CN109535354B - Nanocluster with bactericidal effect and preparation method and application thereof - Google Patents
Nanocluster with bactericidal effect and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a nano-cluster with bactericidal effect and a preparation method and application thereof, wherein the nano-cluster with bactericidal effect has the following structural formula:
wherein the numerical ranges of x, y and z are 1-100 respectively, m is 4 or 5, and n is 5 or 6. The nano-cluster with the bactericidal effect can be prepared into a solution with a certain concentration to be directly sprayed on the surface of a wound,can be used for treating and preventing various bacterial infections. The nano cluster with the bactericidal effect has good water solubility, the concentration of the solution is 5-30 mu g/mL in terms of the concentration of silver particles, the best effect is achieved, and the wound of a mouse is completely healed in 6-8 days generally.
Description
Technical Field
The invention relates to a water-soluble cross-linked nano polymer, in particular to a nano cluster with a bactericidal effect and a preparation method and application thereof.
Background
Staphylococcus aureus is a gram-positive coccoid bacterium, which is arranged in a grape string under a microscope and is a common pathogenic bacterium causing food poisoning. It is commonly found on the skin surface and in the mucosa of the upper respiratory tract. The american centers for disease control report that infections caused by staphylococcus aureus are second place, second only to escherichia coli. Staphylococcus aureus is a pathogenic bacterium causing serious infection, and can cause infection at different sites of human body, from slight infection of epidermis to deep and fatal infection, such as pneumonia, endocarditis, septicemia, osteomyelitis and other metastatic complications.
The nanoparticles are nanoparticles between 1-200 nm. Mainly used for antibiosis in biotechnology, bioengineering, textile engineering and other aspects. The nano particles are small in particle size and high in specific surface area, can be quickly adsorbed on the surface of a cell membrane, can remarkably change physiological functions such as permeability and respiratory function of bacteria and cause bacterial death, however, pure inorganic nano (taking silver nano as an example) has the advantages of high sterilization efficiency and wide sterilization range, but has high biological toxicity, pure nano clusters have good physical and chemical stability and low toxicity, but the sterilization efficiency is low, the sterilization range is narrow and drug resistance is easy to generate, and polymers and the nano clusters are combined, so that the advantages of the polymer and the nano clusters can be effectively combined to avoid disadvantages, and the nano-particle has a wide application prospect.
Disclosure of Invention
Based on the above technology and background, the invention provides a nano-cluster with bactericidal effect and a preparation method and application thereof aiming at the defects of the existing antibacterial material.
The invention relates to a nano cluster with bactericidal effect, which has the following structural formula:
wherein the numerical ranges of x, y and z are 1-100 respectively, m is 4 or 5, and n is 5 or 6.
The preparation method of the nano-cluster with the bactericidal effect takes 4-cyano-4- (phenylthiocarbonylthio) pentanoic acid as a chain transfer agent, Azodiisobutyronitrile (AIBN) as an initiator and polyethylene glycol monomethyl ether methacrylate and polyethylene glycol methacrylate as raw materials, and firstly synthesizes the nano-cluster containing hydroxyl; then, taking hydroxyl-containing nano-clusters, bromocaproyl chloride and triethylamine as raw materials, and synthesizing to obtain bromo-containing nano-clusters; then, a nano-cluster containing a bromo group and a potassium thioacetate raw material are synthesized to obtain a nano-cluster containing a thioester group, then the nano-cluster is cut off under the conditions of piperidine and N, N' -dimethylformamide to obtain a nano-cluster containing a mercapto group, and finally a target product is obtained through in-situ polymerization.
The preparation method of the nano-cluster with the bactericidal effect comprises the following steps:
step 1: synthesis of nanoclusters
Under the protection of nitrogen, adding chain transfer agents 4-cyano-4- (phenylthiocarbonylthio) valeric acid, an initiator Azobisisobutyronitrile (AIBN), polyethylene glycol monomethyl ether methacrylate (300), polyethylene glycol methacrylate (360) and Ethylene Glycol Dimethacrylate (EGDMA) into a Schlenk tube, performing three cycles of oil pump pumping, liquid nitrogen freezing and nitrogen gas charging, wherein each cycle is performed for 8-12 times, after the cycle is finished, heating to 60-100 ℃, stirring for reacting for 8-24 hours, settling in ice n-hexane after the reaction is finished, and performing vacuum drying to obtain a hydroxyl-containing nano cluster;
wherein the molar ratio of the chain transfer agent 4-cyano-4- (phenylthiocarbonylthio) pentanoic acid, the initiator Azobisisobutyronitrile (AIBN), the polyethylene glycol monomethyl ether methacrylate (300), the polyethylene glycol methacrylate (360) and the Ethylene Glycol Dimethacrylate (EGDMA) is 0.1-10:0.01-1:1-100:1-100: 0.1-1.
Step 2: esterification reaction
Adding the hydroxyl-containing nano-cluster obtained in the step (1), bromocaproyl chloride and triethylamine into a two-mouth bottle with a double-row pipe and stirring magnetons according to the molar ratio of 0.1-1:0.1-5:0.1-6, and reacting at normal temperature for 8-24 hours to synthesize a bromo-containing nano-cluster;
and step 3: substitution reaction
Adding the bromine-containing nanocluster obtained in the step (2) and potassium thioacetate into a two-mouth bottle with a double-row pipe and a stirring magneton according to the molar ratio of 0.1-2:0.2-5, and reacting at normal temperature for 8-24 hours to synthesize a thioester-containing nanocluster;
and 4, step 4: cleavage reaction
Adding the nano-cluster containing thioester group obtained in the step 3 into a mixed solution of piperidine and N, N' -dimethylformamide, and reacting at normal temperature for 3-10 hours to obtain a nano-cluster containing sulfhydryl;
the volume ratio of the piperidine to the N, N' -dimethylformamide in the mixed solution is 0.1-10: 0.2-20.
And 5: in situ polymerization
Dissolving 20-80mg of the thiol-containing nanocluster obtained in the step 4 in 5-50mL of deionized water, and adding 1-30mg of NaBH4Dropwise adding AgNO with concentration of 0.01-20mg/mL3The solution is 1-100mL, and the target product can be obtained.
On one hand, the water-soluble polymer with the size less than 200nm can be obtained, and on the other hand, the introduction of the silver nanoparticles in the polymer has good bactericidal performance.
In step 1, the synthesis process of the nanoclusters is as follows:
the organic solvent is selected from tetrahydrofuran, N' -dimethylformamide, chloroform or dioxane, etc.
In the step 2, the esterification reaction process of the hydroxyl and the bromocaproyl chloride is as follows:
the organic solvent is selected from tetrahydrofuran, N' -dimethylformamide, chloroform or dioxane, etc.
In step 3, the substitution reaction process of bromo and potassium thioacetate is as follows:
the organic solvent is selected from tetrahydrofuran, N' -dimethylformamide, chloroform or dioxane, etc.
In step 4, the reaction process for cleaving thiol groups is as follows:
the organic solvent is selected from tetrahydrofuran, N' -dimethylformamide, chloroform or dioxane, etc.
In step 5, the process of in-situ polymerization synthesis of silver nano particles is as follows:
the solvent is selected from water.
The application of the nano-cluster with the bactericidal effect is to prepare a solution with a certain concentration to be directly sprayed on the surface of a wound for treating and preventing infection of various bacteria.
The nano cluster with the bactericidal effect has good water solubility, the concentration of the solution is 5-30 mu g/mL in terms of the concentration of silver particles, the best effect is achieved, and the wound of a mouse is completely healed in 6-8 days generally.
The nano-cluster with the bactericidal effect is simple to prepare, the used materials are environment-friendly, and the nano-cluster has great potential application value in the field of biological medical treatment.
Compared with the prior art, the invention has the beneficial effects that:
1. the nano-cluster is designed and prepared by a reversible addition-fragmentation chain transfer polymerization (RAFT polymerization) method, and the nano-cluster prepared by the method has controllable molecular weight and inherits the excellent water-solubility of the polyethylene glycol methacrylate.
2. The invention adopts polymerization reaction, has simple and quick application, simple and convenient post-treatment, controllable reaction conditions and good repeatability, and is easy to realize industrial production.
3. The method adopts the in-situ synthesis nano-cluster technology, effectively reduces the use of organic solvent, has simple and easy operation method, and can stably distribute and exist in water, and the prepared nano-cluster has stable and uniform size. Compared with pure silver particles or polymers, the nano-cluster prepared by the method has lower toxicity and is expected to be widely applied to the aspect of bacterial infection.
It should be noted that, on the basis of the common general knowledge in the art, the above conditions can be arbitrarily combined to obtain the preferred embodiment of the present invention.
Drawings
FIG. 1 is an infrared spectrum of a nanocluster before and after a change from a thioester group to a thiol group, and it can be seen from FIG. 1 that the thiol-group-containing nanoclusters are all 2500cm-1A thiol-characteristic absorption peak appears, but does not appear in the thioester-containing nanocluster, so that the thioester-based nanocluster is cut off, and the obtained product is the thiol-containing nanocluster.
Fig. 2 is a graph of the particle size distribution of the resulting nanoclusters in Dynamic Light Scattering (DLS). As can be seen from FIG. 2, the water-soluble crosslinked nano-polymer has a good particle size distribution with a size of about 200 nm.
Fig. 3 is a Transmission Electron Microscope (TEM) image of the obtained water-soluble nanocluster with a scale of 200nm, and it can be seen from fig. 3 that the silver particles on the surface of the nanocluster with bactericidal effect are uniformly distributed, and have regular size, and the size is about 15 nm.
Fig. 4 is a graph showing the bactericidal effect of the conventional silver particles.
FIG. 5 is a graph of the bactericidal effect of nanoclusters synthesized by the present invention.
Detailed Description
The present invention will be described in further detail with reference to specific examples. It should be understood that the following examples are illustrative of the present invention only and are not intended to limit the scope of the present invention.
Example 1:
1. 0.028g (0.0001mol) of 4-cyano-4- (phenylthiocarbonylthio) pentanoic acid, 0.0016g (0.00001mol) of Azobisisobutyronitrile (AIBN), 2.7g (0.009mol) of polyethylene glycol monomethyl ether methacrylate (OEGMA-300), 0.36g (0.001mol) of polyethylene glycol methacrylate (OEGMA-360), 0.007928g (0.00004mol) of Ethylene Glycol Dimethacrylate (EGDMA) were charged into a Schlenk's tube under nitrogen, 10ml of N, N' -dimethylformamide was added as a solvent, and three cycles of evacuation-freezing-aeration were carried out 10 times per cycle. After circulation, the temperature is raised to 70 ℃, the mixture is stirred to react for 12 hours, and then the mixture is settled in normal hexane and then is dried in vacuum. Obtaining hydrophilic nanoclusters containing hydroxyl groups, wherein the yield is 98%;
2. taking 2.98g of the hydrophilic nanocluster containing hydroxyl prepared in the step 1 as a raw material, adding 0.85g (0.004mol) of bromohexanoyl chloride and 0.606g (0.006mol) of Triethylamine (TEA) into a two-mouth bottle with a double-row pipe and a stirring magneton, and adding 10ml of N, N' -dimethylformamide as a solvent. After 12h of reaction, it was filtered and settled in n-hexane. The settling was repeated three times and then dried under vacuum. Obtaining hydrophilic nanoclusters containing bromine groups with the yield of 90%;
3. taking 2.8g of the hydrophilic nanocluster containing the bromo group prepared in the step 2 as a raw material, adding 0.68g (0.002mol) of potassium thioacetate (KsAc) into a two-mouth bottle with a double-row pipe and a stirring magneton, and adding 10ml of N, N' -dimethylformamide as a solvent. After reaction for 12h, filtering, and settling in n-hexane to obtain hydrophilic nanoclusters containing thioester groups with a yield of 95%;
4. taking 2.7g of the hydrophilic nanocluster containing the thioester group prepared in the step 3, adding piperidine and 6mLN, N' -dimethylformamide with a molar ratio of 3mL into a double-ported bottle provided with a double-ported tube and a stirring magneton as solvents, reacting for 12h, filtering, and settling in N-hexane to obtain the hydrophilic nanocluster containing the sulfhydryl group, wherein the yield is 86%;
5. adding 50mg of sodium borohydride into 2.55g of sulfhydryl-containing hydrophilic nanocluster raw material prepared in step 4 in a single-neck bottle with stirring magnetons, and dropwise adding 10mg/mL of silver nitrate (AgNO)3) And reacting the solution for 5 hours, centrifuging and redissolving to obtain the nano-cluster with the bactericidal effect.
Example 2:
1. under nitrogen, 0.014g (0.00005mol) of 4-cyano-4- (phenylthioformylthio) pentanoic acid, 0.0032g (0.00002mol) of Azobisisobutyronitrile (AIBN), 2.4g (0.008mol) of polyethylene glycol monomethyl ether methacrylate (OEGMA-300), 0.72g (0.002mol) of polyethylene glycol methacrylate (OEGMA-360), 0.003964g (0.00002mol) of Ethylene Glycol Dimethacrylate (EGDMA) were added to a Schlenk's tube, 20ml of dioxane was added as a solvent, and three cycles of evacuation-freezing-aeration were performed 15 times per cycle. After circulation, the temperature is raised to 80 ℃, the mixture is stirred to react for 10 hours, and then the mixture is settled in normal hexane and then is dried in vacuum. Obtaining hydrophilic nanoclusters containing hydroxyl groups, wherein the yield is 90%;
2. taking 2.81g of the hydrophilic nanocluster containing hydroxyl prepared in the step 1 as a raw material, adding 0.64g (0.003mol) of bromohexanoyl chloride and 0.505g (0.005mol) of Triethylamine (TEA) into a two-mouth bottle with a double-row pipe and a stirring magneton, and adding 20ml of dioxane as a solvent. After 10h of reaction, the mixture was filtered and settled in n-hexane. The settling was repeated three times and then dried under vacuum. Obtaining hydrophilic nanoclusters containing bromine groups with a yield of 91%;
3. taking 2.5g of the hydrophilic nanocluster containing the bromo group prepared in the step 2 as a raw material, adding 0.34g (0.003mol) of potassium thioacetate (KsAc) into a two-mouth bottle with a double-row pipe and a stirring magneton, and adding 20ml of dioxane as a solvent. After reaction for 10h, filtering, and settling in n-hexane to obtain hydrophilic nanoclusters containing thioester groups with a yield of 87%;
4. taking 2.1g of the hydrophilic nanocluster containing the thioester group prepared in the step 3, adding piperidine and 5mLN, N' -dimethylformamide with a molar ratio of 5mL into a double-ported bottle provided with a double-ported tube and a stirring magneton as solvents, reacting for 10 hours, filtering, and settling in N-hexane to obtain the hydrophilic nanocluster containing the sulfhydryl group, wherein the yield is 89%;
5. adding 10mg of sodium borohydride into 1.8g of sulfhydryl-containing hydrophilic nanocluster raw material prepared in step 4 in a single-neck bottle with stirring magnetons, and dropwise adding 1mg/mL of silver nitrate (AgNO)3) The solution is reacted for 8h, centrifuged and redissolved. Obtaining the nano-cluster with bactericidal effect.
Example 3:
1. under nitrogen, 0.028g (0.0001mol) of 4-cyano-4- (phenylthiocarbonylthio) pentanoic acid, 0.0016g (0.00001mol) of Azobisisobutyronitrile (AIBN), 2.7g (0.009mol) of polyethylene glycol monomethyl ether methacrylate (OEGMA-300), 0.36g (0.001mol) of polyethylene glycol methacrylate (OEGMA-360), 0.007928g (0.00004mol) of Ethylene Glycol Dimethacrylate (EGDMA) were charged into a Schlenk's tube, 15ml of N, N' -dimethylformamide was added as a solvent, and evacuation-freezing-aeration were carried out for 10 cycles each. After circulation, the temperature is raised to 70 ℃, the mixture is stirred to react for 16 hours, and the mixture is settled in normal hexane and then is dried in vacuum. Obtaining hydrophilic nanoclusters containing hydroxyl groups, wherein the yield is 89%;
2. taking 2.65g of the hydrophilic nanocluster containing hydroxyl prepared in the step 1 as a raw material, adding 0.64g (0.003mol) of bromohexanoyl chloride and 0.505g (0.005mol) of Triethylamine (TEA) into a two-mouth bottle with a double-row pipe and a stirring magneton, and adding 15ml of N, N' -dimethylformamide as a solvent. After 16h of reaction, it was filtered and settled in n-hexane. The settling was repeated three times and then dried under vacuum. Obtaining the hydrophilic nanocluster containing the bromine group, wherein the yield is 96%;
3. using 2.41g of the hydrophilic nanocluster containing the bromo group prepared in the step 2 as a raw material, adding 0.3426g (0.003mol) of potassium thioacetate (KsAc) into a two-mouth bottle with a double-row pipe and a stirring magneton, and adding 15ml of N, N' -dimethylformamide as a solvent. After 16h of reaction, filtering and settling in n-hexane to obtain the hydrophilic nano-cluster containing the thioester group with the yield of 88%.
4. Taking 2.1g of the hydrophilic nanocluster containing the thioester group prepared in the step 3, adding piperidine and 6mLN, N' -dimethylformamide with a molar ratio of 3mL into a double-ported bottle provided with a double-ported tube and a stirring magneton as solvents, reacting for 16h, filtering, and settling in N-hexane to obtain the hydrophilic nanocluster containing the sulfhydryl group, wherein the yield is 88%;
5. adding 50mg of sodium borohydride into 1.75g of sulfhydryl-containing hydrophilic nanocluster raw material prepared in step 4 in a single-neck bottle with stirring magnetons, and dropwise adding 1mg/mL of silver nitrate (AgNO)3) The solution is reacted for 5h, centrifuged and redissolved. Obtaining the nano-cluster with bactericidal effect.
Example 4: determination of Minimum Inhibitory Concentration (MIC)
Dissolving nanoclusters with different concentrations and sterilization effects in a nutrient broth culture medium, inoculating bacteria, and determining the minimum concentration of the nanoclusters for inhibiting the growth of staphylococcus aureus, namely MIC, according to the growth or non-growth of the bacteria. The operation steps are as follows: (1) preparing a culture medium containing nanoclusters: diluting the nanoclusters into receptor solutions (231, 115.5, 57.7, 28.8, 14.4 and 7.2 mu g/mL) with sterile water in a double-series manner, adding 1mL of each diluted receptor solution into a liquid culture medium containing 1mL of bacterial liquid, measuring the MIC value of the nanoclusters, and slowly reducing the concentration of the nano silver if the value is very small, so that the MIC is accurate as much as possible; (2) taking 100 μ L of bacteria with a bacteria content of about 108cfu/mL of the bacterial suspension is inoculated in nutrient broth containing the nano-clusters to serve as a test group sample; (3) inoculating the bacterial suspension with the same concentration into a test tube of nutrient broth to be used as a positive control group sample; (4) taking two test tubes containing nutrient broth as negative control group samples; (5) placing the test group sample, the positive control group sample and the negative control group sample in an incubator at 37 ℃, culturing for 24h, and observing results; evaluating the bacteriostatic effect: when the positive control tube has bacteria growth and the negative control tube has no bacteria growth, the concentration of the experimental bacterial suspension is 5 multiplied by 105cfu/mL～5×106cfu/mL, highest dilution of sterile growth of the test groupThe corresponding bacteriostatic concentration is the minimum bacteriostatic concentration MIC;
example 5: determination of minimum Sterilization concentration (MBC)
Taking an experimental group, culturing for 24h according to the method, then carrying out viable bacteria culture counting on 100 mu L of a sample corresponding to the highest dilution of aseptic growth, and simultaneously testing the viable bacteria number of a positive control group without the nano-silver polymer according to the same method.
In the formula, N0: the colony number of the positive control group after 24h of culture; n: number of colonies in the experimental group after 24h of culture.
The above description is only a few examples of the present invention, and does not mean that the present invention is implemented by relying on the above-mentioned process flow. Any modification of the invention, equivalent substitution of the raw materials of the invention, addition of auxiliary components, selection of specific modes and the like, falls within the scope of protection and disclosure of the invention.
Table 1 shows the minimum inhibitory concentration and the minimum bactericidal concentration of the ordinary silver particles against staphylococcus aureus and escherichia coli; table 2 shows the minimum inhibitory concentration and the minimum bactericidal concentration of the inventive nanoclusters against staphylococcus aureus and escherichia coli. By comparing with table 2, it can be seen that the nanoclusters having bactericidal effect of the present invention have 3-4 times of that of the common silver particles;
TABLE 1
TABLE 2
Claims (2)
1. A nanocluster with bactericidal effect is characterized by having the following structural formula:
wherein the numerical ranges of x, y and z are respectively 1-100, m is 4 or 5, and n is 5 or 6;
the grey small ball connected with the end of the nano cluster in the structural formula is silver nano particles adsorbed on a mercapto-SH surface.
2. A method for preparing nanoclusters having bactericidal effect as claimed in claim 1, comprising: firstly, synthesizing a hydroxyl-containing nano-cluster by using 4-cyano-4- (phenylthioformylthio) pentanoic acid as a chain transfer agent, azodiisobutyronitrile as an initiator and polyethylene glycol monomethyl ether methacrylate, polyethylene glycol methacrylate and ethylene glycol dimethacrylate as raw materials; then, taking hydroxyl-containing nano-clusters, bromocaproyl chloride and triethylamine as raw materials, and synthesizing to obtain bromo-containing nano-clusters; then, synthesizing a nano-cluster containing thioester groups by using a bromine-containing nano-cluster and potassium thioacetate as raw materials, cutting the nano-cluster under the conditions of piperidine and N, N-dimethylformamide to obtain a nano-cluster containing sulfhydryl groups, and finally combining the nano-cluster containing sulfhydryl groups with silver in the presence of sodium borohydride and silver nitrate to obtain a target product through an in-situ reaction.
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| WO2006118542A1 (en) * | 2005-05-04 | 2006-11-09 | Agency For Science, Technology And Research | Novel water-soluble nanocrystals comprising a polymeric coating reagent, and methods of preparing the same |
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