PH / glucose dual stimulation response controlled-release nano pesticide and preparation method thereof

Abstract

The invention discloses a pH / glucose dual stimulation response controlled release nano pesticide and a preparation method thereof.The nano pesticide comprises a carrier and an original pesticide, the carrier is formed by modifying an amino-containing iron-based MOF carrier material through 4-carboxyphenylboronic acid, and the carboxyl of the 4-carboxyphenylboronic acid is connected with the amino of the iron-based MOF carrier material through a reaction; the preparation method comprises the following steps: (1) carrying out an amidation reaction on an iron-based MOF carrier material and 4-carboxyphenylboronic acid to obtain a modified iron-based MOF carrier material MIL-CBA; and (2) loading the active compound on the carrier MIL-CBA to obtain the compound. According to the invention, the metal organic framework material carrier is modified by 4-carboxyphenylboronic acid, so that the metal organic framework material carrier has pH and glucose dual response, meanwhile, the adhesiveness of the raw pesticide on leaf surfaces is remarkably improved, pesticide loss caused by factors such as bounce and rain wash is reduced, and the pesticide effect is improved.

Description

Technical Field

[0001] The invention relates to the field of pesticides, and in particular to a pH / glucose dual stimulation responsive controlled-release nano pesticide and a preparation method thereof. Background Art

[0002] Traditional pesticide formulations generally have the disadvantages of poor water dispersion stability, easy sudden release, poor leaf retention, short effective period, and high environmental risks. In particular, traditional pesticide formulations (such as water-dispersible granules, emulsifiable concentrates, suspensions, etc.) have weak interaction with the leaves of target crops, and droplets are easily off-target during spraying and are easily washed into the environment after rain, resulting in low pesticide utilization and causing serious environmental pollution.

[0003] Prochloraz is a broad-spectrum, highly effective fungicide, but it has the disadvantages of being easily decomposed at high temperatures, easily causing pollution and harm to the environment and human body during use, and having poor water solubility, which often limits its practical application. The existing technology has improved the thermal stability and poor water solubility of Prochloraz, but the final release amount of the pesticide still needs to be improved. Summary of the invention

[0004] Purpose of the invention: The first purpose of the present invention is to provide a pH / glucose dual stimulus responsive controlled-release nanopesticide; the second purpose of the present invention is to provide a method for preparing the pH / glucose dual stimulus responsive controlled-release nanopesticide.

[0005] Technical solution: The pH / glucose dual stimulus responsive controlled-release nanopesticide described in the present invention includes a carrier and a raw drug. The carrier is an amino-containing iron-based MOF carrier material modified with 4-carboxyphenylboronic acid, and the carboxyl group of the 4-carboxyphenylboronic acid is reacted and connected with the amino group of the iron-based MOF carrier material.

[0006] Preferably, the mass ratio of the iron-based MOF carrier material to 4-carboxyphenylboronic acid in the carrier is (1:3) to (1:7). The ratio of the two has an impact on the sterilization result of the final nanopesticide preparation and the release amount of the pesticide in the sustained-release experiment. With the increase of the proportion of 4-carboxyphenylboronic acid, the sterilization and pesticide release effects first increase and then decrease, and the ratio is 1:5, which is the best.

[0007] Preferably, the organic ligand of the iron-based MOF carrier material is aminoterephthalic acid.

[0008] Preferably, the original drug is prochloraz, and the mass ratio of the carrier to the original drug prochloraz is (1:1) to (3:1). The ratio of the two has an impact on the bactericidal result of the final nanopesticide preparation and the release amount of the pesticide in the sustained-release experiment. As the ratio of the four carriers increases, the bactericidal and pesticide release effects gradually decrease, and the ratio is 1:1, which is the best.

[0009] The method for preparing the pH / glucose dual stimulus responsive controlled release nanopesticide of the present invention is characterized by comprising the following steps:

[0010] (1) dissolving an iron-based MOF carrier material in a solvent, adding 4-carboxyphenylboronic acid, and then adding a catalyst 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to cause an amide reaction, and after the reaction is completed, centrifuging, washing, and drying to obtain a modified iron-based MOF carrier material MIL-CBA;

[0011] (2) The original drug is loaded on the carrier MIL-CBA to obtain a pH / glucose dual-responsive pesticide controlled release nanopesticide.

[0012] The structure of the modified iron-based MOF carrier material MIL-CBA is:

[0013]

[0014] Preferably, in step (1), the reaction temperature is 20 to 30° C., and the reaction time is 2 to 6 hours.

[0015] Preferably, in step (1), the reaction solvent is ethanol.

[0016] Preferably, in step (1), the preparation method of the iron-based MOF carrier material is: dissolving aminoterephthalic acid and iron salt in N,N-dimethylformamide, mixing them evenly, performing a hydrothermal reaction, centrifuging and washing after the reaction, and drying to obtain the iron-based MOF carrier material MIL-101 (Fe).

[0017] Preferably, the hydrothermal reaction temperature is 100-120° C., and the reaction time is 24-36 hours.

[0018] In step (2), the method for loading the original drug on the carrier MIL-CBA is: mixing MIL-CBA and the original drug, adding a solvent, grinding evenly, and drying to obtain.

[0019] When the original drug is prochloraz, the solvent is acetone.

[0020] Invention mechanism: Metal organic framework materials have large specific surface area, rich internal pores, controllable synthesis routes, easy surface modification, and good biocompatibility. The present invention selects iron-based metal organic framework materials as carriers of pesticides. The iron-based MOF material MIL is a regular octahedral structure, has more sites available for grafting, and is easy to surface modify. 4-carboxylphenylboronic acid is used to modify the iron-based MOF material. The boric acid group on the modified material is easy to react with the 1,2-diol and 1,3-diol parts of the sugar substance to form a reversible ester bond of the sugar reaction material. The ester bond breaks under acidic and glucose competitive reaction conditions, thereby forming a drug delivery system with dual response characteristics of pH and glucose. pH response is to enable nanopesticides to achieve precise control of pesticide release according to pH changes in the environment, thereby improving the control effect of pesticides. In this scheme, the grafted phenylboronic acid increases the release of nanopesticide preparations under weak acid conditions. Similarly, under the condition of glucose stimulation response in the external environment, the release of pesticides will also increase.

[0021] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) The metal organic framework material carrier MIL has dual response to pH and glucose after being modified with 4-carboxyphenylboronic acid; (2) The metal organic framework material carrier MIL can significantly improve the adhesion of the original drug on the leaf surface after being modified with 4-carboxyphenylboronic acid, reduce the loss of pesticides caused by factors such as bouncing and rain erosion, and improve the efficacy; (3) The original drug is loaded on the carrier, the drug has good stability, a wide range of use, high efficiency, low environmental pollution, simple operation, and high economic benefits; (4) The preparation process is simple and easy to industrialize. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The infrared spectra of MIL, MIL-CBA, Pro-MIL-CBA prepared in Example 1 and the original drug Pro in Comparative Example 1;

[0023] Figure 2 Thermal analysis diagrams of MIL, MIL-CBA, Pro-MIL-CBA prepared in Example 1 and the original drug Pro of Comparative Example 1;

[0024] Figure 3 The water contact angle diagram of the prepared Pro-MIL-CBA and the original drug Pro of comparative example 1;

[0025] Figure 4 This is the sustained release diagram of the Pro-MIL-CBA nanopesticide preparation prepared in Example 1 at different pH values.

[0026] Figure 5 This is the sustained release diagram of the Pro-MIL-CBA nanopesticide preparation prepared in Example 1 at different glucose concentrations;

[0027] Figure 6 The figure shows the bactericidal effect of the prepared Pro-MIL-CBA and the original drug Pro of comparative example 1 on the cervical cavity fungus at different concentrations. DETAILED DESCRIPTION

[0028] The technical solution of the present invention is further described below in conjunction with embodiments.

[0029] Example 1

[0030] The preparation method of the pH / glucose dual stimulation responsive controlled release nanopesticide of the present invention comprises the following steps:

[0031] (1) Preparation of MIL

[0032] 0.225 g of aminoterephthalic acid and 0.675 g of ferric chloride hexahydrate were respectively dissolved in 7.5 mL of N, N-dimethylformamide solution, the two solutions were ultrasonically mixed and placed in a reactor, and reacted at an oven temperature of 110°C for 24 hours. The solution after the reaction was washed with N, N-dimethylformamide and dried in an oven at 60°C for 10 hours to obtain MIL-101 (Fe).

[0033] (2) Preparation of MIL-CBA

[0034] 100 mg of MIL was dissolved in 100 mL of ethanol and mixed by ultrasonication. 500 mg of 4-carboxyphenylboronic acid was added. 100 mg of catalyst EDC was added every half an hour (a total of 300 mg of EDC was added). The mixture was stirred and reacted for 2 hours at room temperature. The reactant was centrifuged with ethanol for 3 times and dried in an oven at 60°C for 10 hours to obtain MIL-CBA.

[0035] (3) Preparation of Pro-MIL-CBA

[0036] Mix 50 mg of MIL-CBA and 50 mg of Pro in a mortar, add 2-3 mL of acetone, grind evenly, and dry naturally to obtain Pro-MIL-CBA.

[0037] Example 2

[0038] The preparation method of the pH / glucose dual stimulation responsive controlled release nanopesticide of the present invention comprises the following steps:

[0039] (1) Preparation of MIL

[0040] 0.225 g of aminoterephthalic acid and 0.675 g of ferric chloride hexahydrate were respectively dissolved in 7.5 mL of N, N-dimethylformamide solution, the two solutions were ultrasonically mixed and placed in a reactor, and reacted at an oven temperature of 110°C for 24 hours. The solution after the reaction was washed with N, N-dimethylformamide and dried in an oven at 60°C for 10 hours to obtain MIL-101 (Fe).

[0041] (2) Preparation of MIL-CBA

[0042] 100 mg of MIL was dissolved in 100 mL of ethanol and mixed by ultrasonication. 300 mg of 4-carboxyphenylboronic acid was added. 100 mg of catalyst EDC was added every half an hour (a total of 300 mg of EDC was added). The mixture was stirred and reacted for 2 hours at room temperature. The reactant was centrifuged with ethanol for 3 times and dried in an oven at 60°C for 10 hours to obtain MIL-CBA.

[0043] (3) Preparation of Pro-MIL-CBA

[0044] Mix 50 mg of MIL-CBA and 25 mg of Pro in a mortar, add 2-3 mL of acetone, grind evenly, and dry naturally to obtain Pro-MIL-CBA.

[0045] Example 3

[0046] The preparation method of the pH / glucose dual stimulation responsive controlled release nanopesticide of the present invention comprises the following steps:

[0047] (1) Preparation of MIL

[0048] 0.225 g of aminoterephthalic acid and 0.675 g of ferric chloride hexahydrate were respectively dissolved in 7.5 mL of N, N-dimethylformamide solution, the two solutions were ultrasonically mixed and placed in a reactor, and reacted at an oven temperature of 110°C for 24 hours. The solution after the reaction was washed with N, N-dimethylformamide and dried in an oven at 60°C for 10 hours to obtain MIL-101 (Fe).

[0049] (2) Preparation of MIL-CBA

[0050] 100 mg of MIL was dissolved in 100 mL of ethanol and mixed by ultrasonication. 700 mg of 4-carboxyphenylboronic acid was added. 100 mg of catalyst EDC was added every half an hour (a total of 300 mg of EDC was added). The mixture was stirred and reacted at room temperature for 2 hours. The reactant was centrifuged with ethanol for 3 times and dried in an oven at 60°C for 10 hours to obtain MIL-CBA.

[0051] (3) Preparation of Pro-MIL-CBA

[0052] Mix 60 mg of MIL-CBA and 20 mg of Pro in a mortar, add 2-3 mL of acetone, grind evenly, and dry naturally to obtain Pro-MIL-CBA.

[0053] Example 4

[0054] The preparation method of the pH / glucose dual stimulation responsive controlled release nanopesticide of the present invention comprises the following steps:

[0055] (1) Preparation of MIL

[0056] 0.225 g of aminoterephthalic acid and 0.675 g of ferric chloride hexahydrate were respectively dissolved in 7.5 mL of N, N-dimethylformamide solution, the two solutions were ultrasonically mixed and placed in a reactor, and reacted at an oven temperature of 110°C for 24 hours. The solution after the reaction was washed with N, N-dimethylformamide and dried in an oven at 60°C for 10 hours to obtain MIL-101 (Fe).

[0057] (2) Preparation of MIL-CBA

[0058] 100 mg of MIL was dissolved in 100 mL of ethanol and mixed by ultrasonication. 500 mg of 4-carboxyphenylboronic acid was added. 100 mg of catalyst EDC was added every half an hour (a total of 300 mg of EDC was added). The mixture was stirred and reacted at room temperature for 6 hours. The reactant was centrifuged with ethanol for 3 times and dried in an oven at 60°C for 10 hours to obtain MIL-CBA.

[0059] (3) Preparation of Pro-MIL-CBA

[0060] Mix 50 mg of MIL-CBA and 25 mg of Pro in a mortar, add 2-3 mL of acetone, grind evenly, and dry naturally to obtain Pro-MIL-CBA.

[0061] Comparative Example 1

[0062] The original drug prochloraz was not treated in any way.

[0063] Structural characterization

[0064] The MIL, MIL-CBA, Pro-MIL-CBA prepared in Example 1 and the original drug Pro in Comparative Example 1 were characterized by infrared spectroscopy. The results are as follows: Figure 1 shown.

[0065] from Figure 1 It can be seen that the characteristic peak position of MIL is mainly at 1697cm -1 、1572cm -1 、1130cm -1, which correspond to the stretching vibration of C=O on MIL, the skeleton vibration of benzene ring and the stretching vibration of CF, respectively, indicating that the iron-based MOF material MIL has been formed. From the comparison of the infrared spectra of MIL-CBA and Pro-MIL-CBA, it can be seen that Pro-MIL-CBA has a peak at 1570cm -1 、1372cm -1 A new absorption peak appeared, which is the characteristic peak of Pro, indicating that Pro has been successfully loaded.

[0066] Performance Testing

[0067] 1. Thermal stability test

[0068] The thermal stability of MIL, MIL-CBA, Pro-MIL-CBA prepared in Example 1 and the original drug Pro of Comparative Example 1 was tested. The results are as follows: Figure 2 shown.

[0069] Depend on Figure 2 It can be seen that the decomposition temperature of Pro-MIL-CBA is significantly higher than that of the original drug Pro, indicating that the synthesized nanopesticide preparation has good thermal stability.

[0070] 2. Pesticide water contact angle test

[0071] The water contact angles of Pro-MIL-CBA prepared in Example 1 and the original drug Pro in Comparative Example 1 were tested.

[0072] Test method: Prepare solutions of Pro and Pro-MIL-CBA with a concentration of 1 mg / mL and mix them with 1 mg / mL Rhodamine B dye solution in equal volumes. Rinse and dry the harvested kiwifruit leaves and place them on a glass slide. Drop the two sample solutions on the leaves and observe and record the changes in the contact angle at different times. Test results are as follows: Figure 3 shown.

[0073] Depend on Figure 3 It can be seen that with the increase of time, the water contact angles of Pro-MIL-CBA and original drug Pro both decreased significantly, but the water contact angle of Pro-MIL-CBA was always smaller than that of Pro, which proved that Pro-MIL-CBA had good wettability, better fixation effect on the leaves, and higher utilization rate.

[0074] 3. pH response performance test

[0075] The Pro-MIL-CBA prepared in Example 1 was subjected to sustained-release experiments under different pH conditions.

[0076] Test method: Put Pro-MIL-CBA into a dialysis bag (5 mL), and then put the dialysis bag containing the sample into a 30% ethanol solution, and adjust the solution pH to 5.0, 7.0, and 9.0 respectively. Place the beaker on a magnetic stirrer, take out 4 mL of the sustained-release solution at regular intervals, and use a UV spectrophotometer to measure its absorption wavelength at 208 nm. The test results are as follows: Figure 4 shown.

[0077] Depend on Figure 4 It can be seen that the release of active ingredients in nanopesticide preparations is mainly divided into two stages. In the first 48 hours, Pro is released very quickly, which may be due to the detachment of Pro attached to the surface; in the last 48 hours, Pro is released slowly. It can be seen from the figure that the cumulative release rate is 68.21% at pH 5; the cumulative release rate is 48.93% at pH 7; and the cumulative release rate is 46.74% at pH 9. The results show that the protonation of 4-carboxyphenylboronic acid under weak acidic conditions is more conducive to the release of Pro.

[0078] 4. Glucose response performance test

[0079] The Pro-MIL-CBA prepared in Example 1 was subjected to sustained-release experiments at different glucose concentrations.

[0080] Test method: Put Pro-MIL-CBA into a dialysis bag (5mL), and then put the dialysis bag containing the sample into a 30% ethanol solution, with or without 10M mol glucose. Place the beaker on a magnetic stirrer, take out 4mL of the sustained-release solution at regular intervals, and measure its absorption wavelength at 208nm using a UV spectrophotometer. Test results are as follows: Figure 5 shown.

[0081] Depend on Figure 5 It can be seen that after adding 10 Mmol of glucose to the sustained-release solution, the cumulative release rate becomes 61.9%, which is greatly increased compared with the case without glucose. The results show that after adding glucose, glucose cuts off the phenylboronic acid ester bond through competitive coordination, which is more conducive to the release of Pro.

[0082] 5. Sterilization effect test

[0083] The bactericidal effects of Pro-MIL-CBA prepared in Example 1 and the original drug Pro in Comparative Example 1 at different concentrations were tested.

[0084] Test method: Prepare solid culture medium containing different concentrations of Pro-MIL-CBA and Pro respectively. Use a 5mm diameter puncher to punch holes at the edge of the cavity after 7 days of culture to obtain a bacterial cake. The mycelium side of the bacterial cake is placed in the prepared solid culture medium. After sealing the culture medium with sealing film, place it in a 28℃ constant temperature shaking box to observe the growth of the colony. The test results are as follows: Figure 6shown.

[0085] Depend on Figure 6 It can be seen that with the increase of the concentration of the nanopesticide preparation, the colony diameter of the spore bacteria is significantly reduced. Compared with the same concentration of Pro, the antibacterial effect of Pro-MIL-CBA prepared in Example 1 is slightly lower, which may be due to the relatively small amount of active ingredients in the nanopesticide. However, with the increase of concentration, the antibacterial effect of Pro-MIL-CBA is significantly improved. When the concentration is 1ug / mL, the colony diameters after treatment with Pro and Pro-MIL-CBA do not increase significantly. The results show that the bactericidal effect of Pro-MIL-CBA is greater than that of the original drug, proving that the synthesized nanopesticide preparation has a good bactericidal effect.

Claims

1. A pH / glucose dual stimulus response controlled release nanopesticide, characterized in that: The invention comprises a carrier and a raw drug. The carrier is an iron-based MOF carrier material containing amino groups modified by 4-carboxyphenylboronic acid, and the carboxyl group of the 4-carboxyphenylboronic acid is reacted and connected with the amino group of the iron-based MOF carrier material.

2. The pH / glucose dual stimulus responsive controlled release nanopesticide according to claim 1, characterized in that: The mass ratio of the iron-based MOF carrier material to 4-carboxyphenylboronic acid in the carrier is (1:3) to (1:7).

3. The pH / glucose dual stimulus responsive controlled release nanopesticide according to claim 1, characterized in that: The organic ligand of the iron-based MOF carrier material is aminoterephthalic acid.

4. The pH / glucose dual stimulus responsive controlled release nanopesticide according to claim 1, characterized in that: The original drug is prochloraz, and the mass ratio of the carrier to the original drug prochloraz is (1:1) to (3:1).

5. A method for preparing a pH / glucose dual stimulus responsive controlled release nanopesticide according to any one of claims 1 to 4, characterized in that: The following steps are involved: (1) dissolving an iron-based MOF carrier material in a solvent, adding 4-carboxyphenylboronic acid, and then adding a catalyst 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide to cause an amide reaction, and after the reaction is completed, centrifuging, washing, and drying to obtain a modified iron-based MOF carrier material MIL-CBA; (2) The original drug is loaded on the carrier MIL-CBA to obtain a pH / glucose dual-responsive pesticide controlled release nanopesticide.

6. The method for preparing the pH / glucose dual stimulus responsive controlled release nanopesticide according to claim 5, characterized in that: In step (1), the reaction temperature is 20 to 30° C. and the reaction time is 2 to 6 hours.

7. The method for preparing the pH / glucose dual stimulus responsive controlled release nanopesticide according to claim 5, characterized in that: In step (1), the solvent is ethanol.

8. The method for preparing the pH / glucose dual stimulus responsive controlled release nanopesticide according to claim 5, characterized in that: In step (2), the method for loading the original drug on the carrier MIL-CBA is: mixing MIL-CBA and the original drug, adding a solvent, grinding evenly, and drying to obtain.

9. The method for preparing the pH / glucose dual stimulus responsive controlled release nanopesticide according to claim 5, characterized in that: In step (1), the preparation method of the iron-based MOF carrier material is: dissolving aminoterephthalic acid and iron salt in N,N-dimethylformamide, mixing them evenly, performing a hydrothermal reaction, centrifuging and washing after the reaction, and drying to obtain the iron-based MOF carrier material MIL-101 (Fe).

10. The method for preparing the pH / glucose dual stimulus responsive controlled release nanopesticide according to claim 9, characterized in that: The hydrothermal reaction temperature is 100-120° C., and the reaction time is 24-36 hours.

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