Green synthesis of water-compatible fluorescent molecularly imprinted

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Green synthesis of water-compatible fluorescent molecularly imprinted polymeric nanoparticles for efficient detection of paracetamol Jing Huang, Jiexiang Tong, Jing Luo, Ye Zhu, yao gu, and Xiaoya Liu ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/acssuschemeng.8b00823 • Publication Date (Web): 13 Jul 2018 Downloaded from http://pubs.acs.org on July 14, 2018

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ACS Sustainable Chemistry & Engineering

Green synthesis of water-compatible fluorescent molecularly imprinted polymeric nanoparticles for efficient detection of paracetamol Jing Huang, Jiexiang Tong, Jing Luo1, Ye Zhu, Yao Gu, Xiaoya Liu Key laboratory of synthetic and biological colloids, ministry of education, School of chemical and material engineering, Jiangnan University, Lihu Street 1800, Wuxi 214122, China

Abstract: In this work, one-pot green synthesis of a novel kind of water-compatible fluorescent molecularly imprinted polymer nanoparticles for selective optosensing of paracetamol was developed via macromolecular assembly of an amphiphilic fluorescent

copolymer

and

in-situ

photocrosslinking.

An

amphiphilic

photo-crosslinkable and fluorescent copolymer containing carbazole groups was first synthesized which could co-assemble with paracetamol (PCM, template molecule) and photoinitiator in aqueous solution. The obtained photo-crosslinkable fluorescent nanoparticles were then crosslinked triggered by UV-irradiation, generating the hydrophilic and fluorescent molecularly imprinted polymer nanoparticles (FMIP nanoparticles) in aqueous media. The whole procedure was carried out at mild working condition, which is facile, green, and energy-saving. The resulting FMIP nanoparticles showed high selectivity toward PCM and obvious fluorescence quenching, induced by template-binding, in water and were a kind of efficient fluorescent chemosensor for the sensing of PCM. A wide linear range over PCM concentration from 4~1000 µM with a detection limit of 1.0 µM has been demonstrated using FMIP nanoparticles as chemosensor. Moreover, a rapid response of less than 2 min has been demonstrated. Finally, such chemosensor based on FMIP nanoparticles was also successfully employed for the detection of PCM in commercial PCM tablets as well as urine samples. Keywords: fluorescent molecularly imprinting; nanoparticles; self-assembly; paracetamol sensing

1

Corresponding Author E-mail: [email protected] Tel: 86-510-85917763. Fax: 86-510-85917763. 1

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Introduction Paracetamol (PCM) is widely used as antipyretic and analgesic drug in the world1. But overdoses of PCM may result in some side effects such as accumulation of toxic metabolites,

causing

severe,

fetal

hepatoxicity

and

nephrotoxicity2.

Thus,

determination of PCM is of so much significance for quality control and medical control. Various analytical methods have been developed for efficient and sensitive determination

of

PCM

such

as

spectrophotometry3,

chemiluminescence4,

flow-injection analysis5 and chromatography6. However, the above methods are either time-consuming or require pretreatment. Hence, it is of great significance to develop sensitive, efficient, facile and accurate analytical techniques for the detection of PCM. Molecularly imprinted technology, a crucial approach for the preparation of artificial materials with tailor-made recognition sites, has aroused great interest7-9. The resulted molecularly imprinted polymers (MIPs) with affinity and specificity towards templates, facile preparation, good stability and low costs can eventually take the place of biological entities in real applications10, particularly in monitoring the environmental conditions, controlling the food quality and performing medical diagnostics7. MIP-based sensors could be fabricated by combining MIP recognition element with different kinds of sensing technologies such as electrochemical detection (e.g., impedance, cyclic voltammetry, differential pulse voltammetry), fluorescent detection, high performance liquid chromatography (HPLC), surface plasmon resonance (SPR), mass spectrometry (MS) et al. 11-14. Among the above mentioned technologies, fluorescent method is of particular interest owing to several advantages, for example, a small amount of solvent consumption, simple sample pretreatment, time-saving measurement and relatively cheaper instrument 15. And the combination of MIPs and fluorescence technique can achieve both excellent selectivity and sensitivity16. Fluorescent MIPs based chemical sensors are mainly prepared by modification of fluorescent components (e.g., inorganic quantum dots and organic fluorescent moieties) to MIPs for the specific detection of various analytes. Karfa et al17 developed a new approach using stimuli-responsive MIPs with carbon dots as fluorescent components for fluorescent detection of alpha-fetoprotein in trace level. Zhou et al15 fabricated a novel fluorescent sensor on the basic of graphene quantum dots, which was then used for the determination of paranitrophenol. Wang et al18 synthesized molecularly imprinted fluorescent hollow nanoparticles with 5(6)-isothiocyanate as the fluorescent moieties for the efficient determination of toxic insecticide λ-cyhalothrin. 2


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Although great progress has been achieved in the field of fluorescent MIPs sensor, there are still some challenges remaining to be resolved. Previously reported fluorescent MIPs sensors for the detection of organic templates are normally prepared in organic solvents. It is well-known that MIPs show the best selectivity and rebinding capacity to the template in the solvent where they were prepared19. However, the specific recognition would be influenced when MIPs were applied in aqueous solution, owing to the competition of hydrogen bonds from the solvent water. The decrease of specific recognition property would significantly limit their practical application in environmental monitoring, clinical diagnostics, and food safety control, which are normally carried out in aqueous media. Therefore, it is of great interest to develop water-compatible fluorescent MIPs sensors. During recent years, various water-compatible synthesis strategies have been developed to water-compatible fluorescent MIPs nanoparticles. Awino and Zhao19-21 prepared a novel kind of surfactant micelle bearing alkyne groups that can react with azido sugar derivative; after surface-core cross-linking, the resulted water-soluble molecularly imprinted fluorescent nanoparticles were obtained. Although good specific fluorescent response had been demonstrated, the fabrication process was quite complicated which involves preparation of doubly cross-linkable surfactant and sugar-derived ligand. Zhang’s group16, 22, 23 synthesized a series of water dispersible MIP micro/nanoparticles with hydrophilic shells via complicated RAFT precipitation polymerization, which can be applied as chemosensor for drug determination. Recently, our group has done a lot of research on macromolecular assembly and found that macromolecular assembly is an efficient strategy for preparing water-compatible molecularly imprinted nanoparticles. Noncovalent interactions (hydrogen bonding, electrostatic interaction, hydrophobic effect) between templates and the polymer are normally the driven force for the assembly process. The obtained MIP nanoparticles were then combined with electrode transducers to construct electrochemical sensors, which showed good selectivity toward the template molecules in aqueous environment. Owing to the versatility of the amphiphilic copolymer and efficient assembly process in aqueous solution, a number of template molecules24-26 including proteins27-29 could be embedded into the self-assembled nanoparticles. However, the above-mentioned water-compatible MIP nanoparticles did not possess signal response element, so they could only recognize template but not output detectable signals. It is highly envisioned that if a fluorescent component is incorporated into the assembly system, novel fluorescent water-compatible MIP 3



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nanoparticles can be produced which could recognize the target molecule and give a fluorescent response at the same time. In this work, we report the one-step green synthesis of a novel fluorescent molecularly imprinted polymer (FMIP) nanoparticle and its application as fluorescent chemical sensor for PCM determination in aqueous solution. Such water-compatible FMIP nanoparticles were prepared by the co-assembly of a fluorescent and photo-crosslinkable amphiphilic copolymer with PCM as template and the subsequent in-situ phocrosslinking. As shown in Scheme 1, the amphiphilic copolymer bearing fluorescent carbazole groups, carboxylic acid groups and cross-linkable methacrylate groups (named PANV-GMA) could co-assemble with the template molecules (PCM), divinylbenzene

(DVB,

crosslinker),

and

benzoin

dimethyl

ether

(DMPA,

photo-initiator) into nanoparticles via hydrophobic interaction and hydrogen bonding in aqueous solution. The obtained photo-crosslinkable fluorescent nanoparticles were then crosslinked by the free radical polymerization of the methacrylate groups in the copolymer chain and DVB solubilized within the core triggered by UV-irradiation. At the end of the photo-crosslinking, the nanoparticles become highly crosslinked and PCM molecules were trapped in the crosslinked polymer matrix, thus generating the hydrophilic and fluorescent molecular imprinted polymer nanoparticles (FMIP nanoparticles). The FMIP nanoparticles were recovered by precipitation after addition of HAc, followed by the removal of the trapped PCM molecules. The whole procedure was performed in aqueous media at mild working condition, which is facile, green, and energy-saving. The sensing behavior of the FMIP nanoparticles was investigated and the results are shown below.

4


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Scheme 1. Schematic illustration of the synthetic procedure of FMIP nanoparticles and its binding with PCM.

Experimental Reagents Acetic acid (HAc), hydrochloric acid (HCl), N,N-Dimethylformamide (DMF), sodium carbonate (Na2CO3), triphenylphosphine (TPP), ether and tetrahydrofuran (THF) were obtained from Sinopharm Chemical Reagent Shanghai. Paracetamol (PCM), N-vinyl carbazole (NVC), acrylic acid (AA), glycidyl methacrylate (GMA), hydroquinone (HQ), 2,2’-azobisisobutyronitrile (AIBN), benzoin dimethyl ether (DMPA) and divinylbenzene (DVB) were bought from Shanghai Aladdin Reagent. All of these were analytical reagents. The inhibitor in DVB was eliminated via basic alumina column chromatography and AA was distilled under vacuum before using. Other chemicals were used without any purification. Characterization 1

H NMR was employed to evaluate the chemical structure of P(AA-co-NVC) and

PANV-GMA with an AVANCE III 400 MHz Digital NMR spectrometer. Molecular weight and distribution of P(AA-co-NVC) and PANV-GMA were determined by Gel permeation chromatograph (GPC) with a Waters GPC 486. Fourier transmission infrared (FTIR) spectra were characterized with a FTLA 2000-104 FTIR 5



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spectrophotometer. UV−vis spectra were conducted on a TU-1901 spectrophotometer. The mean particle size was recorded with a Zetasizer Nano ZS90 instrument. TEM images of fluorescent molecularly imprinted nanoparticles were observed with JEOL JEM-2100 microscope operating at 200 kV. Fluorescent measurements were operated on a FS-5 fluorescence spectrophotometer. The high

performance liquid

chromatography (HPLC) measurement was conducted on a Waters HPLC system including a binary pump and a wavelength UV detector. The mobile phase consisted of acetonitrile-water (20:80) was used and the flow rate is 2.0 mL min-1. And a Spherigal C18 column (5 µm, 250 mm × 4.6 mm, Guangzhou, China) was used for chromatographic experiments. The wavelength for the UV detector was set at 280 nm. Synthesis of the amphiphilic PANV-GMA copolymer AA (0.72 g, 10 mmol) and NVC (1.93 g, 10 mmol) were dissolved into 30 mL DMF and the mixture was then bubbled with N2 for 20 min to remove O2. The polymerization was carried out at 80 °C in oil bath for 24 h with AIBN as initiator to achieve the copolymer P(AA-co-NVC). GMA (1.42 g, 10 mmol), TPP (0.054 g, 0.2 mmol) and HQ (0.0055 g, 0.05 mmol) were dissolved into 10 mL DMF, and the mixture solution was dropped into the above copolymer P(AA-co-NVC) solution by constant pressure funnel to achieve the final fluorescent and photo-crosslinkable amphiphilic copolymer PANV-GMA. The reaction was carried out at 80 °C in oil bath for 12 h with TPP as catalyst and HQ as inhibitor. The reaction mixture was poured into a large amount of ether. PANV-GMA was collected by centrifuge and then redissolved in THF, precipitated in ether, isolated by centrifuge. This procedure was repeated three times. PANV-GMA was dried under vacuum at 40 °C. Preparation of FMIP nanoparticles PANV-GMA copolymer was dissolved in DMF to produce a PANV-GMA solution with concentration of 8 mg mL-1. PCM (template) and DMPA (photoinitiator) were dissolved in DMF to obtain the concentration of 5 mg mL-1 and 12.8 mg mL-1, respectively. Then, 100 µL of PCM solution, 250 µL of DMPA solution and 5 µL of DVB (crosslinker) were added into the PANV-GMA solution under stirring. The FMIP nanoparticles were obtained via the addition of water into the mixture solution at speed of 10 µL min-1. Induced by hydrophobic interaction and hydrogen bonding, the photo-crosslinkable FMIP nanoparticles were obtained with carbazole groups, double bonds, PCM, DMPA, DVB and carboxylic groups. The mixture solution was kept stirring overnight to ensure full complexation among PANV-GMA and PCM. The photo-crosslinking of the particles was carried out under irradiation for 15 min by 6


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a UV lamp (500 mA, 365 nm) with stirring at room temperature in dark. Finally, the solution was dropped into plenty of water to “freeze” the nanoparticles, resulting in FMIP nanoparticles. As a control sample, the fluorescent non-imprinted (FNIP) nanoparticles were prepared in the same procedure except for the addition of the template PCM. Fluorescent detection of FMIP nanoparticles 1 mL of HAc was added into 9 mL FMIP nanoparticles dispersion, leading to the protonation of carboxylic groups, which contribute to the precipitation of the FMIP nanoparticles. After centrifugation, the obtained FMIP nanoparticles were then washed with HAc/water (1:9, v/v) to remove PCM until no absorbance of PCM in UV-vis spectrum could be observed. Then the FMIP nanoparticles were suspended in buffer solutions. The buffer solutions (pH from 5 to 10) were prepared by adding different volumes of 0.2 M NaOH to the 0.02 M CH3COOH–0.02 M H3BO3–0.02 M H3PO4 combined solutions with the aid of pH meter. The fluorescence measurements were performed with a quartz cell (1 cm path length). The scanning wavelength ranges from 327 to 800 nm with an excitation wavelength of 307 nm. We found out that when the concentration of FMIP nanoparticles was 0.5 mg mL-1, the solution showed an excellent quenching efficiency, thus 0.5 mg mL-1 of FMIP nanoparticles was the optimized concentration in fluorescent detection. PCM solution was added into FMIP nanoparticles buffer solution with stirring to obtain the PCM concentration ranging from 0 µM to 3 µM. The fluorescence quenching efficiency (Eq) can be calculated by the following equation: Eq=F0/F-1

(1)

Where F0 and F are fluorescent intensities of FMIP nanoparticles in the absence and presence of the template PCM, respectively. A linear relationship of PCM concentration and (F0/F-1) could be obtained by fitting. All the study of FNIP nanoparticles was performed under the identical conditions.

Results and discussion Synthesis and characterization of PANV-GMA The synthetic route of PANV-GMA was presented in Fig. 1. The hydrophilic monomer AA and hydrophobic monomer NVC were chosen to prepare the amphiphilic copolymer P(AA-co-NVC). In addition, 9-vinylcarbazole (NVC) was chosen for the introduction of fluorescence labeling into the FMIP nanoparticles. The introduction of GMA, who has a cross-linkable acrylate group, enables FMIP 7



nanoparticles to cross-link when exposed to UV light, contributing to the lock of recognition sites and stability of the nanoparticles. GPC analysis revealed that the molecular weight (Mn) of PANV-GMA was 22198 and the polydispersity index was 1.86.

Figure 1. Schematic illustration of the synthesis of P(AA-co-NVC) (a) and PANV-GMA (b).

The structures of P(AA-co-NVC) and PANV-GMA were characterized by 1H NMR spectroscopy and the results were shown in Fig. 2(a). The peak at 12.2 ppm belongs to the protons of carboxylic groups (He); the peak around 8.1 ppm is assigned to the protons who are close to N atom in carbazole groups (Ha, b, a*, b*); the peak near 7.4 ppm belongs to the protons who are away from N atom in carbazole groups and the protons connected to the C atom bonded to N atom (Hc, d, c*, d*,f). The signal for protons of carboxylic groups was not observed in the 1H-NMR spectrum owing to the exchange of protons. New signals around 6 ppm belong to the protons of the double bond, indicating the successful incorporation of double bonds into the polymer chain. The structure of PANV-GMA was further investigated by FTIR spectroscopy. As shown in Fig. 2(b), the peak around 3415 cm-1 belongs to the hydrogen bond of carboxylic groups; the peak at 1714 cm-1 corresponds to the C=O symmetric stretching mode for carboxylic groups; the bands at 1214 cm-1 and 1155 cm-1 belong to the C-O stretching mode for ester groups of GMA unit; the band at 744 cm-1 is assigned to the C-H out-of-plane deformation for ortho-substituted benzenoid rings of NVC[30]. All the results above indicate the successful synthesis of the copolymer PANV-GMA.

8


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Figure 2. The 1H-NMR spectra (a) of P(AA-co-NVC), PANV-GMA and FT-IR spectrum (b) of PANV-GMA.

Synthesis and characterization of FMIP nanoparticles Owing to the amphiphilic chain structure of PANV-GMA, it could assemble into nanoparticles in aqueous solution. In our work, during the assembly process of PANV-GMA, template PCM, crosslinker divinylbenzene (DVB), and photo-initiator benzoin dimethyl ether (DMPA) were also added to the assembly solution. Driven by the hydrophobic interaction as well as hydrogen bonding between copolymer with these compounds, a photo-crosslinkable fluorescent nanoparticle trapping with PCM, DVB and DMPA could be obtained. Upon the UV-irradiation, the methacrylate groups in the copolymer chain underwent free radical polymerization with DVB solubilized within the nanoparticles, leading to rigid and highly crosslinked nanoparticles trapping with PCM molecules, i.e., FMIP nanoparticles. The formation of FMIP nanoparticles was proved by the DLS and TEM investigations. As given in Fig. 3(a), the average particle size of FMIP nanoparticles was about 150 nm before UV-irradiation, while it decreased to about 114 nm after photo-crossing. This is reasonable considering a more compact structure resulted from photo-crosslinking process.31 In addition, FMIP nanoparticles were approximately spherical in TEM images (Fig. 3(b)), and photo-crosslinking did not change its morphology but led to a great decrease in size, in agreement with the DLS results. Moreover, all of the nanoparticles could disperse well and no cohesion happened during irradiation, demonstrating that no nanoparticles aggregation was caused by photo-crosslinking reaction between nanoparticles.32

9



Figure 3. Size distribution (a) and TEM images (b) of FMIP nanoparticles before and after irradiation As control samples, non-imprinted nanoparticles (FNIPs) were also prepared under the same experimental conditions except for the addition of PCM molecules. As shown in Fig. 4(a), the mean particle size of FNIPs is about 95 nm, smaller than 114 nm of the corresponding FMIP nanoparticles. As reported by literatures33, incorporation of other molecules might increase the diameter of nanoparticles, which gives an evidence of trapping of PCM molecules in FMIP nanoparticles. TEM images in Fig. 4(c) showed that both FNIP and FMIP nanoparticles were spherical and the particle size of FMIP nanoparticles was a bit larger than that of FNIP nanoparticles, which is consistent with DLS results. As a further confirmation of the entrapping of PCM molecules in FMIP nanoparticles, the FTIR spectra of PCM, FNIP and FMIP nanoparticles were recorded and shown in Fig. 4(b). For FNIP nanoparticles, the bands at 1214 cm-1 and 1155 cm-1 are assigned to the C-O stretching mode for ester groups, and the band at 744 cm-1 corresponds to the C-H out-of-plane deformation of ortho-substituted benzenoid rings[30]. The FTIR spectrum of FMIP nanoparticles exhibits similar bands to that of FNIP nanoparticles, while several new bands could also be observed at 1559 cm-1 and 804 cm-1, corresponding to the N-H bending mode and N-H out-of-plane bending of PCM[34], respectively. In addition, the new peak at 10


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834 cm-1 is assigned to the C-H out-of-plane deformation of p-substituted benzenoid rings of PCM. The above results provide the evidence of successful incorporation of PCM, testifying the successful fabrication of FMIP nanoparticles.

Figure 4. Size distribution (a) of FNIP and FMIP nanoparticles, FT-IR spectrum (b) of PCM, FNIP and FMIP nanoparticles and TEM images (c) of FNIP and FMIP nanoparticles.

Template extraction and rebinding of FMIP nanoparticles A suitable removal of the template in the FMIP nanoparticles leads to structurally-related binding sites in the polymeric matrix.35 Thus, an efficient elution progress is crucial for template rebinding. HAc was chosen as the elution reagent. The effect of elution was studied to evaluate the stability of the FMIP nanoparticles. When HAc was added into the dispersion, FMIP nanoparticles precipitated due to the protonation of carboxylic groups, which can re-disperse in water and form homogenous dispersion with blue-opalescent after the addition of Na2CO3 solution. In TEM images (Fig. 5(a)), no obvious difference in morphology and particle size of FMIP nanoparticles before and after elution could be observed, indicating the good stability of the FMIP nanoparticles. The fluorescent emissions of FMIP and FNIP nanoparticles before, after elution and after rebinding of PCM were shown in Fig. 5(b), (c). After the extraction of PCM, the fluorescence intensity of FMIP nanoparticles increased obviously as shown in Fig. 11



5(b). After rebinding with PCM, its fluorescence intensity decreased significantly. In other word, PCM plays a quenching effect for the fluorescence of FMIP nanoparticles. The above results demonstrate that the FMIP nanoparticles could recognize PCM and give a fluorescence response. This phenomenon might originate from the interactions between PANV-GMA chain and PCM molecules, which is responsible for the fluorescence quenching of the FMIP nanoparticles.

Figure 5. TEM images (a) of FMIP nanoparticles before and after elution, fluorescence emissions of FMIP nanoparticles (b) and FNIP nanoparticles (c) before, after elution and after rebinding of PCM.

Charge transfer from the PANV-GMA to PCM might result in the quench of the fluorescence. As shown in Fig. 6(a), there was no overlap between the absorption band of PCM and the fluorescent emission of PANV-GMA, indicating that the fluorescence resonance energy transfer (FRET) was not the quenching mechanism. Additionally, the absorption peak of PCM was close to the band gap of PANV-GMA, which meant that it was possible for charges to transfer from PANV-GMA to the bounded PCM. As shown in Fig. 6(b), the charge transfer might be due to the formation of hydrogen bond between the donor carbazole groups and the acceptor 12


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PCM. As reviewed by Mataga and Kubota36, if both the donor and the acceptor have conjugated π-electron systems, the fluorescence could be quenched, which is attributed to the π-electron delocalization interaction between the donor and acceptor molecules by the hydrogen bond. So when PCM rebinds with FMIP nanoparticles and goes into the imprinted sites, it becomes close enough to the proximity of PANV-GMA, which enable the efficient charge transfer and a maximum quenching.

Figure 6. UV-vis spectrum of paracetamol and PANV-GMA and the fluorescent emission of PANV-GMA (a) and schematic of the fluorescence quenching mechanism on the basic of the hydrogen bonding-induced charge transfer (b).

To demonstrate that the quenching effect was caused by the specific interaction of FMIP nanoparticles and PCM, FNIP nanoparticles were prepared and their fluorescence emissions before, after elution and rebinding of PCM were also investigated. As shown in Fig. 5c, only a slight change in fluorescence intensity of FNIP nanoparticles was observed during the elution and rebinding process under the same condition, suggesting that the fluorescence quenching is based on the binding affinity of the nanoparticles with PCM. For FMIP nanoparticles, the fluorescence quenching was probably owing to the shape complementation and specific interactions between recognition sites and PCM. In comparison, the smaller fluorescence quenching of FNIP nanoparticles might result from weak and nonspecific binding between the FNIP nanoparticles and PCM. Hence, the synthesized FMIP nanoparticles have the potential to specifically recognize PCM and give a fluorescence response. Optimization of the preparation conditions In order to obtain efficient fluorescence quenching efficiency, the experimental conditions of FMIP nanoparticles, including the amount of DVB, concentration of the template PCM and pH were optimized below in detail. To find out the influence of the crosslinker, different amounts of DVB were 13



employed in the preparation procedure. As shown in Fig. 7(a), when the amount of DVB increased from 2.5 µL to 5 µL, the quenching efficiency increased as well. The possible reason is that the increased amount of DVB preferably generates a more compact structure of FMIP nanoparticles, leading to a more obvious quenching efficiency. A maximum quenching efficiency was achieved at DVB amount of 5 µL. When DVB amount is over 5 µL, the quenching efficiency was significantly weakened, owing to the over-crosslinking of the FMIP particles, blocking the template removal and site accessibility. Thus, an optimized DVB amount of 5 µL was selected. The influence of the PCM concentration was also studied in the range of 0.01 mg mL-1 to 0.09 mg mL-1, as given in Fig. 7(b). The quenching efficiency increased with increasing PCM concentration because of the increased number of recognition sites. A maximum quenching efficiency was obtained at PCM concentration of 0.05 mg mL-1. When the PCM concentration was over 0.05 mg mL-1, the quenching efficiency significantly weakened. Hence, the optimized PCM concentration was 0.05 mg mL-1.

Figure 7. Effect of DVB amount (a) and PCM concentration (b) on the fluorescent quenching efficiency of the FMIP nanoparticles towards PCM.

The influence of pH on the particle size and quenching efficiency was also studied, and the results are shown in Figure 8. The pKa value of carboxylic acid is 4.5. As shown in Fig. 8c, at the pH of 3.76 and 4, precipitation could be observed for the FMIP nanoparticles dispersion. This might stem from the protonation of carboxylic acid groups on the particle surface, leading to the aggregation of FMIP nanoparticles. With the increase of pH from 4 to 7, the diameter of FMIP nanoparticles decreased sharply, owing to the deprotonation of carboxylic acid groups, which increased the electrostatic repulsion between FMIP nanoparticles and thus reduced their aggregation. With pH over 7, carboxylic acid groups were totally deprotonated and the diameter of FMIP nanoparticles remained stable due to the cross-linked structure and the 14


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electrostatic repulsion between FMIP nanoparticles. The quenching efficiency increased with increasing pH from 5 to 7, which is attributed to the weakened self-quenching stemmed from the particle aggregation. However, the quenching efficiency decreased slightly with further increase pH to 10. Hence, the optimized pH was 7.

Figure 8. Effect of pH on the particle size (a) and fluorescent response (b) of FMIP nanoparticles, and digital image of FMIP nanoparticles with different pH (c).

Optosensing properties of the prepared FMIP nanoparticles To investigate their sensing ability (including linearity and detection limit), FMIP nanoparticles were applied to detect PCM with different concentrations. Fig. 9(a) shows the fluorescent intensity of FMIP nanoparticles in the presence of various PCM concentrations. The fluorescent intensity of the FMIP nanoparticles decreased as the concentration of PCM increased. The decrease in the fluorescent intensity could be ascribed to the rebinding of PCM molecules, quenching the fluorescence of FMIP nanoparticles. The higher the PCM concentration, the more fluorescence being quenched, and thus the higher quenching efficiency. In addition, a fine linear relationship (Fig. 9(b)) was obtained with PCM concentration in the range of 4 µM~1000 µM. The regression equation is (F0/F-1) = 0.0873logCPCM (mol L-1) + 0.5059 (R2=0.997). The calibration curve deviated from the straight line when the concentration of PCM is above 1000 µM. The detection limit in this system was 1.0 µM.

15



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Figure 9. Fluorescent emissions obtained with FMIP nanoparticles in increasing PCM concentration (a) and the plot of quenching efficiency as a function of the concentration of PCM (from 1 µM to 3000 µM) on FMIP nanoparticles (the red line indicates the calibration curve in PCM concentration ranging from 4 µM to 1000 µM) (b).

To highlight the advantages of the fabricated FMIP nanoparticles, its analytical performance was compared with other sensors for PCM detection reported previously (Table 1). It can be seen that the FMIP nanoparticles offered a rather wide linear range, which might be attributed to their nanostructures bearing high surface-to volume ratio and accommodating more recognition sites close to their surfaces. Plenty of effective recognition sites in FMIP nanoparticles could lead to a wide linear range. Therefore, our FMIP nanoparticles prove to be excellent for fluorescent sensing of PCM. Table 1. Comparison of our prepared FMIP nanoparticles with other published sensors for PCM sensing. Detection limit

Linear range

(µM)

(µM)

Au NPs-DNS/MCNT

0.05

0.8~400

37

Imprinted TiO2 film

0.8

1~100

38

Ethynylferrocene-NiO/MCNT

0.5

0.8~600

39

AuNP-PGA/SWCNT

1.18

8.3~145.6

40

PAY/nano-TiO2

2.0

12~120

41

PEDOT

1.13

2.5~150

42

CE-UV/MS

8.3

83.3~331.1

43

C60

5

50~1500

44

FMIP nanoparticles

1.0

4~1000

Present work

Sensing materials

Reference

DNS: dopamine nanospheres; MCNT: mulwalled carbon nanotubes; PGA: electrochemically 16


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co-depositing glutamic acid; PAY: poly(acid yellow 9); PEDOT: poly(3,4-ethylenedioxythiophene); CE: capillary electrophoresis; UV: ultraviolet; MS: mass spectrometric.

In comparison with other detection methods, for example HPLC and TLC, the fluorescent analysis in this work was more efficient and simple. To study the dynamic binding performance of FMIP nanoparticles towards the template PCM, the fluorescent analysis was further carried out. As shown in Fig. 10(a), after incubation of the target molecules with FMIP nanoparticles, the fluorescent quenching efficiency could rapidly reach to equilibrium within 2 min. The result illustrated that the FMIP nanoparticles possessed very fast rebinding kinetics, which is possibly due to the large surface area, easy accessibility of recognition sites and complete removal of the templates. In other words, there are numerous effectively recognition sites at or near the surface of FMIP nanoparticles, which allowed complete template removal and fast rebinding kinetics. In addition, the quenching efficiencies of FMIP nanoparticles are much higher than those of FNIP nanoparticles under the same incubation time, demonstrating that the FMIP nanoparticles can recognize PCM more specifically, resulting from the imprinting effect. To check the selectivity of the FMIP nanoparticles prepared in this method, phenylalanine acid (PA) was chosen as the interfering specie with similar structure to the template PCM. Uric acid (UA) and ascorbic acid (AA) were also chosen for that they are frequently found together with PCM in biological fluids. Their chemical structures are presented in Fig. 10(c). Fig. 10(b) shows the fluorescent quenching efficiencies of PCM and its interfering species by FNIP and FMIP nanoparticles. It can be observed that the quenching efficiency of FMIP nanoparticles towards PCM was nearly 3 times that of FNIP nanoparticles. Moreover, the imprinting factor (Em/En) was calculated to evaluate the selectivity, where Em and En refer to the quenching efficiencies of the four compounds measured by the FMIP and FNIP nanoparticles, respectively. The values of Em/En for PCM, AA, UA and PA are 3.10, 1.28, 1.11 and 1.06. The highest Em/En value toward PCM indicated that the FMIP nanoparticles could specifically recognize PCM. And the much smaller Em/En values toward the three other compounds demonstrate the good selectivity of the FMIP nanoparticles. The high selectivity might originate from the recognition sites tailed by imprinting technology, which are complementary with both the shape and functional groups of PCM and hence unable to bind other molecules efficiently. Competitive experiments were further employed to prove the potential use of MIPs 17



in recognizing target protein from the mixture. As shown in Fig. 10(c), the presence of AA, PA or UA in PCM solution induced less than 10% of quenching efficiency change compared with that of pure PCM in solution, demonstrating no obvious interference of background molecules on the sensing performance of FMIP nanoparticles toward PCM. The competitive experiment further testifies the good selectivity of FMIP nanoparticles.

Figure 10. Quenching efficiencies recorded with FMIP and FNIP nanoparticles towards

PCM versus the incubation time (a), quenching efficiencies of FMIP and FNIP nanoparticles towards PCM and its interfering species (AA, PA, and UA) (b), the sensing performance of FMIP nanoparticles in different mixed solutions (PCM, PCM+AA, PCM+PA, and PCM+UA) (c) and chemical structures of its interfering species (d).

Determination of PCM in real samples To judge the practical application of FMIP nanoparticles, three commercial PCM tablets (100 mg tablet-1) were chosen for real sample detection. The tablets were grounded into powders and dissolved in water. The supernate after centrifugation was diluted within the working concentration range. The content of PCM in each tablet was evaluated employing our FMIP nanoparticles under the same condition. Each measurement was repeated for three times. As given in Table 2, the results agree well with the contents of PCM as manufacturers’ stated. Moreover, HPLC was employed as a reference method for the determination of PCM amount in the same commercial 18


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tablets. As shown in Table 2, the values found by our method were quite close to those by HPLC. Table 2. Determination of PCM in pharmaceutical samples. Declared (mg tablet-1)

Sample

Found (mg tablet-1) FMIP nanoparticles

HPLC

1

100

106.7 (RSD = 5.9%)

104.8 (RSD = 4.6%)

2

100

104.8 (RSD = 4.2%)

102.6 (RSD = 2.4%)

3

100

95.7 (RSD = 3.9%)

95.4 (RSD = 3.1%)

The practical application of FMIP nanoparticles was further validated with PCM-spiked human urine samples. The urine samples were collected from healthy volunteers. 2.5 ml of urine was diluted to 10 ml with PBS buffer solution (pH 7.0) and filtered through a 0.45 µm syringe filter. A certain amount of PCM was subsequently added. The obtained PCM-spiked human urine samples were then directly analyzed. As shown in Table 3, the recovery of the spiked sample was from 97.6% to 105.2%, coupled with acceptable standard derivations (RSD). All the results demonstrate that FMIP nanoparticles have good practical analytical utility. Table 3. Determination of PCM in human urine samples. Sample

Spiked (µM)

Recovery (%)

1

500

97.6 (RSD = 3.5%)

2

100

102.1 (RSD = 4.6%)

3

50

105.2 (RSD = 4.9%)

Conclusion We have reported a one-pot green synthesis of fluorescent molecular imprinted nanoparticles with good water compatibility via macromolecular assembly and in-situ photo-crosslinking. The whole procedure is simple in design, environmentally friendly in reaction conditions and economic in operation, which meets the principles of green chemistry. The obtained FMIP nanoparticles can both recognize PCM molecules and give sensitive signal response in aqueous media. A wide linear range from 4 µM to 1000 µM with detection limit of 1.0 µM has been demonstrated using FMIP nanoparticles as chemosensors with a fast response time (2 min). As a practical application, the prepared FMIP nanoparticles were successfully employed for direct, sensitive, and accurate drug quantification of commercial PCM tablets as well as 19



Page 20 of 25

urine samples.

Acknowledge The authors would thank Jiangnan University, Wuxi, for facilities support and the National Natural Science Foundation of China (NNSFC) Project (51573072), national first-class discipline program of Light Industry Technology and Engineering (LITE2018-19) and MOE & SAFEA for the 111 Project (B13025) for financial support.

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For Table of Contents Use Only

Synopsis: One-pot green synthesis of water-compatible fluorescent molecularly imprinted polymer nanoparticles for selective optosensing paracetamol was developed via assembly and photocrosslinking.

25


Green synthesis of water-compatible fluorescent molecularly imprinted

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