomedicine.\u003c/p\u003e \u003cp\u003eCovalent organic frameworks are a class of highly ordered, porous, and designable crystalline materials linked by strong covalent bonds. Constructed from light elements such as carbon, nitrogen, boron, and oxygen using segmental polymer chemistry methods, COFs offer high structural tunability, large specific surface areas, and excellent thermal and chemical stability [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Their tunable pore channels and functionalized surfaces give them significant potential in various applications, including the SERS field. For example, Yuan successfully synthesized Au@Ag core-shell composites on sea urchin-like COFs for the detection of sulfonamide antibiotics and nanoplastics [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. They found that the large surface area and high adsorption capacity of COFs greatly enhanced pollutant enrichment and detection. Similarly, Wei and colleagues used silver nanoparticle-modified COFs as SERS substrates for the adsorption and detection of fungicides [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Their results showed that the substrates exhibited a high enhancement factor, along with excellent reproducibility and stability. Additionally, Xie and team employed a photoreduction deposition method to generate gold nanoparticles in situ on COFs surfaces. This method produced larger gold nanoparticles compared to traditional methods, leading to improved detection performance [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Their study successfully detected four macrolide antibiotics, offering new insights into SERS substrate detection.\u003c/p\u003e \u003cp\u003eIn this study, we employed a relatively simple method to synthesize COFs@Ag substrates, enabling the sensitive and rapid detection of PEF in milk. The substrate is rich in hydroxyl groups, allowing for electrostatic adsorption with PEF's functional groups, thereby significantly amplifying the Raman signal of PEF molecules on the substrate. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Additionally, by comparing the Raman intensity of crystal violet (CV) across different substrates, we demonstrated that the substrate possesses a high enhancement factor. The substrate's excellent anti-interference capability is demonstrated through the mixed detection of common macromolecular substances. By establishing a linear relationship between the SERS intensity at the PEF characteristic peak of 1374 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e and the concentration of PEF, we successfully achieved the detection of PEF in milk.\u003c/p\u003e"},{"header":"2. Experimental section","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Reagents\u003c/h2\u003e \u003cp\u003e2,5-Dimethyl-1,4-phenylenediamine, 2,5-dihydroxyterephthalaldehyde, 1,4-dioxane, acetic acid, and β-cyclodextrin were purchased from China National Pharmaceutical Group Corporation (Shanghai, China). Silver nitrate, sodium hydroxide, CV, and pefloxacin were sourced from Beijing InnoChem Technology Co., Ltd (Beijing, China). Galactose, maltose, glucose, and sucrose were obtained from J\u0026amp;K Scientific Co., Ltd (Shanghai, China). Methionine, glycine, tryptophan, aspartic acid, phenylalanine, lysine, proline, and threonine were purchased from Shanghai Aladdin Biochemical Technology Co., Ltd (Shanghai, China). Milk was procured from a local supermarket.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Experimental instruments and parameters\u003c/h2\u003e \u003cp\u003eSERS spectra were acquired utilizing a confocal Raman spectrometer (Renishaw Ltd., UK). The laser wavelength employed for all SERS measurements was 532 nm, operating at a power of 12.5 mW (10%), with sampling conducted through a capillary tube.\u003c/p\u003e \u003cp\u003eAbsorption spectra were obtained using a UV-2600 UV-Vis spectrophotometer (Shimadzu, Japan), spanning the wavelength range from 200 nm to 700 nm.\u003c/p\u003e \u003cp\u003eScanning electron microscopy images of covalent organic frameworks (COFs) and substrates were captured using a Zeiss-G500 (Carl Zeiss AG, Germany).\u003c/p\u003e \u003cp\u003eZeta potential measurements were performed with a Zetasizer Nano ZS 90 (Malvern Instruments Ltd., UK), within a range of -100 mV to 100 mV.\u003c/p\u003e \u003cp\u003eThe Fourier Transform Infrared (FTIR) spectra of COFs and substrates were recorded using a Nicolet iS5 spectrometer (Thermo Fisher Scientific, USA), featuring a wavelength resolution of 0.1 cm⁻\u0026sup1; and an accuracy of 0.5 cm⁻\u0026sup1;.\u003c/p\u003e \u003cp\u003eX-ray photoelectron spectroscopy (XPS) analyses were conducted on an ESCALAB 250Xi (Thermo Fisher Scientific, USA), with a binding energy range of 0\u0026ndash;1000 eV. The pass energy was calibrated to 40 eV, and the scan step size was meticulously set at 0.1 eV per step.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Synthesis of COFs and COFs@Ag\u003c/h2\u003e \u003cp\u003eThe synthesis of COFs materials begins with selecting 2,5-dimethyl-1,4-phenylenediamine and 2,5-dihydroxyterephthalaldehyde as precursors. Using 1,4-dioxane as a solvent and 3 mol/L acetic acid as a catalyst, the mixture is heated at 80\u0026deg;C for 24 hours, resulting in the formation of the COFs material.\u003c/p\u003e \u003cp\u003eThe COFs@Ag substrate is prepared through an in-situ synthesis method, employing β-cyclodextrin as both a binder and a reducing agent in a one-step reduction process. The synthesis procedure is as follows: Weigh 0.13 g of β-cyclodextrin and 10 mg of COFs, and mix them with 30 mL of deionized water. Incubate the mixture at 60\u0026deg;C for 20 minutes, then adjust the pH by adding 1 mL of 0.1 M sodium hydroxide solution. Finally, add 20 mL of 10 mM silver nitrate solution and allow the reaction to proceed at 60\u0026deg;C for 20 minutes to synthesize the desired composite substrate.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Sample preparation\u003c/h2\u003e \u003cp\u003eTo prepare a 100 mg/L standard solution of pefloxacin, dissolve 10 mg of pefloxacin powder in 100 mL of deionized water. Subsequently, dilute this standard solution to various concentration gradients. Mix the pefloxacin solutions with the COFs@Ag substrate in a 3:1 volume ratio, and then perform SERS measurements.\u003c/p\u003e \u003cp\u003eFor testing in milk, follow these steps: Vortex 10 mL of milk with 2 mL of methanol containing 1% acetic acid for 2 minutes. Centrifuge the mixture at 5000 rpm for 10 minutes and collect the supernatant, then filter it. Dissolve pefloxacin powder in the pre-treated milk to create solutions at different concentration gradients. Mix these solutions with the substrate in a 3:1 ratio and conduct SERS measurements.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results and discussion","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Scheme\u003c/h2\u003e \u003cp\u003eAs illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, the COFs materials and COFs@Ag substrate were synthesized using the method outlined in section \u003cspan refid=\"Sec5\" class=\"InternalRef\"\u003e2.3\u003c/span\u003e. The synthesized substrate features numerous hydroxyl functional groups, which can attract the pefloxacin analyte. Concurrently, COFs are capable of securely anchoring AgNPs hotspots, thereby expanding the hotspot region and enhancing both the stability of the substrate and the detection sensitivity.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.2.Characterization of substrate\u003c/h2\u003e \u003cp\u003eThe substrate and COFs were examined utilizing a scanning electron microscope. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea, the synthesized COFs material appears as a fibrous 2D structure. After in-situ synthesis, abundant AgNPs are encapsulated on the COFs material, as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb. These immobilized AgNPs enhance the substrate\u0026rsquo;s stability, while the densely packed Raman hotspots facilitate improved Raman signal detection.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFourier Transform Infrared Spectroscopy was conducted for both COFs and COFs@Ag. The resulting FTIR spectra are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea. The peak at 3385 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e indicates a significant presence of hydroxyl groups in the synthesized COFs@Ag. The peak at 1659 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e is typically attributed to the C\u0026thinsp;=\u0026thinsp;O stretching vibration of unreacted aldehyde groups on the COFs, or the C\u0026thinsp;=\u0026thinsp;C stretching vibration of unsaturated double bonds. The peak at 1604 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e corresponds to the C\u0026thinsp;=\u0026thinsp;N double bond stretching vibration, signifying the successful occurrence of the condensation reaction and thus the successful synthesis of COFs. The peak at 1035 cm\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e may be associated with the C-O stretching vibration of the reducing agent β-cyclodextrin [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The abundance of hydroxyl groups not only provides more adsorption sites for AgNPs [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] but also facilitates the formation of hydrogen bonds and charge transfers with the analyte, allowing it to approach the substrate closely. Additionally, it can be observed that the peaks characteristic of COFs are generally weakened on the substrate, indicating that AgNPs are encapsulating the COFs.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAs shown in Fig. S3, the electrostatic potential maps of the precursor and the analyte were calculated using Gaussian and the related software Multiwfn [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. From the potential maps, it can be seen that the hydroxyl groups on the COFs are very likely to undergo electrostatic adsorption with the aldehyde or carboxyl groups on PEF, which also corroborates the explanation provided by the infrared spectroscopy discussed above.\u003c/p\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb, the increase in Zeta potential indicates that the composite substrate is more stable. X-ray photoelectron spectroscopy (XPS) analysis was conducted on the substrate, as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed. The substrate exhibits three main elemental peaks located at 531 eV, 285 eV, and 367 eV and 373 eV, corresponding to O1s, C1s, and Ag3d, respectively. High-resolution XPS spectra for Ag3d reveal two symmetric peaks at 367 eV and 373 eV, attributed to the Ag3d3/2 and Ag3d5/2 binding energies. According to the peak fitting results, the purple and green peaks correspond to Ag⁰, while the blue and yellow peaks are associated with Ag⁺. These findings suggest that silver in the substrate predominantly exists in the form of silver nanoparticles. Additionally, the UV-Vis absorption spectrum (Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e) shows a peak for COFs at 409 nm, which shifts to 430 nm after the assembly of AgNPs, further confirming the effective synthesis of AgNPs on the COFs surface.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Spectral Characteristics of the Substrate\u003c/h2\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea compares the detection of a 1 mg/L pefloxacin solution using AgNPs synthesized via the classic Lee-Meisel method [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] and the substrate. It is evident that the substrate exhibits a significantly stronger response to pefloxacin than the AgNPs. The main Raman characteristic peaks include: at 1050 cm⁻\u0026sup1;, in-plane bending vibrations of C-H single bonds and stretching vibrations of C-C and C-F single bonds; at 1130 cm⁻\u0026sup1;, symmetric stretching vibrations of C-N single bonds and twisting vibrations of C-H bonds; at 1325 cm⁻\u0026sup1;, bending vibrations of O-H and C-H single bonds; at 1374 cm⁻\u0026sup1;, bending vibrations of C-H single bonds; at 1542 cm⁻\u0026sup1; and 1552 cm⁻\u0026sup1;, stretching vibrations of C-C single bonds and bending vibrations of C-H bonds; and at 1612 cm⁻\u0026sup1;, stretching vibrations of C\u0026thinsp;=\u0026thinsp;C double bonds [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe Raman enhancement factor (EF) of the substrate was evaluated using Crystal CV. As shown in Fig. S2, COFs@Ag, AgNPs, and CV solution were mixed, and their SERS intensity was measured, along with the Raman spectrum intensity of CV. Using the formula provided in [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], the EF of the substrate was calculated to be 4.4 \u0026times; 10\u003csup\u003e4\u003c/sup\u003e. These results indicate that the substrate exhibits a strong Raman enhancement effect.\u003c/p\u003e \u003cp\u003eA 2 mg/L solution of common sugars and amino acids was mixed with a 2 mg/L pefloxacin solution. This mixture was then combined with the substrate in a 3:1 ratio for SERS measurements. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb, using the characteristic peak at 1374 cm⁻\u0026sup1; as a criterion, it is evident that while the intensity of pefloxacin fluctuates within a certain range upon the addition of interferents, the Raman spectral peak shape remains largely unchanged. This indicates that the identification of the analyte is not affected, demonstrating the substrate's strong anti-interference capability. In Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ec, the SERS spectra of the aforementioned macromolecules and pefloxacin are measured separately, with the Raman intensity at 1374 cm⁻\u0026sup1; recorded. The results show that these substrates effectively resist interference from these macromolecules.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.4. SERS measurement of PEF solutions\u003c/h2\u003e \u003cp\u003eA series of SERS spectra for PEF aqueous solutions with varying concentration gradients were measured. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea, the characteristic peak at 1374 cm⁻\u0026sup1; remains observable even when the concentration of the PEF aqueous solution decreases to 50 \u0026micro;g/L. Figure\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eb illustrates the linear fit of these results, with a linear range from 50 \u0026micro;g/L to 200 \u0026micro;g/L. The fitted linear equation is \u003cem\u003ey\u003c/em\u003e\u0026thinsp;=\u0026thinsp;33458.54\u003cem\u003ex\u003c/em\u003e\u0026thinsp;\u0026minus;\u0026thinsp;239.86, with a correlation coefficient of R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.991. The limit of detection (LOD) is determined to be 6.31 \u0026micro;g/L.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe detection results in milk are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ec and Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ed. The pretreatment method for milk has been previously described. Upon measurement, the linear range for PEF in milk was found to be 200 \u0026micro;g/L to 600 \u0026micro;g/L, with a fitted linear equation of \u003cem\u003ey\u003c/em\u003e\u0026thinsp;=\u0026thinsp;14107.09\u003cem\u003ex\u003c/em\u003e\u0026thinsp;\u0026minus;\u0026thinsp;767.91 and a correlation coefficient of R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.998. The LOD in milk was determined to be 82 \u0026micro;g/L.\u003c/p\u003e \u003cp\u003eComparing the detection results in water and milk reveals that, although the intensities of certain Raman characteristic peaks vary, the fundamental peak profile attributable to PEF remains unchanged. As the concentration increases, the Raman signal initially rises rapidly before gradually declining. This decline is hypothesized to result from an excess of target molecules covering the substrate surface, potentially blocking or covering hotspot regions, thereby reducing the substrate's enhancement effect on the analyte molecules.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.5. Recovery rate experiment\u003c/h2\u003e \u003cp\u003eTo ensure accurate recovery experiments for varying spiked concentrations of PEF in milk, results were summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The findings indicate that the average recovery rate of PEF in milk ranges from 96.25\u0026ndash;106.17%, with a relative standard deviation (RSD) between 4.32% and 8.88%.\u003c/p\u003e \u003cp\u003eTable 1\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResults of average recovery rate and relative standard deviation (RSD) (n = 5).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003eSpiked(mg/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003eDetected(mg/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003eRecovery(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003eRSD(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e0.3658\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e96.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e5.48\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e0.4778\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e106.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e4.32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e0.5636\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e102.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 25%;\"\u003e\n \u003cp\u003e8.88\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.6. Comparison with other methods\u003c/h2\u003e \u003cp\u003eThis work was compared with other methods for detecting PEF, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The table lists the linear range and limit of detection (LOD) for this study alongside those of other detection methods.\u003c/p\u003e\u003cp\u003eTable 2\u003c/p\u003e\n\u003cp\u003eComparison of this method with other methods\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"548\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 21.1679%;\"\u003e\n \u003cp\u003eDetection method\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.7153%;\"\u003e\n \u003cp\u003eLOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.2774%;\"\u003e\n \u003cp\u003eLinear range\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.7007%;\"\u003e\n \u003cp\u003eEnvironment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.1387%;\"\u003e\n \u003cp\u003eRef.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 21.1679%;\"\u003e\n \u003cp\u003eFluorescence\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.7153%;\"\u003e\n \u003cp\u003e5.8\u0026times;10\u003csup\u003e-7\u0026nbsp;\u003c/sup\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.2774%;\"\u003e\n \u003cp\u003e0 -1.5 \u0026times;10\u003csup\u003e\u0026ndash;5\u003c/sup\u003emol\u0026middot;L\u003csup\u003e\u0026ndash;1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.7007%;\"\u003e\n \u003cp\u003eWater\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.1387%;\"\u003e\n \u003cp\u003e[5]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 21.1679%;\"\u003e\n \u003cp\u003e[Zn(L)0.5(NDC)]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.7153%;\"\u003e\n \u003cp\u003e2.1\u0026times;10\u003csup\u003e-7\u0026nbsp;\u003c/sup\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.2774%;\"\u003e\n \u003cp\u003e0 -4.0 \u0026times;10\u003csup\u003e\u0026ndash;5\u003c/sup\u003emol\u0026middot;L\u003csup\u003e\u0026ndash;1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.7007%;\"\u003e\n \u003cp\u003eWater\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.1387%;\"\u003e\n \u003cp\u003e[27]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 21.1679%;\"\u003e\n \u003cp\u003eSERS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.7153%;\"\u003e\n \u003cp\u003e0.17\u0026mu;g/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.2774%;\"\u003e\n \u003cp\u003e1-6 \u0026mu;g mL\u003csup\u003e-1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.7007%;\"\u003e\n \u003cp\u003eBlood plasma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.1387%;\"\u003e\n \u003cp\u003e[13]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 21.1679%;\"\u003e\n \u003cp\u003eFluorescent probe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.7153%;\"\u003e\n \u003cp\u003e6.25 nM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.2774%;\"\u003e\n \u003cp\u003e0- 2.0 \u0026times; 10\u003csup\u003e\u0026ndash;6\u003c/sup\u003emol\u0026middot;L\u003csup\u003e\u0026ndash;1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.7007%;\"\u003e\n \u003cp\u003eWater\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.1387%;\"\u003e\n \u003cp\u003e[6]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 21.1679%;\"\u003e\n \u003cp\u003efluorescent sensors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.7153%;\"\u003e\n \u003cp\u003e13.6 nM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.2774%;\"\u003e\n \u003cp\u003e0 - 6.50 \u0026mu;mol\u0026middot;L\u003csup\u003e\u0026minus;1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.7007%;\"\u003e\n \u003cp\u003eWater\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.1387%;\"\u003e\n \u003cp\u003e[7]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 21.1679%;\"\u003e\n \u003cp\u003eThis work\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.7153%;\"\u003e\n \u003cp\u003e6.31\u0026mu;g/L (18 nM)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.2774%;\"\u003e\n \u003cp\u003e1.49-5.99\u0026times;10\u003csup\u003e\u0026ndash;7\u003c/sup\u003emol\u0026middot;L\u003csup\u003e\u0026ndash;1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.7007%;\"\u003e\n \u003cp\u003eWater\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.1387%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 21.1679%;\"\u003e\n \u003cp\u003eThis work\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21.7153%;\"\u003e\n \u003cp\u003e82\u0026mu;g/L (0.24 \u0026mu;M)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26.2774%;\"\u003e\n \u003cp\u003e6.0-18.0\u0026times;10\u003csup\u003e\u0026ndash;7\u003c/sup\u003emol\u0026middot;L\u003csup\u003e\u0026ndash;1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.7007%;\"\u003e\n \u003cp\u003emilk\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.1387%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"4. Conclusions","content":"\u003cp\u003eThis study developed a straightforward method for determining PEF concentration using AgNPs and COFs materials combined with β-cyclodextrin as a SERS substrate. The COFs materials provide an exceptionally high surface area for the stabilization of AgNP hotspots, and their abundant hydroxyl groups facilitate the adsorption of PEF molecules into these hotspots, significantly enhancing the Raman signal. Through a series of experiments, the limits of detection (LOD) in water and milk were found to be 6.31 \u0026micro;g/L and 82 \u0026micro;g/L, respectively. The results demonstrate excellent linearity for PEF detection in milk, with a linear range of 200\u0026ndash;600 \u0026micro;g/L, a correlation coefficient of 0.998, an average recovery rate between 96.25% and 106.17%, and a relative standard deviation (RSD) ranging from 4.32\u0026ndash;8.88%. In summary, this method enables rapid detection of PEF with good sensitivity and reliability, and it also expands the application of SERS technology in food detection to some extent.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work was supported by the National Natural Science Foundation of China [62375112] and the Postgraduate Research \u0026amp; Practice Innovation Program of Jiangsu Province [KYCX23_2554].\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eKun Chen：Conceptualization, Methodology, Writing \u0026ndash; original draft. Chaoqun Ma: Project administration, Funding acquisition. Guoqing Chen: Resources. Taiqun Yang: Resources. Lei Li: Supervision. Anqi Hu: Investigation. Jun Cao: Validation. Chenkai Zheng: Data curation. Longyao Ma:Writing \u0026ndash; review \u0026amp; editing. Zehao Chen: Data curation. Gao Hui: Supervision.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e \u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSchwarz S, Kehrenberg C, Walsh TR (2001) Use of antimicrobial agents in veterinary medicine and food animal production. Int J Antimicrob Agents 17(6):431\u0026ndash;437. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S0924-8579(01)00297-7\u003c/span\u003e\u003cspan address=\"10.1016/S0924-8579(01)00297-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBhatt S (2022) Fluoroquinolone antibiotics: Occurrence, mode of action, resistance, environmental detection, and remediation\u0026ndash;A comprehensive review. 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Inorg Chem Commun 156:111247. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.inoche.2023.111247\u003c/span\u003e\u003cspan address=\"10.1016/j.inoche.2023.111247\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"plasmonics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"plas","sideBox":"Learn more about [Plasmonics](https://www.springer.com/journal/11468)","snPcode":"11468","submissionUrl":"https://submission.nature.com/new-submission/11468/3","title":"Plasmonics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"SERS, Pefloxacin, COFs, AgNPs, Milk","lastPublishedDoi":"10.21203/rs.3.rs-6055076/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6055076/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe detection of pefloxacin in milk is of significant importance for food safety. Traditional methods for detecting pefloxacin often rely on techniques such as high-performance liquid chromatography (HPLC), which are complex and time-consuming. This article introduces a surface-enhanced Raman scattering (SERS) substrate based on a composite of covalent organic frameworks (COFs) and silver nanoparticles (AgNPs) for the rapid detection of pefloxacin in milk. After testing pefloxacin (PEF) in both water and milk, the detection limits were calculated to be 6.31 \u0026micro;g/L for water and 82 \u0026micro;g/L for milk, with correlation coefficients of 0.991 and 0.998, respectively. Furthermore, the average recovery rate of pefloxacin in milk ranged from 96.25\u0026ndash;106.17%, with a relative standard deviation (RSD) of 4.32\u0026ndash;8.88%. This work offers a simple and rapid method for detecting pefloxacin in milk.\u003c/p\u003e","manuscriptTitle":"SERS substrate based on COFs@Ag for rapid detection of pefloxacin","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-21 07:11:39","doi":"10.21203/rs.3.rs-6055076/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-03-11T16:14:18+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-11T12:18:49+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-10T15:08:26+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-09T06:38:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"51616974266852804320887286477903801465","date":"2025-03-01T16:23:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"92667032828537648490163717463299569968","date":"2025-03-01T14:15:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"331710336642213591104567316623371496751","date":"2025-02-28T13:59:13+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-02-28T13:40:37+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-02-19T08:42:53+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-02-19T08:40:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"Plasmonics","date":"2025-02-18T09:55:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"plasmonics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"plas","sideBox":"Learn more about [Plasmonics](https://www.springer.com/journal/11468)","snPcode":"11468","submissionUrl":"https://submission.nature.com/new-submission/11468/3","title":"Plasmonics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f61198fb-326d-4157-9298-4d2edcc9b63b","owner":[],"postedDate":"February 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-04-07T16:03:56+00:00","versionOfRecord":{"articleIdentity":"rs-6055076","link":"https://doi.org/10.1007/s11468-025-02935-3","journal":{"identity":"plasmonics","isVorOnly":false,"title":"Plasmonics"},"publishedOn":"2025-03-31 15:57:27","publishedOnDateReadable":"March 31st, 2025"},"versionCreatedAt":"2025-02-21 07:11:39","video":"","vorDoi":"10.1007/s11468-025-02935-3","vorDoiUrl":"https://doi.org/10.1007/s11468-025-02935-3","workflowStages":[]},"version":"v1","identity":"rs-6055076","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6055076","identity":"rs-6055076","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}