Carboxymethyl Chitosan Modified Carbon Nanoparticle for Controlled

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Functional Nanostructured Materials (including low-D carbon)

Carboxymethyl Chitosan Modified Carbon Nanoparticle for Controlled Emamectin Benzoate Delivery: Improved Solubility, pH-Responsive Release, and Sustainable Pest Control Saijie Song, Yuli Wang, Jing Xie, Baohong Sun, Ning-Lin Zhou, He Shen, and Jian Shen ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.9b12564 • Publication Date (Web): 28 Aug 2019 Downloaded from pubs.acs.org on August 29, 2019

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ACS Applied Materials & Interfaces

Carboxymethyl Chitosan Modified Carbon Nanoparticle for Controlled Emamectin Benzoate Delivery: Improved Solubility, pH-Responsive Release, and Sustainable Pest Control

Saijie Song,a,b Yuli Wang,a Jing Xie,a,c Baohong Sun,a Ninglin Zhou,a,d,* He Shen,b,* Jian Shena,*

a

National & Local Joint Engineering Research Center of Biomedical Functional

Materials, Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Jiangsu Engineering Research Center of Biomedical Functional Materials, Jiangsu Key Laboratory of Bio-functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, 210023, China b

CAS Key Laboratory of Nano-Bio Interface, CAS Center for Excellence in

Nanoscience, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, 215123, China c

Honors College, Nanjing Normal University, Nanjing, 210023, China

d

Institute of Agricultural Development, Nanjing Normal University, Nanjing, 210023,

China

*Corresponding authors: [email protected]

(N.

Zhou);

[email protected]

[email protected] (J. Shen)

ACS Paragon Plus Environment

(H.

Shen);

ACS Applied Materials & Interfaces 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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Abstract: Environmentally friendly pesticide delivery system has drawn extensive attention in recent years, which shows great promise in sustainable development of agriculture. We herein report a multifunctional nanoplatform, carboxymethyl chitosan modified carbon nanoparticles (CMC@CNP), as the carrier for emamectin benzoate (EB, a widely used insecticide), and investigate its sustainable anti-pest activity. EB was loaded on CMC@CNP nanocarrier via simple physisorption process, with a high loading ratio of 55.56 %. The EB@CMC@CNP nanoformulation showed improved solubility and dispersion stability in aqueous solution, which is of vital importance to its practical application. Different from free EB, EB@CMC@CNP exhibited pH-responsive controlled release performance, leading to sustained and steady EB release and prolonged persistence time. In addition, the significantly enhanced anti-UV property of EB@CMC@CNP further ensured its anti-pest activity. Therefore, EB@CMC@CNP exhibited superior pest control performance than free EB. In consideration of its low cost, easy preparation, free of organic solution, and enhanced bioactivity, we expect, CMC@CNP holds brilliant future in pest control and green agriculture.

Keywords: carbon nanoparticals; emamectin benzoate; pesticide delivery system; stimuli-responsive release; sustainable development



1 Introduction Pesticide plays an irreplaceable role in agriculture, and has made great contribution to the yield and quality of crop.1,2 Meanwhile, the low efficiency and overuse of pesticide also has caused serious problems, including environmental pollution, pesticide residue in soil and plant, and pesticide resistance of pest.3-5 Therefore, it is of vital importance to develop environmentally friendly vectors and smart pesticide delivery systems, which would overcome the current defects of traditional pesticides.6 During the past ten years, pesticide delivery system has drawn great attention for its sustained and steady pesticide release property and prolonged persistence period.7-9 The main efforts are focus on constructing multifunctional carrier based pesticide delivery systems,10 including mesoporous silica nanoparticles,11 polymer,12 clay,13 porous inorganic materials,14 and carbon nanomaterials15. Through adsorption or encapsulation process, pesticides can be effectively loaded on nanocarriers.16 For example, Cui group have reported polylactic acid (PLA) microspheres for chlorantraniliprole (CAP) delivery, and found that PLA encapsulated CAP exhibited controlled release behavior and improved stability to UV light and temperature.17 Inorganic mesoporous materials also play important role in pesticide delivery field. Recently, Wu and colleagues developed a high-loading porous CaCO3 based prometryn microspheres for weeds control, providing a promising approach to enhance the utilization and activity of pesticide.14 However, traditional polymers or mesoporous carriers often suffer from low pesticide loading capacity, relative complex synthesis steps, and limited production/output.18,19 The use of carbon


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nanomaterials as the vector for pesticides have drawn growing attention during recent years, because of their outstanding pesticide loading performance, ultrahigh stability and solubility, easy modified surface, and low risk to environment and organism.15,20 For instance, graphene oxide (GO), a 2D nanoplatform that widely used in drug delivery field, has been developed as high-efficiency vector for pesticides (e. g. hymexazol), and exhibited ultrahigh loading capacity, improved anti-UV property, and prolonged persistent period.21 Nevertheless, the poor stability of GO in acid solution and hard water would greatly hinder its practical application in agriculture.22,23 CNP, a small-sized carbon nanomaterial prepared from activated carbon, which possess excellent water solubility, stability, and biocompatibility, have been developed as smart nanotheranostic platform for tumor diagnosis and therapy, holding potential application in drug delivery and biomedicime.24-27 According to the previous reports, CNP based nanocarrier exhibits excellent drug loading performance (e. g. about 80 % loading rate of doxorubicin, a hydrophobic anticancer drug) and controlled drug release behavior.25,27 Moreover, the strong light absorption capability of CNP contributes to improved anti-photolysis of unstable molecules.26 Therefore, inspired by the satisfactory performance of CNP in nanomedicine, we infer that it should also have far prospect in pesticide delivery and plant protection field. Emamectin benzoate (EB) is an important derivative of avermectin family, which possesses much higher anti-pest activity than traditional pesticides.28,29 Since its ultrahigh-efficiency, low toxicity and broad spectrum characteristics, EB has been



widely used across the world for pest control, especially for lepidopteran pest, e.g. mythimna separata.30,31 However, the poor stability of EB under ultraviolet (UV) light irradiation results in fast degradation in field and rapid loss of biological activity, so its practical application in agriculture has been greatly limited.32,33 Besides, the poor solubility and burst release behavior of EB also leads to low activity for pest control.34 Moreover, the most-used traditional formulation, e.g. emulsifiable concentrate (EC), often contains high toxic solvent, which is not environmentally friendly. To overcome the above defects, mutifunctional nanoplatform and smart pesticide delivery strategy are of urgent demand. Natural polymers play important role in surface engineering of nanoparticles, which have been widely applied in catalysis,35,36 environment,37 drug delivery,38 and biomedical39-42 fields. Nanoparticles modified with natural polymers often possess stimuli-responsive property, and act as multifunctional carriers for constructing smart drug delivery system.38,43 Herein, in this work, we developed carboxymethyl chitosan (CMC, a natural polysaccharide that has been widely used as pH-response switch in drug delivery system)43 modified CNP as a multifunctional nanocarrier for controlled EB delivery and stimuli-responsive EB release (Scheme 1). As a high-efficiency carrier for EB, the loading capacity of CMC@CNP was calculated as high as 555.6 mg/g. The EB@CMC@CNP nanopesticide exhibited excellent solubility and dispersion stability in aqueous solution. Different from the burst release behavior of free EB, EB@CMC@CNP formulation possesses pH-responsive pesticide release behavior, which is vital to prolonging the persistence of EB. In addition, the


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outstanding anti-UV light property of EB@CMC@CNP further ensures its pest control activity. Therefore, the EB@CMC@CNP showed significant enhanced pest control activity. In consideration of the brilliant advantages, including simple preparation, outstanding water solubility and stability, controlled and sustained release behavior, free of organic solvents or additives, and enhanced anti-pest performance, we anticipate, EB@CMC@CNP formulation holds brilliant promise in plant protection and sustainable agriculture.

Scheme 1. Schematic illustration of the preparation of EB@CMC@CNP and its application for pH-responsive pesticide release and sustainable pest control.



4 Experimental Section 4.1 Materials Activated carbon powder, 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) and carboxymethyl chitosan (CMC) was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., emamectin benzoate (EB) was obtained from Jiangsu Yangnong Chemical Co., Ltd., other chemical agents were obtained from Sinopharm Chemical Reagent Company. 4.2 Characterizations The morphology of of EB@CMC@CNP was determined by 200 kV transmission electron microscopy (TEM, JEM-2100F, Japan). The surface chemical characteristics were studied by fourier transform infrared spectrometer (FTIR, Thermo Nicolet 6700). The hydrate particle size and zeta-potential of samples were collected by a Malvern analyzer (ZEN3600-nanoZS). The adsorption spectra were determined by UV-Vis-NIR spectrophotometer (Cary 5000). 4.3 Synthesis of CMC@CNP CNP was synthesized by fast oxidation of activated carbon (AC) in a mixed solution of HNO3 and H2SO4. In brief, 0.25 g AC was added in a round-bottom flask with 24 mL HNO3/H2SO4 mixed solution (v/v=1:3), and then the mixture was treated by sonication for 12 min to form a homogeneous suspension. Next, the black suspension


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was kept at 125 ± 2 oC for 10 min in an oil-bath. The obtained hot suspension was poured into 100 mL D. I. water slowly. After which, NaOH and Na2CO3 was added to adjust its pH value to neutral. The obtained black-yellow production was further purified by dialysis (Mw=3500 Da) for at least 48 h. CMC@CNP was synthesized via amidation reaction. Briefly, 20 mg CMC and 30 mg EDC were added into 100 mL 0.1 mg/mL CNP solution under mild stirring for 2 h. The obtained solution was purified by ultrafiltration (10000 Da, 6000 rpm, 5 min) for 5 times. 4.4 Pesticide Loading Performance EB was loaded on CMC@CNP through a simple physical adsorption process. For a typically process, 10 mg adsorbent was added into 10 mL EB solutions (0, 0.2, 0.4, 0.6, 0.8, 1.0 mg/mL) and stirred for 30 min, after which the mixture was treated by centrifugation (13,000 rpm, 30 min) to remove excessive EB. The obtained EB@CMC@CNP was washed by D. I. water for 3 times and then dissolved in D. I. water for further use. The EB loading content (LC)19 was obtained from the following equation (equ.1): LC (%) = WEB/WCMC@CNP×100

(equ.1)

Where WEB is the weight of EB loaded on CMC@CNP (mg), WCMC@CNP is the weight of CMC@CNP which acts as the adsorbent (mg), respectively. Two classical adsorption isotherm models, Langmuir model (equ.2) and Freundlich model (equ.3), were used to deeply understand the adsorption progress of EB on



CMC@CNP: Ce Ce 1   qe qm qm K L

(equ.2)

1 ln qe  ln K F  ln Ce n

(equ.3)

Where Ce (mg/L) is the concentration of EB at equilibration, qe is the EB loading amount at equilibration, qm (mg/g) is the maximum loading amount of EB on CMC@CNP, KL (L/mg) is the Langmuir constant, n is an adsorption intensity constant, KF (g/L) is the Freundlich constant. 4.5 pH-Response Release Behavior of EB The EB release performance were surveyed by the following method: 10 mL EB@CMC@CNP solution (containing 10 mg EB) was added into a dialysis bag (8 k-14k Da) and then put in 1 L 30 % ethanol aqueous solution under mild stirring for 240 h. At various time points, the dialysate was collected and the EB concentration was measured by UV spectra at 245 nm. The free EB (dissolved in 30 % ethanol solution) was used as a control group. To investigate the pH value responsive EB release performance, the 30 % ethanol aqueous was adjusted to pH 5.0, 6.0 and 7.0 by PBS buffer. Other operations were similar with the above process. Two release kinetic models19 were used to analyze the release behavior of EB from CMC@CNP, including Korsmeyer-Peppas model (equ.4) and Higuchi model (equ.5):

M t / M   kt n

(equ.4)


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M t / M   kt 0.5

(equ.5)

Where Mt (mg) is the cumulative EB release amount at various time points, M∞ (mg) is the total EB release amount at equilibration, k (d-n) is the kinetic constant, t (d) is the time points, n is a constant which is relevant to release mechanism. 4.6 Stability Analysis 4.6.1 Colloidal Stability EB@CMC@CNP solution was added in a glass bottle and then kept still for 48 h. The sedimentation ratio was observed to evaluate its stability. 4.6.2 Storage Stability at Low or High Temperature EB@CMC@CNP aqueous solutions (containing 1 mg/mL EB) were added in glass bottles and kept at 0 oC for 7 d or 54 oC for 14 d. Then, the content of EB was detected by UV spectra. 4.6.3 Long-Term Storage Stability EB@CMC@CNP formulation in a glass bottle was placed in a dark, dry and ventilated place for 1 year, and the content of EB was detected every 2 months. 4.6.4 Stability in Different Aqueous Solution 10 mg/mL EB@CMC@CNP formulation was diluted to 100-fold by different solutions, including D. I. water, standard hard water, tap-water in Nanjing, Nanning, Zhengzhou and Beijing, respectively. The stability of EB@CMC@CNP formulation in different conditions were evaluated by observing the precipitation.



4.7 Photostability Performance EB or EB@CMC@CNP were added into 24-well plates and dried by freeze drying. Then, the plates were irradiated under a 36 W UV lamp (254 nm, 20 nm) for 0, 1, 2, 4, 8, 12, 24, 36, 48, 72, 96, and 120 h. After which, the EB concentration in different groups were detected by UV-vis spectra. The degradation process was studied by pseudo-first-order kinetic model,44 according to equ.6:

ln

Mt   kt M0

(equ.6)

Where Mt (mg) is the degradation mass of EB at time point t, M0 (mg) is the initial EB mass, k (h-1) is the degradation kinetic constant. 4.8 Anti-Pest Activity Maize leaves were treated by contacting with different concentration of EB or EB@CMC@CNP (containing 0, 0.25, 0.5, 1, 2, 4, 8, 16 mg/L of EB, respectively) for 10 s, and then dried in the air for 4 h. After which, the above maize leaves were used to feed mythimna separata for 48 h. The dead mythimna separata were counted to evaluate the anti-pest activity of free EB and EB@CMC@CNP formulation. The persistent anti-pest activity of EB or EB@CMC@CNP was also surveyed. In a typically process, EB ethanol solution or EB@CMC@CNP aqueous solution were sprayed uniformly at a density of 10 mg/m2, respectively. Following by, all of the maize samples were put in the standardized greenrhouse in Jiangsu Yangnong


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Chemical Co., LTD. At 0, 1, 2, 4, 7, 10, 14 d, the maize leaves of different groups were picked to feed mythimna separata. The dead ratio of mythimna separata in each group was recorded to evaluate the sustained anti-pest activity of free EB or EB@CMC@CNP formulation.

3 Results and Discussions 3.1 Synthesis and Characterization of EB@CMC@CNP CNP was prepared by oxidation of activated carbon in a mixed acid solution. Then, CMC was grafted on the surface of CNP to further enhance its stability and acted as a stabilizer and pH responsive switch. The as-prepared CMC modified CNP was used as the carrier for hydrophobic pesticide EB. By simple physisorption progress, EB@CMC@CNP formulation formed, and the loading rate of EB reached 55.56 %. The EB@CMC@CNP exhibits excellent solubility in water, which is mainly due to the outstanding solubility of CMC@CNP. As the photographs of EB@CMC@CNP showed in Figure S1, all of the samples present clear, homogeneous, and stable condition. No precipitation or phase separation occurs at each concentration (0.001-10 mg/mL). The morphology of CMC@CNP and EB@CMC@CNP were investigated by TEM image (Figure 1a and 1b). As showed in Figure 1b, EB@CMC@CNP present approximately spherical shape, with a size about 12 nm. The nanoscale EB@CMC@CNP contributes greatly to its solubility in aqueous solution, because the



ultrasmall size is benefit to improve the solubility of hydrophobic matter.45,46 The hydrate particle size of EB@CMC@CNP is 28.21 nm, as shown in Figure 1c. The value is larger than that obtained from TEM ,because of the hydration effect of nanoparticles in aqueous solution, as Wang group has reported.47 The surface change properties of CMC, CNP, CMC@CNP, and EB@CMC@CNP were evaluated by zeta potential (showed in Figure 1d), respectively. The surface chemical property of EB@CMC@CNP was studied by FTIR spectra. Showed in Figure 2, obviously, the specific peaks at 3434 cm-1 (O-H stretching vibration), 1631 cm-1 (C=O stretching mode of N-acetylgluscosamine), 1400 cm-1 (symmetric stretching vibration of COO-), 1095 cm-1 (C-O stretching vibration), 1048 cm-1 (stretching vibration of C-O-C) are belongs to CMC, respectively.48 The specific peaks at 2966 cm-1 (C-H stretching vibrations of aromatic ring from benzoate fraction), 1730 cm-1 (C=O stretching vibration of acrylics ester), 1629 cm-1 (C=C stretching vibration), 1460 and 1382 cm-1 (C-H skeleton vibration), 1168, 1114, and 1056 cm-1 (C-O stretching vibration, O-H flexion, C-O-C flexion), 986 cm-1 (bending vibration of C-H flexion outside the plane in an aromatic ring or C=C cis bond) are assignable to EB, respectively.49 Compared with CNP, the corresponding peaks of CMC and EB occurred in EB@CMC@CNP, solidly verifying the formation of EB@CMC@CNP.


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a

b

20 nm

20 nm c

d

Figure 1. TEM images of (a) CMC@CNP and (b) EB@CMC@CNP. (c) Hydrate particle size of CMC@CNP and EB@CMC@CNP. (d) Zeta potential of CNP, CMC, CMC@CNP, EB@CMC@CNP.



Figure 2. FTIR spectra of EB, CNP, CMC, CMC@CNP, EB@CMC@CNP.

3.2 Pesticide Loading and pH-Responsive Release Performance CMC@CNP possesses excellent adsorption ability and acts as a satisfactory carrier for EB. As showed in Figure 3a, the specific absorbance peak of EB at 245 nm occurred in EB@CMC@CNP, indicating that EB has been successful loaded on CMC@CNP nanocarrier. The adsorption capacities of EB on CMC@CNP at different initial EB concentrations are also studied (Figure 3b). Obviously, the amount of EB on CMC@CNP increases with the initial EB concentration, and it tends to balance at high initial EB concentration. To further understand the loading behavior of EB on CMC@CNP, two classical adsorption isotherm models, Langmuir model and Freundlich model, are studied.50 By fitting the adsorption isotherm models (Figure S2


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and Table S1), we find, the adsorption progress fits Langmuir model well (R2=0.9976), and the maximum adsorption capacity of CMC@CNP is calculated as 555.6 mg/g. The high EB loading capacity of CMC@CNP is mainly inherited from the excellent adsorption ability of CNP, which can act as vector for both hydrophobic and hydrophilic molecules.24-26

Figure 3. (a) UV spectra of EB, CMC@CNP, and EB@CMC@CNP. (b) Pesticide loading capacity of CMC@CNP at different initial EB concentrations.

Traditional pesticide formulations, e. g. emulsifiable concentrate (EC), often present burst release behavior in surrounding environment, leading to significant reduced bioavailability and weakened pest control efficiency.14,19 Therefore, to control the loss of pesticides and enhance their anti-pest activity, multifunctional nanoplatform has been introduced as smart vector for stimuli-responsive pesticide release. The release behavior of free EB, EB@CMC and EB@CMC@CNP were showed in Figure 4a. Obviously, free EB releases into the medium solution with a very fast speed, which reaches 100 % within 24 h. On the contrast, EB@CMC@CNP exhibits excellent



slow-release performance, and EB can sustained escape from CMC@CNP nanocarrier after 240 h. The release progress of EB@CMC@CNP presents a relative fast period (10.04 % cumulative release during the initial 4 h) and gradual period (44.56 % cumulative release after 240 h), which fits the characteristic release pattern of controlled drug delivery system.51,52 This phenomenon is caused by the meta-stable combination of outer layer EB, which can easily escape from the carrier.53 The initial burst release and subsequent slow release behavior contributes to sustaining effective concentration for a long time, which is benefit for maintaining high anti-pest activity. The pH responsive release behavior of EB was further studied by adjusting the pH range of dialysate at room temperature. As showed in Figure 4b, after 20 d dialysis period, the cumulative release amount of EB from EB@CMC@CNP were 76.0 % (pH 5.0), 57.33 % (pH 6.0), and 47.7 % (pH 7.0), respectively. Obviously, the release speed and cumulative release amount of EB at acid condition were higher than that at neutral condition. Therefore, the acid pH value is benefit for EB release from CMC@CNP nanocarrier. The faster release of EB at acid pH is probably caused by the protonated amines and swelling process of CMC, which is similar to the previous reported drug release behavior of CMC based delivery system.54-56 To further confirm the active effect of CMC to pH responsive release behavior, the release performance of EB@CMC at different pH values were also studied (Figure 4b). The cumulative release amount of EB is much higher at acid condition than that at neutral condition.


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a

b

Figure 4. (a) The release performance of free EB EB@CMC, and EB@CMC@CNP (pH=7.0, T=298.15 K). (b) EB release performance of EB@CMC and EB@CMC@CNP at pH 5.0, 7.0 and 9.0,respectively.

To further understand the mechanism of EB release from CMC@CNP nanocarrier, two classical kinetic models, Korsmeyer-Peppas model and Higuchi model, were studied. The parameters of the release kinetics are listed in Table 1. Clearly, the release kinetics fitted Korsmeyer-Peppas model better, with higher regression coefficients (R2) than Higuchi model. The values of n were calculated as 0.2957, 0.2593, and 0.2158, respectively. Therefore, the release process of EB from CMC@CNP followed Fickian diffusion mechanism (n

Carboxymethyl Chitosan Modified Carbon Nanoparticle for Controlled

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