Construction of Persistent Luminescence-Plastic Antibody Hybrid

May 30, 2019 - Meanwhile, the properties of the prepared antibody may not be stable ..... In vivo NIR luminescence images of nude mice at different ti...
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Cite This: J. Agric. Food Chem. 2019, 67, 6874−6883

Construction of Persistent Luminescence-Plastic Antibody Hybrid Nanoprobe for In Vivo Recognition and Clearance of Pesticide Using Background-Free Nanobioimaging Dong-Dong Zhang,†,‡ Jing-Min Liu,§ Shi-Ming Sun,† Chang Liu,† Guo-Zhen Fang,*,† and Shuo Wang*,†,§ †

State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science & Technology, Tianjin 300457, P. R. China Tianjin Key Laboratory of Food Science and Health, School of Medicine, Nankai University, Tianjin 300071, P. R. China ‡ Collaborative Innovation Center of Henan Grain Crops, Henan Collaborative Innovation Center of Grain Storage and Security, Henan University of Technology, Zhengzhou 450001, P. R. China

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ABSTRACT: We prepared a specific adsorptive nanocarrier for pesticide due to its challenge to cleanup and low detoxification in the treatment after intake, whether intentional or by mistake. We modified the plastic antibody (molecularly imprinted polymer (MIP)) on the surface of persistent luminescence nanoparticle (La3Ga5GeO14: Cr3+, Zn2+, LGGO) as the specific adsorptive nanocarrier for toxic molecules and realized the nanocarrier was widely distributed for absorbing pesticide and realtime in vivo bioimaging. We used LGGO as the core and trichlorphon as the template to prepare the plastic antibody nanocarrier. After in vivo bioimaging and biodistribution of mice, LGGO@MIP could be distributed evenly in the gastrointestinal tract, circulated in the blood for a long time, and finally excreted to achieve the adsorption and removal of pesticide in the body. The LGGO@MIP nanocarrier prepared in this study opens a new way for the treatment of poisoning. KEYWORDS: persistent luminescence, plastic antibody, pesticide, specific adsorption, bioimaging



INTRODUCTION Pesticide, as an indispensable part of agricultural production, is a powerful tool for people to fight crop diseases and insect pests and ensure a good harvest of agriculture.1 However, the lack of safe storage could lead to accidental ingestion or the deliberate swallowing by someone attempting suicide, which could cause poisoning and even death. This continues to be a worldwide public health problem.2,3 According to epidemiological studies, up to 300 000 deaths in the world are caused by intentional swallowing of pesticides each year.4−6 The number of cases of pesticide poisoning has been increasing, especially in developing countries.7,8 Organophosphorus pesticides are the most common pesticides associated with these poisoning events. Organophosphorus pesticides inhibit the activity of acetylcholinesterase (AChE) and some other esterases in the body, resulting in the accumulation of acetylcholine in the nervous system. The excess accumulation of acetylchomine in the nerve cell often leads to continuous excitement of the cell, resulting in continuous excitement. The continuous excitement of nerve receptors can result in human organ dysfunction, respiratory failure, coma, and death.9,10 In the treatment of pesticide poisoning, if the poison is taken orally, the first step is to expel the drug that is not absorbed in the stomach from the body; it includes vomiting and adsorption. Vomiting and adsorbing are two commonly used effective physical therapies in the treatment of poisoning. Some toxic substances absorbed slowly by the body could be completely removed by these two methods. Vomiting, repeated decompression, and gastric lavage are the methods generally used to remove the unabsorbed pesticides directly from the stomach in vitro. There are some adsorbents, such as granular © 2019 American Chemical Society

activated carbon, that would be used to further adsorb the residual pesticides in the stomach.11,12 In the second step, sufficient cholinesterase resurrection agents (such as atropine and oximes) are used repeatedly.13−15 However, treatment with anticholinesterase drugs has not improved significantly in the past 50 years.10,13 To improve the therapeutic effect of pesticide poisoning, various attempts have been made, including the establishment of standardized procedure for gastric lavage, the establishment of standardized nursing process, the combination of multiple detoxification drugs, and so on, as well as the treatment of blood replacement.8,13,16 However, the development of specific drug adsorbents used in the treatment of pesticide poisoning is limited, and the treatment using drugs is simplistic in many cases with a limited cure rate and is often accompanied by sequelae. The limited and costly development of therapeutic drugs is due to the longer drug-development cycle and the high cost of drug research and development.6,17 Therefore, we should start at an early stage in the potential exposure process to remove the exposure to pesticides as thoroughly as possible. As an important immune method to identify and specifically bind the invading antigen in vivo, antibodies have the advantages of high specificity and selectivity, which can quickly and accurately remove the foreign antigens and play an important role in the body immunity.18,19 The preparation process of natural antibodies is complicated, the preparation Received: Revised: Accepted: Published: 6874

April 30, 2019 May 29, 2019 May 30, 2019 May 30, 2019 DOI: 10.1021/acs.jafc.9b02712 J. Agric. Food Chem. 2019, 67, 6874−6883

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Journal of Agricultural and Food Chemistry cycle is longer, and an antibody needs to be prepared in the animal body. It is expensive. Meanwhile, the properties of the prepared antibody may not be stable for extended periods of time, they may require special storage conditions, and the actual use conditions may be harsh.20,21 Within a rapidly developing subgroup of polymer chemistry, the emergence of molecular imprinting technology is playing an increasingly important role in target recognition. The prepared molecularly imprinted polymer (MIP), known as plastic antibody, not only has higher specificity and selectivity than that of a natural antibody but also can be more easily synthesized using simple monomers with high stability and more easily suitable to large batch preparation. MIP has two characteristics in adsorbing target molecules: (i) the special configuration of imprinted template molecule in MIP and (ii) the chemical bonding between functional monomer and template molecule. It has become an ideal choice for biomimetic antibodies.22,23 In the process of preparation, the molecularly imprinted polymer is a polymer formed using the target molecule (pesticide) as the template. A functional monomer and a cross-linker are prepared under the action of the initiator. After eluting the template drugs through the eluant, the MIP has formed a template with a three-dimensional structure of the moleculespecific hole. The prepared MIP has the specific pore structure of the target molecule, has the ability to adsorb the template molecule specifically, and is stable, reusable, and biocompatible. The MIP thus formed can be used for the poison adsorption in vivo.24−27 If the MIP is used for the adsorption of toxic and harmful substances in the organism, it would further reduce the absorption of poisons by the body, reduce the development of the toxic symptoms, and improve the cure rate.28,29 In the construction of a nanocarrier, consideration may be given to the use of persistent luminescence nanoparticles as the core. This would add the ability of realtime optical bioimaging of the targeted pesticide in vivo.30 Using biomimetic molecularly imprinted polymer as the adsorption layer and persistent luminescence nanoparticles as the luminescent core, we prepared a long afterglow bionic antibody nanocarrier LGGO@MIP. In this experiment, a plastic antibody was synthesized on the surface of persistent luminescence nanoparticles (LGGO@ MIP) using trichlorofon, as a model for the class of pesticides, as the template, methacrylic acid (MAA) as the functional monomer, ethylene glycol dimethacrylate (EDMA) as the cross-linker, and azobisisobutanonitrile (AIBN) as the initiator. The prepared LGGO@MIP achieved specific adsorption of pesticides and real-time bioimaging. In the preparation of plastic antibodies, we optimized the proportion of several components on the basis of previous studies, tested the elution times of the eluant, and tested the physiological and biochemical characteristics of the LGGO@MIP nanoparticles. Finally, we used the prepared LGGO@MIP nanoparticles as a bioimaging agent for in vivo bioimaging after oral administration and intravenous injection of mice (Figure 1).



Figure 1. Illustration of the synthesis and surface modification of LGGO and its application in in vivo bioimaging post oral administration and intravenous injection. (product no. A104256) were purchased from Aladdin Company, China. Characterization. The phosphorescence properties and structural and morphological characterization of the prepared materials were performed in accordance with literature references.31,32 The phosphorescence excitation and emission spectra and the afterglow decay curves of LGGO were recorded by a Lumina spectrofluorometer (Thermo Scientific, Waltham, MA, U.S.A.) equipped with a 150 W xenon lamp. X-ray diffraction (XRD) patterns were acquired on a Bruker AXS D8 Advance diffractometer (Bruker, Germany) equipped with Cu Kα radiation (λ = 1.5418 Å). The morphology and microstructure of the prepared LGGO were characterized by transmission electron microscope (TEM, JEM-2010FEF, JEOL, Japan) operating at accelerating voltage of 200 kV and equipped with a Phoenix 60T energy-dispersive spectrometer (EDS). Preparation of LGGO@MIP. The LGGO was synthesized by one-pot method in combination with calcination in air.31,32 The precipitated precursor was obtained by mixing gallium nitrate, lanthanum nitrate, chromium nitrate, zinc nitrate, and germanium nitrate according to the chemical formula of La3Ga5GeO14: 0.1% Cr3+, 1% Zn2+ under vigorous stirring. After adjusting pH value (determined by Whatman pH indicator paper) to 7.0 with tertbutylamine, the resulting solution was stirred for 2 h at room temperature. After that, the solution was mixed with oleic acid and toluene at a ratio of 15:2:15 as biphasic synthesis method. The mixture was transferred to Teflon-lined stainless steel autoclave and kept at 120 °C for 24 h. After being cooled to room temperature, the resulting compound was precipitated upon addition of excess ethanol and washed with ethanol. Before being annealed in air at 1000 °C for 1 h, the prepared precipitate was dried at 80 °C for 4 h. The process for preparing LGGO nanoparticles as the core of LGGO@MIP is as follows. (Step 1) The harvested LGGO was placed in fresh methanol in a polypropylene centrifugal tube and treated with ultrasonic bath (KQ-500B, Ningbo Scientz Biotechnology Co., Ltd., Zhejiang, China) at room temperature until it was evenly dispersed. LGGO precipitation was obtained by centrifugation. This was repeated twice. The LGGO was suspended in 20 mL of fresh methanol in a glass flask with round bottom and treated with ultrasonic bath for 5 min. (Step 2) MAA (0.45 mmol) was added dropwise; after beubg treated with ultrasonic bath in the glass flask for 20 min, it was kept at 40 °C for 18 h with magnetic stirring. (Step 3) The resulting suspension was the LGGO-MAA (La3Ga5GeO14: Cr3+, Zn 2+ connected to methacrylic acid). It was collected by centrifugation, washed with ethanol 3 times, and suspended in 30 mL of acetonitrile solution. (Step 4) Trichlorfon (0.6 mmol) and 0.9

MATERIALS AND METHODS

Chemicals and Materials. All reagents used for synthesis were at least analytical grade. All the water used in the experiment was obtained through Milli-Q (Millipore, Bradford, MA, U.S.A.). All glassware should be soaked in aqua regia (HCl/HNO3 = 3:1, v/v) for at least 24 h and cleaned with ultrapure water. Trichlorofon (product no. 586164) was purchased from J&K Scientific Ltd., China. MAA (product no. M102640), EDMA (product no. E106223), and AIBN 6875

DOI: 10.1021/acs.jafc.9b02712 J. Agric. Food Chem. 2019, 67, 6874−6883

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Journal of Agricultural and Food Chemistry

Figure 2. Characterization of the prepared LGGO and LGGO@MIP/NIP. (A) TEM images of the LGGO@MIP (a, c) and LGGO@NIP (b, d). (B) Phosphorescence intensities of the LGGO and LGGO@MIP. (C) NIR luminescence images of LGGO@MIP at different times after excitation and LED reactive. (D) EDS image of the LGGO, LGGO-MAA, LGGO@MIP, and LGGO@NIP. (E) Size distributions of the LGGO and LGGO@MIP. (F) Zeta potential changes of the LGGO, LGGO-MAA, and LGGO@MIP. (G) XRD patterns of LGGO, LGGO@MIP, and LGGO@NIP compared with standard PDF cards. (H) Nitrogen adsorption and desorption isotherms of LGGO and LGGO@MIP. (I) Multipoint BET curve of LGGO@MIP. mmol MAA were added and stirred for 2 h. (Step 5) After 2 h, 1.2 mmol of EDMA and 10 mg of AIBN were added. (Step 6) The glass flask with the mixture was treated with ultrasonic bath for 20 min and kept stirring at 60 °C for 24 h under nitrogen. (Step 7) The resulting compound was washed with ethanol 3 times and suspended in 100 mL of methanol/acetic acid (8:2, v/v). This was followed by ultrasonic treatment for 3 h and stirring for 2 h; then the solution was replaced with fresh solution and the same treatment was repeated until there was no trichlorfon in the supernatant. The collected LGGO@MIP was washed 3 times by sterile phosphate-buffered saline (PBS) solution before use and finally suspended in PBS solution. As control, the LGGO modified without template polymer (La3Ga5GeO14:Cr3+, Zn2+@nonmolecularly imprinted polymer, LGGO@NIP) was prepared with the same procedures in the absence of trichlorfon. Adsorption of Trichlorfon on LGGO@MIP. The amount of triclorfon absorbed by LGGO@MIP was quantified by determining the concentration of trichlorfon in the supernatant before and after adsorption using high-performance liquid chromatography (HPLC) (1260, Agilent Technologies, Santa Clara, CA, U.S.A.) with UV detection; separation was achieved using a C18 column. The detection wavelength was 200 nm, the mobile phase was water/ acetonitrile = 9:1 (v/v), pH = 3.0 (regulated by phosphoric acid), and the flow rate was 1.5 mL/min. The column temperature was kept at 35 °C. The quantification was calculated by external reference standards. Cytotoxicity Assay. MC 38 and HeLa cells were used to evaluate the cytotoxicity of LGGO@MIP in this study. The MC 38 is a tumorigenic epithelial cell line isolated from mice with colon adenocarcinoma, and the HeLa cell is cancer cell line isolated from malignant cervical tumor; they were purchased from National

Infrastructure of Cell Line Resource, China. The MC 38 cell was cultured in RPMI Medium 1640 basic (Thermo Fisher Scientific, Suzhou, Jiangsu, China), and the HeLa cell was cultured in Dulbecco’s modified Eagle medium (DMEM) (Thermo Fisher Scientific, Suzhou, Jiangsu, China); 10% fetal bovine serum was added to all of them (Life Technologies, Inc., Gaithersburg, MD, U.S.A.). After 48 h of incubation, the cell concentration was adjusted to 104 mL−1, and 100 μL/well was added into 96-well microplates. Then, it was cultured in the 37 °C incubator containing 5% CO2. After being mixed with various concentrations of sterile LGGO@MIP (sterilization by ultraviolet radiation), the in vitro cytotoxicity of LGGO@MIP was assessed using the WST-1 Cell Proliferation and Cytotoxicity Assay kit (following the product instructions, Beyotime Biotechnology, Haimen, JiangSu, China). At last, the absorbance of 96-well microplates at 450 wavelength was measured by a Varioskan LUX spectrophotometer (Thermo Scientific, Vantaa, Finland). In Vivo Fluorescence Image of LGGO@MIP in Mice. All animal experiments were approved by the Animal Ethics Committee of Tianjin University of Science and Technology and followed the guidelines of the Tianjin Committee of Use and Care of Laboratory Animals. This requires us to have a standard feeding environment, to monitor the quality of mice regularly, to purchase qualified mice, and to limit the quality of food and water for mice. To minimize the impact on mice, all experiments on mice were carried out after the mice were anesthetized with chloral hydrate. Five-week-old nude mice (BALB/c-nu, weight 20−25 g) were purchased from National Institutes for Food and Drug Control, China. Before the animal experiments, the mice were fed in the laboratory environment for more than 7 days to allow the animals to adapt to the new environment. 6876

DOI: 10.1021/acs.jafc.9b02712 J. Agric. Food Chem. 2019, 67, 6874−6883

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Journal of Agricultural and Food Chemistry The concentration of LGGO@MIP was adjusted to 2 mg/mL, which was excited by UV for 5 min. Soon, 200 μL of LGGO@MIP was injected into anesthetized mice by gavage or caudal vein injection. The luminescence signal in mice was regularly acquired by a small animal imaging system (NightOWL LB983, Bethold Technologies, Bad Wildbad, Germany), and the LGGO@MIP in mice was repeatedly excited by a LED red lamp (650 nm) after the luminescence signal disappeared. LGGO@MIP was injected into anesthetized mice at the dose of 200 μL, 2 mg/mL; after 5 h, the mice were euthanized with an overdose of anesthetic to death. Then, the main organs of mice were collected and irradiated by the LED red lamp; the luminescence signal was acquired by the small animal imaging system (NightOWL LB983, Bethold Technologies, Bad Wildbad, Germany). Later, the collected organs were ground in an agate mortar, and the concentration of Ga3+ was determined by inductively coupled plasma mass spectrometry (ICP-MS) (7500CX, Agilent, Palo Alto, U.S.A.) after microwave digestion; the quantity of LGGO@MIP was calculated by the quantity of Ga3+. Detoxicate Test of LGGO@MIP on Poisoned Mice. All animal experiments were approved by the Animal Ethics Committee of Tianjin University of Science and Technology and followed the guidelines of the Tianjin Committee of Use and Care of Laboratory Animals. (Step 1) Twenty mice were randomly selected; 50 mg/mL trichlorfon solution was injected into mice by gavage at a dose of 380 mg/kg body mass. (Step 2) The prepared LGGO@MIP was injected into mice by gavage at a dose of 30 mg/kg immediately (within 1 min), which was used as adsorbent and antidote. (Step 3) The survival rate and body weight change of mice after 48 h were measured. Another group of mice received the same dose of trichlorfon solution treatment but did not have LGGO@MIP injected as control.

LGGO core) appeared. Obviously, this could increase the adsorption capacity of LGGO@MIP on target molecules. However, it also affects the particle size and luminescence characteristics of LGGO@MIP nanocarriers. As shown in Figure 2A (c, d) of TEM images, the particle size of nanocarriers was significantly increased. Previous studies have shown that the thicker MIP-coated nanocarriers could be used for the development of adsorbent and antidote in the gastrointestinal tract. In this study, we focus on the main features of LGGO@MIP nanocarrier with smaller particle sizes (∼100 nm) and its application on specific adsorption and in vivo bioimaging. Effect on Particle Size and Luminescence of LGGO. After the LGGO was modified with MIP, a layer of molecularly imprinted polymer was coated on the surface (Figure 2A), which resulted in a slight decrease of luminous intensity (decreased by 8.46%, Figure 2B) and a slight increase of nanoparticle size (Figure 2E). The particle size of LGGO@ MIP was measured by dynamic light scattering (DLS) method. The measured hydrate particle size was larger than that of TEM images, and the reason was explained by previous reports.35 The LGGO@MIP particle size ranged from 88.9 to 158 nm; the average particle size was 125 nm (PDI = 0.038). According to previous reports and our study,19,31 nanoparticles with this size range could be used not only in the gastrointestinal tract of mice but also in intravenous injection of mice. After modification, the MIP layer on the LGGO surface would inevitably affect the luminescence. First, the MIP layer would weaken the arrival of excitation light. Second, the MIP layer would weaken the emission of light. However, compared with LGGO, the luminescence intensity of the optimized LGGO@MIP still has 91.54% residual (Figure 2B), and after UV or LED red lamp excitation, the luminescence signal of LGGO@MIP could be captured continuously. It has ideal NIR luminescence images and would not affect the application of in vivo bioimaging (Figure 2C). Structural Characterization of LGGO@MIP. Compared with LGGO, EDS data revealed the reduction of C/O ratio (the ratio of the number of carbon atoms to oxygen atoms) in LGGO-MAA due to the C/O in MAA (C4H6O2), the changes of C/O ratio, and the appearance of P/Cl (the ratio of the number of phosphorus atoms to chlorine atoms) due to EDMA (C10H14O4), AIBN (C8H12N4), and trichlorfon (C4H8Cl3O4P) (Figure 2D). Modified by MAA and MIP, the zeta potential of LGGO decreased continuously (Figure 2F), which was beneficial not only to the stability of the nanocarrier system but also to the adsorption of positive potential molecules.35,36 The pure crystallization of LGGO, LGGO@MIP, and LGGO@NIP was confirmed by XRD (Xray diffraction) (Figure 2G); after modification by MIP and NIP, the peak intensity decreased but the position of the peak remained unchanged. This is consistent with La3Ga5GeO14 (ICSD no. 72-2464) and indicated that the crystal structure was stable and unchanged after MIP and NIP modification.37 Pore Size and Specific Surface Area of LGGO@MIP. Through the nitrogen adsorption and desorption isotherms of LGGO and LGGO@MIP (Figure 2H, I), when the pressure of nitrogen was low, the adsorption volume of nitrogen was small; when the pressure of nitrogen was high, the adsorption volume of nitrogen increased. This would indicate that the prepared LGGO@MIP was porous and the pore size was within the micropore range (75%, even in a high concentration of LGGO@MIP (400 μg/mL), and when the concentration of LGGO@MIP was CO at 1731 cm−1, the splitting stretching vibration of C−O−C at 1255 and 1160 cm−1, the out-of-plane deformation of −CH3 at 755 cm−1, and the stretching vibration of C−H in alkane at 2955 and 2987 cm−1 all indicated that the MIP on LGGO surface has complex covalent bonding, long chain structure, and high degree of 6878

DOI: 10.1021/acs.jafc.9b02712 J. Agric. Food Chem. 2019, 67, 6874−6883

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Figure 4. In vivo NIR luminescence images of nude mice at different times after oral administration and intravenous injection of LGGO@MIP.

Figure 5. NIR luminescence images of isolated organs of mice after oral administration (A) and intravenous injection (C) of LGGO@MIP for 5 h. (B) NIR luminescence images of feces after oral LGGO@MIP. (D) Quantification of LGGO@MIP in isolated organs of mice detected by in vivo imaging system. (E) Quantification of LGGO@MIP concentration in isolated organs of mice detected by ICP-MS.

activity was >95% (Figure 3D). This indicated that the prepared LGGO@MIP has low cytotoxicity. The long-term toxicity of LGGO@MIP was assessed by body weight change of mice. After 30 days of oral administration, the mice of LGGO@MIP treatment group and control were in good health without obvious disease and death. The results of mouse weight monitoring showed that there was no significant difference in weight change between the treatment and control, and the weight of mice increased slightly in 30 days (Figure 3C). This indicated that the mice were in good condition and LGGO@MIP had no obvious toxic and side effects. We prepared the section of MC38 or HeLa cells coculture with LGGO@MIP for TEM observation. When cells cocultured with LGGO@MIP grew normally, there was no significant difference in cell morphology under optical microscope. In the view of TEM, a large number of LGGO@MIP nanoparticles adhere to the cell membrane, and some of them could be free in the cytoplasm through the cell membrane (Figure 3E, F). The ability of LGGO@MIP to enter different cells indicated that it could be used to adsorb and remove target molecules in cells. Bioimaging of LGGO@MIP In Vivo of Mice. The mice were anesthetized before bioimaging, and it was approved. The

prepared LGGO@MIP had a long persistent luminescence after being excited by UV or LED red lamp; the NIR luminescence emitted by LGGO@MIP has strong penetration in mice and could be used for in vivo bioimaging. In this part, different bioimaging effects of different administration methods (oral administration and intravenous injection) were compared, and the prepared LGGO@MIP was irradiated under UV light for 5 min before oral administration or intravenous injection. Oral Administration. After oral administration, LGGO@ MIP showed strong luminescence signal in the mouth, esophagus, and stomach of mice (Figure 4). As time goes on, the luminescence signal in the mouth of mice gradually weakened, and the luminescence signal gradually gathered in the stomach and continuously moved in the intestinal tract. After oral administration for 40 min, the luminescence signals were mainly transferred from stomach to small intestine and moved along the distribution of the intestinal tract, which indicated that the LGGO@MIP moved continuously in the intestine of mice. After taking LGGO@MIP for 5 h, the luminescence signal of LGGO@MIP decreased continuously, and the luminous intensity was weak. After the re-excitation by the LED red lamp, the abdomen of the mice showed a strong luminescence signal, and the luminescence signal covered the 6879

DOI: 10.1021/acs.jafc.9b02712 J. Agric. Food Chem. 2019, 67, 6874−6883

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Journal of Agricultural and Food Chemistry

similar to our previous studies19,31,32 (Figure 5C, D). Although the liver had a strong luminescence signal due to the capture of a large number of LGGO@MIP, the concentration of LGGO@MIP in the spleen was higher than that in the liver (Figure 5E). As the largest immune organs in the body, the liver and spleen identify and capture foreign substances in blood. The efficiency of recognition and capture depends on the biochemical characteristics and morphology of nanoparticles; in this study, the prepared LGGO@MIP has small particle size, regular spherical shape, and abundant hydrophilic groups on its surface, which improves its stability, reduces the recognition probability of immune cells, and prolongs the circulation time in the blood. This avoids LGGO@MIP being captured by liver and spleen in a short time and is beneficial for LGGO@MIP to adsorb target molecules in blood. Detoxicate Test of LGGO@MIP on Poisoned Mice. After the mice were fed in the laboratory environment for more than 7 days, the average body weight of mice was 20.59 ± 1.29 g. A separate control group (10 mice) was treated with trichlorphon solution by gavage at 380 mg/kg according to the weight of mice. After administration of trichlorphon solution, the mice suffered from acute breathing, convulsions, limb weakness, and other obvious poisoning symptoms. Eight of 10 mice died within 30 min of dosing, and the remaining mice died within 1 h. In another treatment group, the LGGO@MIP was orally administered to 20 mice at a dose rate of 30 mg/kg body weight. After oral administration of trichlorphon solution, 20 mice were randomly selected for oral administration of LGGO@MIP. Three mice died within 1 h, and one additional mouse died shortly thereafter. Within 48 h of oral administration of LGGO@MIP suspension, the total survival rate was 80%. In the first few hours after that, the mice had the phenomena of breathlessness, convulsions, and limb weakness. After that, the mice ate freely but were not as active as before in cages, and 48 h later, the poisoning symptoms of mice improved significantly. In the LGGO treatment group, the average body weight of the 20 mice was 20.93 ± 1.68 g before treatment. After 48 h of oral administration of trichlorphon and LGGO@MIP, the average body weight of the surviving mice was 17.74 ± 1.79 g, indicating a slight decrease in body weight. This may be due to the fact that trichlorphon poisoning had not completely disappeared, affecting the normal activity and appetite of mice. When LGGO@MIP was used to adsorb toxic substances in vivo, some toxic substances were absorbed by mice and could not be completely adsorbed by LGGO@MIP. These results would indicate that some additional antidotes will be needed to improve the survival rate and reduce the sequential effects in the mice.52,53 In general, we have synthesized a novel nanocarrier (LGGO@MIP) for drug-specific adsorption and bioimaging and validated the detoxification effect on trichlorphon in mice. First, long persistent luminescence nanoparticles LGGO (La3Ga5GeO14: Cr3+, Zn2+) was prepared by one-pot method. Then, we modified the molecularly imprinted polymer with specific adsorption function on the surface of LGGO and constructed nanocarrier (LGGO@MIP) with bright nearinfrared luminescence and specific adsorption function. The prepared LGGO@MIP has small particle size, uniform size, good dispersion, high stability, and low biological toxicity. In this study, LGGO@MIP nanocarriers were constructed using trichlorphon as template to achieve adsorption equilibrium for trichlorphon in a short time. The fast adsorption rate has great

whole abdomen of the mice. This would indicate that the prepared LGGO@MIP had been distributed within the gastrointestinal tract of the mice after oral administration. If target molecules were in the gastrointestinal tract of the mice, it would be adsorbed (Figure 4). Twenty-four hours following the ending of the dose period, no obvious luminescence signal was detected in the mice, indicating that oral LGGO@MIP had been excreted from mice. The collected feces of mice had strong luminescence signal after being irradiated by UV. This indicated that the prepared LGGO@MIP passed through the stomach and intestine of mice and was excreted from the mice after oral administration. In this process, no obvious discomfort occurred in mice; after anesthesia recovery, the diet and activities of mice were normal, and no death occurred. This also showed that the prepared LGGO@MIP did not affect the body of mice, nor did it threaten the life and health of mice. Intravenous Injection. When the LGGO@MIP was injected into the mice through the tail vein, the LGGO@ MIP rapidly spread throughout the entire body as evidenced by a strong luminescence signal. A strong and evenly distributed luminescence signal persisted for 15 min after injection. This would indicate the uniform dispersion, small particle size, good stability, and abundant hydrophilic groups on the surface of the prepared LGGO@MIP. It is likely that these properties reduced the probability of the LGGO@MIP being intercepted by the liver and spleen and increased the circulation time in the blood.34,51 Thirty minutes after injection, the luminous signal in the head and limbs of the mice weakened. This would tend to indicate a decrease of LGGO@MIP concentration and the decay of luminous intensity (Figure 4). Therefore, we believe that the distribution of LGGO@MIP in mice is sufficient for adsorption of the target molecules for up to 1 h postinjection. The LGGO@MIP was gradually captured by liver and spleen, and only these organs showed the luminescence signal. Five hours after LGGO@MIP was injected into mice, the liver and spleen still showed strong luminescence signal after the re-excitation by the LED red lamp. This would indicate that most of the LGGO@MIP was captured by the liver and spleen but that there was sufficient material in the body to continue adsorbing the target molecules, especially the target molecules gathered in the liver. The luminescence signal was captured in the main organs of mice in the other group after taking LGGO@MIP for 5 h (Figure 5). After oral administration of LGGO@MIP for 5 h, the whole gastrointestinal tract of mice showed strong luminescence signal (Figure 5A/D), and the concentration of LGGO@MIP in stomach and intestine had no significant difference after ICP-MS detection (Figure 5E). This indicated that LGGO@MIP was well-distributed in the gastrointestinal tract of mice after oral administration, and its specific adsorption ability to target molecules could be used to uniformly adsorb free toxic drugs in the gastrointestinal tract. In addition, there were weak luminescence signals in the lungs, liver, and spleen of mice, which may be due to the absorption of LGGO@MIP into the blood circulation in the intestine and stomach. After LGGO@MIP was injected into mice via tail vein, it mainly flowed with blood circulation. After 5 h, the luminescence signals were mainly concentrated in the liver, spleen, and lungs of mice, and there were also weak luminescence signals in the heart and stomach, which was 6880

DOI: 10.1021/acs.jafc.9b02712 J. Agric. Food Chem. 2019, 67, 6874−6883

Article

Journal of Agricultural and Food Chemistry

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advantages in the development and application of adsorbents. Thanks to the bright near-infrared luminescence of LGGO and the repeated excitation by LED red lamp, LGGO@MIP could be used for in vivo long-term bioimaging applications. Through in vivo bioimaging, we found that LGGO@MIP could be uniformly dispersed in the intestine and stomach of mice after oral administration and excreted in vitro with feces, and when LGGO@MIP was injected into the blood circulation of mice through tail vein, it could circulate for a long time in vivo and then be captured by liver and spleen. We have confirmed in the mice that took trichlorphon orally that LGGO@MIP could be used to effectively adsorb trichlorphon in vivo and reduce the mortality of mice.



AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Tel.: +86-22-60912493. Fax: +86 22 6091 2493. *E-mail: [email protected]. Tel.: +86-22-85358445. ORCID

Dong-Dong Zhang: 0000-0001-9489-7995 Guo-Zhen Fang: 0000-0001-5346-953X Shuo Wang: 0000-0003-0910-6146 Funding

This work was supported by the Open Project Program of State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science & Technology (no. SKLFNS-KF201812). Notes

The authors declare no competing financial interest.



ABBREVIATIONS USED AIBN, azobisisobutanonitrile; BET method, Brunauer−Emmett−Taylor method, method of mathematical description of physical adsorption based on the theory of polymolecular (multilayer) adsorption; BJH method, Barrett−Joyner−Halenda method, method of calculating pore size distribution in a porous material using adsorption or desorption isotherms; C/ O ratio, the ratio of the number of carbon atoms to oxygen atoms; DLS, dynamic light scattering; EDMA, ethylene glycol dimethacrylate; EDS, energy-dispersive spectrometer; FT-IR, Fourier transform infrared spectroscopy; LED, light-emitting diode; LGGO, La3Ga5GeO14: Cr3+, Zn2+; LGGO@MIP, La3Ga5GeO14: Cr3+, Zn2+@ molecularly imprinted polymer; LGGO@NIP, La3Ga5GeO14: Cr3+, Zn2+@nonmolecularly imprinted polymer; LGGO-MAA, La3Ga5GeO14: Cr3+, Zn2+ connected to methacrylic acid; MAA, methacrylic acid; MIP, molecularly imprinted polymer; NIP, nonmolecularly imprinted polymer; NIR, near-infrared; P/Cl ratio, the ratio of the number of phosphorus atoms to chlorine atoms; TEM, transmission electron microscope; XRD, X-ray diffraction



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DOI: 10.1021/acs.jafc.9b02712 J. Agric. Food Chem. 2019, 67, 6874−6883