CN107441490B - Composite nano antibacterial agent with bacteria specificity recognition capability and application thereof - Google Patents
Composite nano antibacterial agent with bacteria specificity recognition capability and application thereof Download PDFInfo
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- CN107441490B CN107441490B CN201710639308.4A CN201710639308A CN107441490B CN 107441490 B CN107441490 B CN 107441490B CN 201710639308 A CN201710639308 A CN 201710639308A CN 107441490 B CN107441490 B CN 107441490B
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Abstract
The invention discloses a composite nano antibacterial agent with bacteria specificity recognition capability and application thereof, belonging to the technical field of high molecular polymers. Constitute by silver nanoparticle, boron fluoride dipyrrole molecule and polygalactose, silver nanoparticle constitutes the silver nanosphere, and the polygalactose is the polygalactose chain, and the silver nanosphere is connected the one end of a plurality of polygalactose chain respectively, and a boron fluoride dipyrrole molecule is all connected to the other end of every polygalactose chain, and silver nanosphere is all surrounded to all boron fluoride dipyrrole molecules, also forms similar globular structure. The composite nano antibacterial agent particles prepared by the invention have selective recognition capability on pseudomonas aeruginosa, escherichia coli, tetanus bacillus and staphylococcus aureus, and are not or rarely adsorbed by normal human body cells, so that the antibacterial purpose can be selectively realized on the basis of less toxic and side effects on a human body.
Description
Technical Field
The invention relates to a composite nano antibacterial agent, belongs to the technical field of high molecular polymers, and particularly relates to a composite nano antibacterial agent with bacteria specificity recognition capability and application thereof.
Background
Pathogenic microorganisms are diverse and rapidly mutate, making antimicrobial therapy a great challenge. Although antibiotics have definite treatment effect on infection of many pathogenic microorganisms, antibiotics no longer have overwhelming advantages in the game of antibiotics and pathogenic microorganisms, and many pathogenic microorganisms which are easy to fight against before have drug resistance, so that the incidence rate caused by infection is increased continuously. Although people are going to develop new antibiotics to their full extent, the development speed is far behind the mutation speed of pathogenic microorganisms; more serious is that the drug resistance problem is not solved at all, but is more serious, and 'superbacteria' with drug resistance to various antibiotics appear, so that the alertness and even the panic of the whole world are caused. Therefore, the development of novel antibacterial drugs and antibacterial methods having specific recognition of bacteria has been urgently needed.
Disclosure of Invention
In order to solve the technical problem of bacterial drug resistance, the invention discloses a composite nano antibacterial agent with bacterial specificity recognition capability and application thereof.
In order to achieve the purpose, the invention discloses a technical scheme, namely a composite nano antibacterial agent with bacteria specificity recognition capability, which is composed of silver nano particles, boron fluoride dipyrrole molecules and polygalactose, wherein the silver nano particles form silver nano spheres, the polygalactose is a polygalactose chain, the silver nano spheres are respectively connected with one ends of a plurality of polygalactose chains, the other end of each polygalactose chain is connected with one boron dipyrrole molecule, and all the boron fluoride dipyrrole molecules surround the silver nano spheres to form a similar spherical structure.
Further, the length of the polygalactose chain is 30-60 nm.
Still further, the monomer of the polygalactose is 2-methacryloyloxyethyl galactose peracetate.
Still further, the structural formula of the boron fluoride dipyrrole molecule is shown as formula B:
furthermore, the diameter of the silver nano particles is 40-50 nm.
Meanwhile, the invention also provides another technical scheme, namely the application of the composite nano antibacterial agent in the specific recognition of bacteria.
Further, the bacterium is one of pseudomonas aeruginosa, escherichia coli, tetanus bacillus or staphylococcus aureus.
The selection principle of each component substance of the composite nano antibacterial agent is as follows:
1. the polygalactose is selected because the sugar can interact with the protein, and the polygalactose has good biocompatibility, so that the prepared composite nano antibacterial agent can intelligently identify bacteria and has high cell compatibility; the length of the polygalactose chain is 30-60 nm, because one end of the polygalactose chain is connected with photosensitizer molecules, if the length is too long, the nanoparticles still have enhanced photodynamic antibacterial capability through energy resonance transfer, and if the length is too short, the number of functional glycosyl molecules is not enough, but the targeting effect on various bacteria is weak;
2. the silver nano particles are selected, and the aim of antibiosis is fulfilled due to the fact that common components of microorganisms are damaged or dysfunction is generated due to the contact reaction of silver ions; the diameter of the silver nanoparticles is controlled to be 40-50 nm, because the silver nanoparticles are too small, the silver nanoparticles can easily enter the interior of cells through endocytosis and other processes, and the specific recognition effect of the silver nanoparticles on bacteria is weakened;
3. the photosensitizer molecule itself has a self-enhancing photodynamic antibacterial effect.
Therefore, under the condition of no illumination, the polygalactose chain carries the silver nanoparticles to realize selective recognition targeting effect on cells, and under the condition of illumination, the polygalactose chain carries the silver nanoparticles and photosensitizer molecules to realize stronger antibacterial effect on targeted bacteria.
Has the advantages that:
the composite nano antibacterial agent particles prepared by the invention have selective recognition capability on pseudomonas aeruginosa, escherichia coli, tetanus bacillus and staphylococcus aureus, and are not or rarely adsorbed by normal human body cells, so that the antibacterial purpose can be selectively realized on the basis of less toxic and side effects on a human body.
Drawings
FIG. 1 is a schematic structural view of a composite nanoantimicrobial of the present invention;
wherein the numbers in the figures are as follows:
Detailed Description
In order to better explain the invention, the following further illustrate the main content of the invention in connection with specific examples, but the content of the invention is not limited to the following examples.
The preparation method of the composite nano antibacterial agent comprises the following preparation steps:
1) adding p-benzyl chlorobenzoyl chloride (1.5g,8mmol) into a dichloromethane (90mL) solution of 2, 4-dimethylpyrrole (2.2mL) under the conditions of room temperature, nitrogen protection and stirring, and performing water removal treatment on the 2, 4-dimethylpyrrole and the dichloromethane before use to obtain a reaction system; heating the reaction system to 25 ℃, and reacting for 6 h; adding triethylamine (3.88g,38mmol) into the reaction system, continuing to react for 20min, and then adding boron trifluoride diethyl etherate complex (7.82g,55mmol) for 4h to obtain a substance of a chemical formula shown in the formula A;
2) under the stirring state, adding pyrrole (0.17mL,2.38mmol) into dimethyl sulfoxide suspension of sodium hydride (57.1mg2.38mmol), reacting for 20min after the solution turns brown-yellow, adding carbon disulfide (0.14mL,2.38mmol), continuing to stir for reaction for 25min, adding the substance (1.02g,2.38mmol) of the chemical formula shown in the formula A prepared in the step 1), reacting at 40 ℃ for 15h, and carrying out post-treatment on the reaction solution to prepare boron fluoride dipyrrole molecules with reversible addition-fragmentation chain transfer polymerization initiation activity, wherein the molecular formula is shown in B;
the operation process of carrying out post-treatment on the reaction liquid in the step 2) is as follows: adding 500mL of water into the reaction solution, extracting with trichloromethane (50mL) for three times, combining the extract solutions, concentrating, and separating the concentrated solution by a silica gel chromatographic column to obtain the boron fluoride dipyrrole molecule.
3) Adding a galactose monomer 2-methacryloyloxyethyl galactose peracetate (AcGEMA) into the 1, 4-dioxane to obtain a galactose polymerization monomer solution with the mass concentration of 45-55%; then, respectively adding azodiisobutyronitrile and the boron fluoride dipyrromethene molecules prepared in the step 2) in an ice-water bath environment, wherein the molar weight of the azodiisobutyronitrile is 0.8-1.2% of that of the galactose polymerization monomer, gradually heating a reaction system to 70-75 ℃ in a nitrogen protection atmosphere for 8-12 hours, and finally adding diethyl ether as a precipitator to obtain a solid polymer, wherein the molecular formula is shown as a formula C;
the value range of n in the molecular formula C is controlled to be 170-340, and the length of the polygalactose chain is 10-60 nm.
4) Dissolving the solid polymer prepared in the step 3) into dichloromethane to obtain a polymer solution with the mass concentration of 20%; adding N-iodo-succinimide, wherein the molar weight of the N-iodo-succinimide is 10 times that of the polymer, and reacting for 3 hours under the conditions of room-temperature stirring, nitrogen protection atmosphere and dark until the system turns red; then adding a precipitator n-hexane to react to obtain an iodo-macromolecular photosensitizer;
5) dissolving 100mg of iodo-macromolecular photosensitizer polymer prepared in the step 4) and 10mmol of hydrazine hydrate into 20mL of DMSO together, deacetylating the polymer at 25 ℃ under the nitrogen atmosphere, reacting for 24h, adding 1mL of acetone into a reaction system to terminate the reaction, then placing the reactant solution into distilled water for dialysis, and freeze-drying to obtain a polymer;
6) dissolving the polymer prepared in the step 5) into deionized water to prepare a polymerization solution with the concentration of 250 mg/mL; respectively adding 100mL of polymerization solution and silver nitrate solution (the concentration is 8mg/mL) with the same volume into the aqueous solution under the condition that the stirring speed is 800r/min, wherein the volume of the aqueous solution is 10000mL, then adding sodium borohydride (2.34mmol, 89.9mg), and stirring for reacting for 35min to obtain the composite nano antibacterial agent.
The preparation process is as follows:
the composite nano antibacterial agent shown in fig. 1 is prepared, as can be seen from fig. 1, silver nanoparticles 1 with antibacterial ability form silver nanospheres, one end of each polygalactose chain 2 is connected with the silver nanospheres, the other end of each polygalactose chain 2 is connected with a boron fluoride dipyrrole molecule 3, and all the boron fluoride dipyrrole molecules surround the silver nanospheres and also form a similar spherical structure.
Detailed description of antibacterial property test:
1. cytotoxicity test:
the cytotoxicity test of the poly (N, N-dimethylaminoethyl methacrylate) functionalized nanoparticles and the galactose functionalized nanoparticles (composite nano antibacterial agent) prepared by the invention was performed by measuring the contents of the poly (N, N-dimethylaminoethyl methacrylate) functionalized nanoparticles and the galactose functionalized nanoparticles (composite nano antibacterial agent) by an MTT colorimetric method with mouse embryo fibroblasts under the conditions of illumination (15min) and no illumination, and the following table 1 was obtained by taking a blank cell culture as a negative control test and setting the survival rate to 100%.
TABLE 1 cytotoxicity test data
As can be seen from table 1, the higher the survival rate of the cells, the weaker the toxic and side effects on the cells, i.e., the toxic and side effects on the cells of the composite nano antibacterial agent of the present invention are smaller.
2. And (3) antibacterial testing:
respectively giving the samples with the same concentration to the conditions of light and no light at the same time to obtain bacteriostatic ability test data shown in the following table 2;
TABLE 2 bacteriostatic ability test data
As can be seen from table 2, the bacteriostatic ability under non-illuminated conditions was weak because only the antibacterial action of the silver particles themselves was present in the non-illuminated conditions, but no photodynamic antibacterial action was present, so that the antibacterial ability under the non-illuminated conditions was weaker than that under the illuminated conditions.
The two nano particles have similar high-efficiency antibacterial capability under the illumination condition, probably because the two nano particles can be adsorbed by bacteria, thereby effectively playing the synergistic antibacterial action of the photodynamic and the silver. As can be seen from Table 1, under the same conditions, the cytotoxicity of the galactose-functionalized nanoparticles is significantly lower than that of the poly (N, N-dimethylaminoethyl methacrylate) -functionalized nanoparticles; namely, the galactose functionalized nano particles can effectively reduce the side effect of the antibacterial agent on human body while keeping high-efficiency antibacterial ability.
3. And (3) selective bacteriostasis test:
using a non-iodo compound nano antibacterial agent as a fluorescent molecule, culturing 5nmol/mL fluorescent molecule solution with HepG2 cells and NIH3T3 cells for 30min respectively, and then performing laser confocal imaging test to obtain selective bacteriostatic ability test data shown in Table 3;
TABLE 3 Selective bacteriostatic ability test data
As can be seen from Table 3, Pseudomonas aeruginosa and Staphylococcus aureus have a large amount of adsorption to the fluorescent molecules of the composite nano antibacterial agent, so that the selective antibacterial ability to the bacteria is strong, and human renal epithelial cells and human lung fibroblasts have a small amount of adsorption to the fluorescent molecules of the composite nano antibacterial agent, so that the fluorescent molecules are not or rarely adsorbed by normal human cells, and the toxic and side effects to human bodies are reduced.
Claims (5)
1. A composite nano antibacterial agent with bacteria specificity recognition capability is characterized in that: the high-concentration galactose-free silver nanoparticle composite material is composed of silver nanoparticles, boron fluoride dipyrrole molecules and polygalactose, wherein the silver nanoparticles form silver nanospheres, the polygalactose is a polygalactose chain, the silver nanospheres are respectively connected with one end of a plurality of polygalactose chains, the other end of each polygalactose chain is connected with one boron fluoride dipyrrole molecule, all the boron fluoride dipyrrole molecules surround the silver nanospheres, and a similar spherical structure is also formed; the monomer of the polygalactose is 2-methacryloyloxyethyl galactose peracetate; and the length of the polygalactose chain is 30-60 nm.
2. The composite nanobacteria agent with bacteria-specific recognition ability according to claim 1, wherein: the structural formula of the boron fluoride dipyrrole molecule is shown as a formula B:
3. the composite nanobacteria agent with bacteria-specific recognition ability according to claim 1 or 2, wherein: the diameter of the silver nano particles is 40-50 nm.
4. The use of the composite nano antibacterial agent according to any one of claims 1 to 3 in the preparation of a bacteria specific recognition reagent.
5. Use of the composite nano antibacterial agent according to claim 4 for preparing bacteria-specific recognition reagent, characterized in that: the bacteria is one of pseudomonas aeruginosa, escherichia coli, tetanus bacillus or staphylococcus aureus.
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| CN1822867A (en) * | 2003-07-16 | 2006-08-23 | 诺瓦提斯公司 | Antimicrobial medical devices |
| WO2011104497A1 (en) * | 2010-02-24 | 2011-09-01 | University Of Exeter | Method for the preparation of a novel nanoparticle conjugate |
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| CN1822867A (en) * | 2003-07-16 | 2006-08-23 | 诺瓦提斯公司 | Antimicrobial medical devices |
| WO2011104497A1 (en) * | 2010-02-24 | 2011-09-01 | University Of Exeter | Method for the preparation of a novel nanoparticle conjugate |
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