CN108653727B - Bionic hollow silica composite particle modified by beta-1, 3-D-glucan and application thereof - Google Patents
Bionic hollow silica composite particle modified by beta-1, 3-D-glucan and application thereof Download PDFInfo
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 title claims abstract description 160
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55505—Inorganic adjuvants
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- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
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- Pharmacology & Pharmacy (AREA)
- Inorganic Chemistry (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a bionic hollow silica composite particle modified by beta-1, 3-D-glucan and application thereof. The composite particles are obtained by coupling reaction of bionic hollow silica particles and beta-1, 3-D-glucan; wherein the pore diameter range of the nanometer transmission pore canal of the bionic hollow silica particles is 1.7-15.2 nm. The composite particles have nanometer transmission pore canals with proper shapes and pore size distribution of bacteria, are convenient for passing through antigens and medicines with different molecular weights, have higher antigen loading capacity, can continuously release the antigens, can improve the utilization rate of the antigens, reduce the injection times, reduce the toxic and side effects of the antigens and vaccine adjuvants, and continuously generate immune protection effect; the level of the induced antigen-specific antibody is equivalent to that of an aluminum adjuvant and a Freund adjuvant, and the induced antigen-specific antibody has wide application prospect in the field of biomedicine. In addition, the preparation method of the composite particle is simple, low in cost, environment-friendly, low in preparation cost and has industrial production potential.
Description
Technical Field
The invention relates to the field of vaccine adjuvants and drug carriers, in particular to a bionic hollow silica composite particle modified by beta-1, 3-D-glucan and application thereof.
Background
The porous silica particle material has the advantages of high specific surface area, high pore volume, high physical and chemical stability, low toxicity, high biocompatibility, easy functionalization of surface rich silicon hydroxyl, low cost and the like, and is widely used in the medical and biological engineering fields of vaccine antigen carriers, drug carriers, gene carriers, biological imaging and the like. Particularly, the chemical stability of the porous silicon dioxide particle material protects the active medicament loaded therein from being damaged by the in-vivo environment, and the porous silicon dioxide particle material simultaneously endows the sustained-release function of the medicament. In recent years, attention has been drawn to hollow silica particle materials having not only the advantages of the above conventional porous silica particle materials but also the advantages of low density, higher drug loading amount, high specific surface area, etc., which have a larger cavity to accommodate more drugs and facilitate dispersion in the body and drug transfer, as compared to conventional solid porous silica particle materials.
The current common method for preparing hollow silica particle materials is the template method. The template method comprises the steps of firstly taking a particle substance with a specific shape as a template, then coating a silicon source reaction on the surface of the template by methods such as adsorption, precipitation or sol-gel, and the like, and finally removing the template to obtain the hollow silica particle material. The template method is divided into a hard template method and a soft template method. The hard template method generally uses polymer microspheres, carbon materials, metal oxides such as alumina, calcium carbonate, silicon dioxide and the like as templates, a silicon source is coated on the surface of a core through reaction, and finally the templates are removed through methods such as high-temperature burning, organic solvent dissolution, acid-base etching and the like to obtain a final product. The soft template method is to take the high molecular micelle, the polymer microcapsule and the air bubbles as templates, precipitate a silicon source on the surface of the template, react, and then remove the soft template to obtain the hollow silicon dioxide particle material. Although many hollow silica particle materials have been successfully prepared using synthetic templates, there are still some problems that the synthesis of some templates requires complicated synthetic routes and raw materials, is high in cost, lacks environmental friendliness, and may leave toxic and harmful substances. Some templates with special shapes are not easy to obtain, and the synthesized templates are subjected to surface chemical modification, so that the preparation complexity is increased.
In view of the above problems, people aim at nature, which provides many biological templates with complex structures, such as double-helix structure DNA, various shapes of bacteria and viruses, special structure proteins, etc. Biological templates used for preparing the hollow silicon dioxide particle material at present comprise pollen, bacteria, viruses, yeasts and the like.
Although the hollow silica particle material prepared by taking bacteria as a template can exert morphological advantages as a vaccine adjuvant and a drug carrier, the unmodified hollow silica particle material has relatively low drug-loading rate, high drug release speed and surface lack of biological activity, and the problems need to be solved urgently.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide the bionic hollow silica composite particle modified by beta-1, 3-D-glucan and containing the nano-transmission pore canal. The composite particle is prepared by grafting modification of the surface of a bionic hollow silica particle and grafting beta-1, 3-D-glucan with good immunoregulation activity, biocompatibility and biodegradability, so that on one hand, the load capacity of the antigen of the composite particle is improved, and the antigen protein can be continuously released; on the other hand, the interaction between the bionic hollow silica particles and cells is promoted, and the function of the bionic hollow silica particles as a drug carrier or a vaccine adjuvant is better exerted.
The invention also aims to provide the application of the beta-1, 3-D-glucan modified bionic hollow silica composite particle in preparing vaccines.
Meanwhile, the vaccine containing the bionic hollow silica composite particle modified by the beta-1, 3-D-glucan is also in the protection scope of the invention.
The above object of the present invention is achieved by the following scheme:
a bionic hollow silica composite particle modified by beta-1, 3-D-glucan is obtained by coupling reaction of the bionic hollow silica particle and the beta-1, 3-D-glucan; wherein the pore diameter range of the nanometer transmission pore canal of the bionic hollow silica particles is 1.7-15.2 nm.
The composite particle is prepared by grafting modification of the surface of a bionic hollow silica particle and grafting beta-1, 3-D-glucan with good immunoregulation activity, biocompatibility and biodegradability; on one hand, the antigen loading capacity of the composite particles is improved, and the antigen protein can be continuously released; on the other hand, the surface modification of beta-1, 3-D-glucan leads the hollow silica particles to have positive charge and endows the hollow silica particles with biological activity, and the modification also establishes a basis for other biological activity modification on the surface of the hollow silica particle material; meanwhile, the interaction between the bionic hollow silica particles and cells can be promoted, and the function of the bionic hollow silica particles as a drug carrier or a vaccine adjuvant can be better exerted.
Preferably, the size of the bionic hollow silica particles is 1-3 micrometers; the bionic hollow silica particles are prepared by taking bacteria as a template to obtain the bionic hollow silica particles containing the nanometer transmission pore canal; the bionic hollow silica particles have the shape of a bacterial template.
The bacteria are used as templates, so that the method has the following advantages: 1. the bacteria exist in large quantity in the nature, the culture condition is simple, the bacteria can be obtained in large quantity, and the environment pollution is not caused, so that the method has the characteristics of economy, safety and environmental protection compared with other templates; 2. the mechanism that some bacteria act as pathogenic microorganisms and the immune system of the organism is possibly related to the shapes of the bacteria, so that the hollow silicon dioxide particle material inheriting the shapes of the bacterial templates is used as a vaccine adjuvant and a drug carrier, and the advantages of the shapes are possibly exerted to strengthen the action of the bacteria on the immune system of the organism; 3. the bacterial cell wall has many protein and glycolipid substances, and the substances have various active functional groups and do not need to be chemically modified additionally.
Most bacteria can be used as templates to prepare the bionic hollow silica particles, and the invention takes escherichia coli and staphylococcus aureus as examples to prepare 2 kinds of bionic hollow silica particles. Firstly, a shell of silicon dioxide is generated on the surface of bacteria; and then removing the bacterial template to obtain the bionic hollow silica particles containing the nano-transmission pore canal. The particles have the shape of a bacterial template, and the size of the particles is equivalent to that of the bacterial template and is between 1 and 3 micrometers; has a nano-transmission pore passage which is a through hole with the pore diameter range of 1.7-15.2 nm.
The process for preparing the bionic hollow silica particles containing the nanometer transmission pore canal by taking the escherichia coli or the staphylococcus aureus as the template comprises the following steps:
(1) carrying out amplification culture on escherichia coli and staphylococcus aureus in an LB (lysogeny broth) culture medium, centrifugally collecting thalli when the bacteria reach a growth stabilization phase, and fixing and washing the thalli;
(2) sequentially adding ammonia water, ethanol and tetraethoxysilane into the fixed bacterial aqueous solution, and reacting for 12-72 hours at room temperature;
(3) and (3) centrifugally separating, washing and drying the product obtained in the step (2), calcining at 300-350 ℃ for 2-3 h, heating to 600-650 ℃ and calcining for 6-8 h to obtain the bionic hollow silica particles with the nano transmission pore channel.
Preferably, the LB medium in step (1) is prepared from the following raw materials: 10g/L tryptone, 5g/L yeast extract and 10g/L sodium chloride; the fixing time of the bacteria is 4-12 h; the bacteria were fixed with 4% glutaraldehyde.
Preferably, the step (2) process is as follows: take 1.44X 1010～1.44×1012Putting the water solution of the fixed bacteria into a flask, adding 3-6 mL of 25% ammonia water, adding absolute ethyl alcohol, ultrasonically mixing for 5-20 min, adding 2.23-13.38 mL of tetraethoxysilane under stirring, and reacting for 12-72 h at room temperature within a short time;
preferably, the washing in step (3) is performed with a mixed solution of ethanol and water, and the washing may be performed multiple times.
Preferably, the preparation process of the beta-1, 3-D-glucan modified bionic hollow silica particle comprises the following steps:
s1, activating hydroxyl on the surface of the bionic hollow silica particle, and modifying by using an aminosilane coupling agent to obtain amino-modified bionic hollow silica; activating hydroxyl in the beta-1, 3-D-glucan;
and S2, performing coupling reaction on the amino-modified bionic hollow silica and the activated beta-1, 3-D-glucan to obtain the composite particle.
Preferably, in order to increase the reaction rate in step S2, a certain amount of catalyst, which is triethylamine, may be added.
Preferably, the mass ratio of the amino-modified bionic hollow silica particles to the activated beta-1, 3-D-glucan to the catalyst is 10-40: 5-40: 15-36.
Preferably, the hydroxyl of the bionic hollow silica particles can be activated by Piranha solution; hydroxyl activation of beta-1, 3-D-glucan can be performed using N' N-carbonyldiimidazole.
Preferably, the aminosilane coupling agent is gamma-aminopropyltriethoxysilane, gamma-aminopropyltrimethoxysilane, N-beta- (aminoethyl) -gamma-aminopropyltrimethoxysilane or N-beta- (aminoethyl) -gamma-aminopropylmethyldimethoxysilane.
More preferably, the aminosilane coupling agent is gamma-aminopropyltriethoxysilane (KH 550).
Preferably, the reaction temperature in step S2 is room temperature; the reaction time is 3-7 h.
More specifically, the specific process of modifying the bionic hollow silica by the beta-1, 3-D-glucan is as follows:
the specific process of step S1 is:
s11, activating the bionic hollow silica particles by using a Piranha solution, and carrying out reflux reaction on the bionic hollow silica particles and an aminosilane coupling agent at the temperature of 110-120 ℃; after the reaction is finished, separating and drying to obtain amino-modified bionic hollow silica particles;
s12, dissolving the purified water-soluble beta-1, 3-D-glucan in an anhydrous organic solvent, and adding N' N-carbonyldiimidazole to activate hydroxyl in the beta-1, 3-D-glucan structure under the protection of inert gas; after the reaction is finished, separating and airing to obtain activated beta-1, 3-D-glucan;
the specific process of step S2 is: dissolving activated beta-1, 3-D-glucan in an anhydrous organic solvent, adding a small amount of triethylamine, uniformly mixing, adding amino-modified bionic hollow silica particles into a reaction solution, and reacting at room temperature; after the reaction is finished, separating, washing and drying to obtain the bionic hollow silica particles modified by the beta-1, 3-D-glucan.
The invention also protects the application of the bionic hollow silica composite particle modified by the beta-1, 3-D-glucan as a carrier or a vaccine adjuvant.
Preferably, the composite particle may be loaded with a proteinaceous antigen. The protein antigen is loaded on the sugar chains in or on the surface of the composite particle by a penetration and electrostatic adsorption method, so that the composite particle is prepared.
More specifically, the process of preparing the composite particle by taking the composite particle as a carrier to load the protein antigen comprises the following steps:
s4: preparing the antigen protein into an aqueous solution, wherein the concentration is not limited, and the maximum concentration is the concentration of the antigen protein saturated aqueous solution;
s5: adjusting the pH of a protein antigen solution to deviate from the isoelectric point of protein, mixing the bionic hollow silica particles containing the nano transmission pore canal and the protein antigen solution, wherein the surface of the bionic hollow silica particles is modified with beta-1, 3-D-glucan, and oscillating at room temperature to ensure that the protein antigen fully permeates into the cavity, the pore canal and the surface sugar chain layer of the hollow composite particles; and then adjusting the pH of the solution to the isoelectric point of the protein antigens to enable the protein antigens to be agglutinated in the particles, centrifuging to obtain protein-loaded antigen particles, washing with water with the pH being the isoelectric point of the protein antigens to remove the protein antigens adsorbed on the surfaces, and drying in vacuum to obtain the protein-loaded composite particles taking the composite particles as carriers.
Preferably, the proteinaceous antigen comprises a chicken ovalbumin antigen.
The application of the protein antigen loaded composite particle in the preparation of vaccines is also within the protection scope of the invention.
Compared with the prior art, the invention has the following beneficial effects:
the composite particles have nanometer transmission pore canals with proper shapes and pore size distribution of bacteria, are convenient for passing through antigens and medicines with different molecular weights, have higher antigen loading capacity, can continuously release the antigens, can improve the utilization rate of the antigens, reduce the injection times, reduce the toxic and side effects of the antigens and vaccine adjuvants, and continuously generate immune protection effect; the level of the induced antigen-specific antibody is equivalent to that of an aluminum adjuvant and a Freund adjuvant, and the induced antigen-specific antibody has wide application prospect in the field of biomedicine.
In addition, the preparation method of the composite particle is simple, the preparation cost is low, and the composite particle has industrial production potential.
Drawings
FIG. 1 is a schematic diagram of a preparation process of beta-1, 3-D-glucan modified bacteria-based bionic hollow silica particles containing a nano-transmission pore passage.
FIG. 2 is a scanning electron microscope image of beta-1, 3-D-glucan modified hollow silica particles containing nano-transmission pore canals, namely imitated escherichia coli (A) and staphylococcus aureus (B).
FIG. 3 is a transmission electron microscope image of beta-1, 3-D-glucan modified hollow silica particles containing nano-transmission pore canals, such as simulated escherichia coli (A) and staphylococcus aureus (B).
FIG. 4 is an in vitro release curve of a bionic hollow silica composite particle which is modified by chicken egg white albumin-beta-1, 3-D-glucan and contains a nano-transmission pore channel.
FIG. 5 shows antigen-specific antibody titer generated by animal immunoassay of bionic hollow silica composite particles containing nano-transmission pore channels modified by chicken egg white albumin-beta-1, 3-D-glucan.
Detailed Description
The present invention is further described in detail below with reference to specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
Example 1
A bionic hollow silica composite particle modified by beta-1, 3-D-glucan is prepared according to the process shown in figure 1, and the specific preparation process is as follows:
(1) preparation of bacteria-based bionic hollow silica particles containing nano-transmission pore canal
Most bacteria can be used as a soft template for preparing the hollow silica particles, and in the embodiment, 2 common bacteria (escherichia coli and staphylococcus aureus) are used as templates for preparing the biomimetic hollow silica particles containing the nano-transmission pore bacteria base.
1.8mL of 8X 10 was taken10Putting each/mL of escherichia coli or staphylococcus aureus aqueous solution into a flask, then adding 5mL of 25% ammonia water, then adding 73.2mL of absolute ethyl alcohol, and ultrasonically mixing for 10 min; under magnetic stirring, dropwise adding a mixed solution of 2.23mL of ethyl orthosilicate and 17.77mL of ethanol solution, and reacting for 72h at room temperature; and (3) after the reaction is finished, centrifuging at 4000rpm for 10min, collecting the obtained particles, washing the obtained particles with 50% ethanol water solution for 8 times, removing white nano particles formed by the reaction, drying the obtained sample, calcining at 350 ℃ for 2h, and heating to 600 ℃ for 8h to obtain the bacteria-based bionic hollow silica particles. The particle has a nano-transmission pore passage which is a through hole, and the pore diameter range is 1.7-15.2 nm. The particles have the shape of a bacterial template, and the size of the particles is equivalent to that of the bacterial template and is between 1 and 3 micrometers.
(2) Preparation of amino-modified bionic hollow silica particles
Dispersing 1g of the bionic hollow silica particles containing the nano-transmission pore channel in 30mL of Piranha solution (the volume ratio of concentrated sulfuric acid to 30% hydrogen peroxide is 3: 1), performing ultrasonic dispersion for 10min, and stirring and refluxing for 1h at 100 ℃; after the reaction is finished, centrifuging for 10min at 4000rpm, washing the precipitate for 8 times by using deionized water, then washing for 2 times by using absolute ethyl alcohol, and finally drying for 24h in vacuum at 60 ℃; taking 0.1g of the dried sample, adding 30mL of toluene, carrying out ultrasonic dispersion for 15min, heating to 100 ℃, adding 0.4mL of gamma-aminopropyltriethoxysilane (KH 550) while stirring, heating to 110 ℃, and carrying out reflux reaction for 6 h; after the reaction, the mixed solution was cooled to room temperature, centrifuged, and ultrasonically washed 6 times with ethanol and distilled water, respectively, and dried in a vacuum oven at 60 ℃ for 12 hours, followed by Soxhlet extraction with ethanol at 100 ℃ for 24 hours to remove the silane coupling agent physically adsorbed on the particle surface. And finally drying the mixture in a vacuum oven at 100 ℃ for 24 hours to obtain the bionic hollow silica particles grafted with the coupling agent gamma-aminopropyltriethoxysilane.
(3) Preparation of activated beta-1, 3-D-glucan
Weighing 0.162g of purified water-soluble beta-1, 3-D-glucan, dissolving in 30mL of anhydrous dimethyl sulfoxide, then adding 0.5g of N' -N-carbonyl diimidazole, and reacting for 1.5h under the protection of nitrogen and magnetic stirring at room temperature; after the reaction is finished, 120mL of absolute ethyl alcohol is added, the precipitate is separated out, the supernatant is removed by centrifugation, the precipitate is washed for 6 times, and then the precipitate is dried at room temperature.
(4) Preparation of bionic hollow silica particles modified by beta-1, 3-D-glucan
Weighing 0.1g of the bionic hollow silica particles grafted with the gamma-aminopropyltriethoxysilane, dispersing in 30mL of dimethyl sulfoxide, and performing ultrasonic dispersion for 10 min; dissolving 0.1g of the activated beta-1, 3-D-glucan sample in 10mL of dimethyl sulfoxide, adding 0.5mL of triethylamine, uniformly mixing, dropwise adding the mixture into the bionic hollow silica particle solution grafted with the gamma-aminopropyltriethoxysilane by using a constant-pressure dropping funnel, wherein the dropwise adding time is not less than 1.5h, and continuously reacting for 5h at room temperature after the dropwise adding is finished; and (3) centrifuging at 4000rpm for 10min after the reaction is finished, washing the precipitate for 3 times by using dimethyl sulfoxide, then washing for 3 times by using deionized water, then washing for 1 time by using absolute ethyl alcohol, and finally drying for 24h in vacuum at 60 ℃ to obtain the beta-1, 3-D-glucan modified bacteria-based bionic hollow silica particles containing the nano transmission pore, wherein the scanning electron microscope and transmission electron microscope results are shown in fig. 2 and fig. 3.
(5) Preparation of chicken Ovalbumin (OVA) -loaded beta-1, 3-D-glucan modified bionic hollow silica particles
In the example of chicken egg white albumin, protein antigen loaded conjugate particles were prepared. Preparing an aqueous solution of egg white albumin with the concentration of 10mg/mL, adjusting the pH value of the protein antigen solution to deviate from the isoelectric point of protein, then ultrasonically dispersing 0.5mL of the bionic hollow silica particles with the surfaces grafted with beta-1, 3-D-glucan in the 0.5mL of the egg white albumin solution, and oscillating at room temperature for 12 hours to ensure that the protein antigen fully enters cavities, pore canals and surface sugar chain layers of the hollow composite particles; and then adjusting the pH of the solution to the isoelectric point of the protein antigen to enable the protein antigen to be agglutinated in the particles, centrifuging at 4000rpm to obtain protein antigen-loaded particles, washing with water with the pH being the isoelectric point of the protein antigen for 3-5 times, removing the protein antigen adsorbed on the surface, and drying in vacuum to obtain the protein antigen-loaded composite particles.
Test methods and calculation methods for antigen loading reference "Immunization of microorganism nanoparticles as carriers of sodium circovirus type 2 ORF2 protein" (Virology journal 9 (2012) 1-10. H.C. Guo, X.M. Feng, S.Q. Sun, Y.Q. Wei, D.H. Sun, X.T. Liu, et al.).
The method comprises the following specific steps: the total mass of added OVA protein was first determined, and after formation of the composite particles, the OVA mass in the supernatant was determined by centrifugation at 4000 rpm. The mass of antigen loaded into the hollow silica particles is equal to the sum of the added OVA protein and the OVA mass in the supernatant after centrifugation, and the calculation formula of the load is as follows:
load = mass of antigen loaded into hollow silica particles/mass of hollow silica particles.
The antigen load capacity of the beta-1, 3-D-glucan modified escherichia coli-imitated hollow silica particle (E.coli HSP @ glucan) containing the nano-transmission pore channel and the antigen load capacity of the staphylococcus aureus hollow silica particle (S. aureus HSP @ glucan) are 343.1.3 mu g/mg and 326.8 mu g/mg respectively.
Scanning electron micrographs and transmission electron micrographs of 2 types of composite particles are shown in FIGS. 2 and 3. Wherein, FIGS. 2-A and 3-A are scanning electron microscope and transmission electron microscope images of the beta-1, 3-D-glucan modified Escherichia coli-imitated hollow silica particles containing the nano transmission pore canal; FIGS. 2-B and 3-B are scanning electron microscope images and transmission electron microscope images of beta-1, 3-D-glucan modified staphylococcus aureus imitation hollow silica particles containing nano transmission pore canals.
Application example
1. Example 1 in vitro Release test of the composite particles prepared
In example 1, 2 kinds of composite particles prepared using escherichia coli and staphylococcus aureus as templates were used as test subjects.
The test method comprises the following steps: dispersing the 2 composite particles in 1mL of PBS respectively, then placing the dispersion liquid in a constant temperature oscillator at 37 ℃ and 150r/min for oscillation, centrifuging the dispersion liquid at 4000rpm at different time, taking 0.1mL of supernatant liquid for measuring the concentration of the protein, simultaneously adding 0.1mL of PBS into the centrifuged sample, uniformly mixing the precipitate by using a vortex oscillator, and continuing oscillation in the constant temperature oscillator.
The in vitro release curves of the antigens of the two composite particles (e. coli HSP @ glucan and s. aureus HSP @ glucan) are shown in fig. 4. From the figure, it can be known that the two composite particles loaded with the chicken ovalbumin continuously release the antigen for more than 96 hours in vitro, and the explosive release rates within 4 hours are 22.9% and 20% respectively.
The results show that the bionic hollow silica composite particles modified by two types of beta-1, 3-D-glucan of E, coli HSP @ glucan and S, aureus HSP @ glucan prepared by the invention have good stability, can continuously release antigens for a long time, is beneficial to continuously generating immune response, and can reduce the dosage and the injection frequency of vaccines.
2. Preparation of bionic hollow silica particle vaccine modified by chicken egg white albumin beta-1, 3-D-glucan and animal immunity test
The preparation process of the vaccine comprises the following steps: two kinds of composite particles loaded with the chicken egg white albumin prepared in the test, 0.9mg, are respectively dispersed in 1.2mL PBS to prepare a vaccine E, coli HSP @ glucan-OVA group and an S, aureus HSP @ glucan-OVA group.
Animal immunity test method: 30 SPF Balb/C mice 6-8 weeks old were selected and divided into 5 groups of 6 mice each. The first group is a chicken egg white albumin group (OVA, comparative example 1), the second group is an imitative escherichia coli hollow silica particle group (E. coli HSP-OVA) containing a nano-transmission pore channel and loaded with chicken egg white albumin, the third group is an imitative escherichia coli hollow silica particle group (E. coli HSP @ glucan-OVA) containing a nano-transmission pore channel and modified by beta-1, 3-D-glucan loaded with chicken egg white albumin, the fourth group is an imitative gold yellow staphylococcus hollow silica particle group (S. aureus HSP-OVA, comparative example 3) containing a nano-transmission pore channel and loaded with chicken egg white albumin, the fifth group is an imitative gold yellow staphylococcus hollow silica particle group (S. aureus HSP @ glucan-OVA) containing a nano-transmission pore channel and modified by beta-1, 3-D-glucan loaded with chicken egg white albumin, the sixth group was the chicken egg white albumin aluminum adjuvant group (Alum, comparative example 4), and the seventh group was the chicken egg white albumin Freund adjuvant group (Freund's adjuvant, comparative example 5). Three times of subcutaneous injections were administered, each time at two weeks intervals, and two weeks after the pre-and last immunizations were bled to determine the antigen-specific IgG antibody titers in each group.
The results of the test are shown in FIG. 5. As can be seen from fig. 5, the antigen-specific IgG titers in mice treated with group 3 (e. coli HSP @ glucan-OVA) and group 5 (s. aureus HSP @ glucan-OVA) were significantly increased compared to groups 1, 2 and 4, and in particular, the IgG titers in mice treated with group 3 (e. coli @ HSP @ glucan-OVA) were substantially equal to those in groups 6 and 7; therefore, the antigen-loaded beta-1, 3-D-glucan modified bacteria-based bionic hollow silica particle containing the nano transmission pore channel can obviously improve the IgG titer in a mouse body, and particularly, the E, coli HSP @ glucan-OVA group using escherichia coli as a template can obviously enhance the immune activity of the mouse.
Claims (6)
1. The bionic hollow silica composite particle modified by beta-1, 3-D-glucan is characterized in that the composite particle is obtained by coupling reaction of the bionic hollow silica particle and the beta-1, 3-D-glucan; wherein the pore diameter range of the nanometer transmission pore canal of the bionic hollow silica is 1.7-15.2 nm;
the bionic hollow silica takes bacteria as a template to prepare bionic hollow silica particles containing nanometer transmission pore canals; the bionic hollow silicon dioxide has the shape of a bacterial template;
the preparation process of the bionic hollow silicon dioxide modified by the beta-1, 3-D-glucan comprises the following steps:
s1, activating hydroxyl on the surface of a bionic hollow silica particle, and modifying by using an aminosilane coupling agent to obtain amino-modified bionic hollow silica; activating hydroxyl in the beta-1, 3-D-glucan;
s2, performing coupling reaction on the amino-modified bionic hollow silica particles and activated beta-1, 3-D-glucan to obtain the composite particles;
adding a catalyst in step S2; the catalyst is triethylamine;
in the step S2, the mass ratio of the amino-modified bionic hollow silica particles to the activated beta-1, 3-D-glucan to the catalyst is 10-40: 5-40: 15-36.
2. The composite particle according to claim 1, wherein the aminosilane coupling agent is gamma-aminopropyltriethoxysilane, gamma-aminopropyltrimethoxysilane, N-beta- (aminoethyl) -gamma-aminopropyltrimethoxysilane or N-beta- (aminoethyl) -gamma-aminopropylmethyldimethoxysilane.
3. The composite particle according to claim 1, wherein the reaction temperature in step S2 is room temperature; the reaction time is 3-7 h.
4. Use of the beta-1, 3-D-glucan modified biomimetic hollow silica composite particles of any of claims 1-3 as a carrier or vaccine adjuvant.
5. The use of claim 4, wherein the composite particles are loaded with a proteinaceous antigen.
6. The use according to claim 5, wherein the proteinaceous antigen-loaded composite particles are used in the preparation of a vaccine.
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Non-Patent Citations (5)
| Title |
|---|
| A new receptor for β-glucans;Gordon D. Brown,et al;《nature》;20010906;第413卷;36-37页 * |
| Antigen uptake and immunoadjuvant activity of pathogen-mimetic hollow silica particles conjugated with b-glucan;Jing Wei Jin,et al;《Journal of Materials Chemistry B》;20181231;6288-6301 * |
| Fabrication of silica hollow particles using Escherichia coli as a template;T.Nomura，et al;《Materials Letters》;20080416;3727-3729页 * |
| Hollow Silica Nanocontainers as Drug Delivery Vehicles;Jaemoon Yang，et al;《Langmuir》;20081231;第24卷(第7期);3417-3421页 * |
| 葡聚糖药物载体功能化分子修饰方法;王路等;《卫生研究》;20160331;第45卷(第2期);306-309,323页 * |
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