CN104383533A - Application of cationic polymer to prepare nanometer immunologic adjuvant and preparation method - Google Patents
Application of cationic polymer to prepare nanometer immunologic adjuvant and preparation method Download PDFInfo
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- CN104383533A CN104383533A CN201410519465.8A CN201410519465A CN104383533A CN 104383533 A CN104383533 A CN 104383533A CN 201410519465 A CN201410519465 A CN 201410519465A CN 104383533 A CN104383533 A CN 104383533A
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Abstract
The invention relates to application of a cationic polymer to prepare a nanometer immunologic adjuvant and a preparation method. Polyethylene glycol-polycaprolactone is employed for synthesizing a scaffold, and the scaffold is combined with polyethyleneimine for forming a cationic nanometer micelle, and physical attraction of positive and negative charges is utilized for finishing surface adsorption on a protein antigen, so that the cationic nanometer micelle-antigen particle composite system is prepared. The nanometer immunologic adjuvant is simple in synthesis, low in cost, simple in operation, good in reappearance, capability of realizing immunopotentiation and good in biocompatibility. The preparation method of the nanometer immunologic adjuvant is simple and easy to operate, the cost is low, and the prepared nanometer micelle is stably distributed in a water phase, is uniform in morphology and low in toxicity, and is capable of using simple electrostatic combination to finish loading and transmitting of an antibody, and enhancing immune response of body to an antigen.
Description
Technical field
The present invention relates to field of immunology, be specifically related to a kind of cationic polymer as application and the preparation method of preparing nano immune adjuvant.
Background technology
Along with the development of biotechnology, the safety of inactivated vaccine is greatly improved, but when the DNA developed based on recombinant antigen or purification pathogen subunit or polypeptide are as vaccine, immunogenicity is very weak, limit the use of this type of vaccine, thus need immunological adjuvant to improve body fluid or the cellullar immunologic response effect of this type of antigen.Traditional immunological adjuvant toxic action is comparatively large, needs badly and will develop more safe and effective immunologic adjuvant to improve the immune effect of biovaccine of new generation.
Immunological adjuvant, another name nonspecific immunity proliferant agent, itself does not have antigenicity, after synantigen is injected together or is expelled to body in advance, can increase the immunogenicity of antigen or change immunization type.According to custom and source, adjuvant is divided into four classes: conventional immune adjuvant, as Alum adjuvant, adsorbed onto alum adjuvant, oil emulsion adjuvant and Freund adjuvant etc.; Cytokine immunological adjuvant, as interleukin II and interferon; Natural origin immunological adjuvant, as polysaccharide adjuvant, flavone adjuvant, saponin adjuvant and propolis adjuvant; Immunologic adjuvant, comprises immunostimulating complex adjuvant, CpG ODN adjuvant, Liposome Adjuvant and nanometer adjuvant etc.
The immunological enhancement that different adjuvants causes is not quite similar, but as a kind of good adjuvant, must possess: (1) is nontoxic and side effect is low, non-immunogenicity; (2) direct or indirect activate immunity competent cell cause immune cell proliferation, strengthens immune effect; (3) increase the surface area of antigen and protect antigen, lowering antigen degraded in vivo.
For existing immunological adjuvant, be analyzed as follows: first, existing immunologic adjuvant majority is not positively charged, and certain electric charge is the necessary physical condition that immune stimulatory cell response and enhancement antigen are presented; Secondly, the safety of immunological adjuvant wants height, immunogenicity low.The Freund adjuvant of use for laboratory widely uses because its side effect limits.Finally, as immunostimulating auxiliary reinforcing agent, cost is low as far as possible.The cost of biological recombination protide or DNA class antigen reduces gradually, and the production cost of immunological adjuvant also needs must play improvement accordingly.
Nano-micelle, as the one of high molecular polymer nano-particle, diameter is generally not more than 100 nm, for the carrier of genomic medicine and classic chemotherapy medicine, becomes the new direction of medicament nano chemical preparation research just gradually.In the polymer forming nano-micelle, introduce cationic polymer block, the surface charge of micelle can be changed, for the slow Co ntrolled release of DNA or peptide molecule; Meanwhile, cationic micelle can stimulate the dendritic cell (dendritic cells, DC) of antigen-presenting, improves body to the immunne response of its delivery of antigens and effcient memory immunity.
Summary of the invention
In order to solve the shortcoming of prior art, the PEG-PCL that the present invention utilizes biocompatibility good is as the molecule of the skeleton of synthesis, introduce the molecular weight polymers polymine of positively charged core, the effect utilizing hydrophobe to attract each other forms the cationic polymerization objects system of nanorize, invent and the present invention relates to field of immunology, be specifically related to a kind of cationic polymer as application and the preparation method of preparing nano immune adjuvant.
A preparation method for cationic polymer nano immune adjuvant, described preparation method comprises the following steps:
(1) anhydrous poly glycol monomethyl ether is added in container, take caprolactone, instill the stannous octoate of 0.5% w/w, oil bath is heated to 120-160 DEG C, stir and react 4-12h, vacuum cooled under nitrogen protection condition, adding dichloromethane solubilizing reaction mixture, wash by the petroleum ether repeated precipitation of in advance pre-cooling, obtain MPEG-PCL;
(2) obtained MPEG-PCL is dry and dissolve with anhydrous methylene chloride, after first adding 5 triethylamines, dropwise add acryloyl chloride, 35 DEG C, react 4-8 hour under anhydrous, nitrogen protection condition, must MPEG-PCL containing carbon-carbon double bond with petroleum ether precipitation;
(3) MPEG-PCL containing carbon-carbon double bond is dissolved in dichloromethane, instill the dichloromethane solution of excessive polymine, 45 DEG C, under magnetic agitation condition, react more than 24 hours, after the petroleum ether precipitation several of pre-cooling, oven dry, dialysis purification reaction product, obtain MPEG-PCL-PEI triblock polymer after lyophilization.
The preparation method of described a kind of cationic polymer nano immune adjuvant, in described step (1), the mol ratio of caprolactone and poly glycol monomethyl ether is 1.2:1.
The preparation method of described a kind of cationic polymer nano immune adjuvant, the mol ratio 1.2:1 of acryloyl chloride and MPEG-PCL in described step (2).
The preparation method of described a kind of cationic polymer nano immune adjuvant, in described step (3), the excessive dichloromethane solution of polymine of instillation is greater than 1 with the ratio of the MPEG-PCL amount of substance containing carbon-carbon double bond.
The preparation method of described a kind of cationic polymer nano immune adjuvant, is characterized in that, MW in described MPEG-PCL-PEI triblock polymer
mPEG=5000, MW
pCL=2000, MW
pEI=2000.
Cationic polymer is as the application preparing nano immune adjuvant, and described cationic polymer is MPEG-PCL-PEI triblock polymer.
Synthetic route of the present invention:
First chemical formula is poly glycol monomethyl ether, obtains amphipathic nature polyalcohol A by open loop, and A represents intermediate product PEG-PCL (MPEG-PCL); B represents the PEG-PCL containing carbon-carbon double bond after acryloyl chloride modification; Synthesis end product is PEG-PCL-polymine (MPEG-PCL-PEI).
The invention has the beneficial effects as follows: the invention provides a kind of cationic polymer as application and the preparation method of preparing nano immune adjuvant, with PEG-PCL synthesis skeleton, cation nanometer micelle is formed by being combined with polymine, complete the surface adsorption to protide antigen by the physical attraction of positive and negative charge, prepare a kind of cation nanometer micelle-antigen particles compound system.This invention synthesis easy, with low cost, simple to operate, favorable reproducibility, immunostimulant, good biocompatibility.The positive charge of small-molecular-weight polymine is utilized to complete the active adsorption of albumen and the biodegradation of protected protein class or DNA class antigen; utilize positive charge stimulator antigen to be delivery cell (as macrophage) simultaneously; enhancing body, to the immunne response of micelle institute delivery of antigens, completes the effect of polymer micelle as immunological adjuvant.This type nano immune adjuvant preparation method is simple to operation, and cost is low, obtained nano-micelle Stable distritation in aqueous phase, and pattern is homogeneous and toxicity is low, and simple electrostatic compound can be used to complete the loading of antibody and send, and enhancing body is to the immunne response of antigen.
accompanying drawing explanation
Fig. 1 be different molecular weight MPEG-PCL-PEI polymer of the present invention nucleus magnetic hydrogen spectrum (
1h-NMR).
Fig. 2 is antibody titer testing result figure after mouse immune of the present invention.
Fig. 3 is the outer immunostimulating effect test result figure of T cell reproduction test detection bodies of the present invention.
detailed description of the invention
embodiment 1
Anhydrous for 10g MPEG (molecular weight MW=5000Da) is added in there-necked flask, take 4.8g caprolactone, the stannous octoate of instillation 0.5%w/w, oil bath is heated to 120 DEG C, magnetic agitation is also reacted 4 hours under nitrogen protection condition, vacuum cooled, uses dichloromethane solubilizing reaction mixture, wash, purification, nuclear-magnetism identification of M PEG-PCL molecular weight by the petroleum ether repeated precipitation of in advance pre-cooling; Take 10 g of dry MPEG5000-PCL2000 and dissolve with anhydrous 100 mL dichloromethane, after adding 5 triethylamines in advance, dropwise adding the acryloyl of 0.16g, 35 DEG C, reaction 4 hours under anhydrous, nitrogen protection condition, petroleum ether precipitation synthetic product; The MPEG-PCL being connected to-C=C-double bond is dissolved in dichloromethane, instill the dichloromethane solution (ensureing that PEI is excessive) of the polymine (PEI) of excessive (molecular weight MW=2000Da), 45 DEG C, under magnetic agitation condition, react 25 hours, after pre-cooling petroleum ether precipitation several, oven dry, dialysis purification reaction product; MPEG is obtained after lyophilization
5000-PCL
2000-PEI
2000triblock polymer.
embodiment 2
Anhydrous for 10g MPEG (molecular weight MW=2000Da) is added in there-necked flask, take 36g caprolactone, the stannous octoate of instillation 0.5%w/w, oil bath is heated to 130 DEG C, magnetic agitation is also reacted 6 hours under nitrogen protection condition, vacuum cooled, uses dichloromethane solubilizing reaction mixture, wash, purification, nuclear-magnetism identification of M PEG-PCL molecular weight by the petroleum ether repeated precipitation of in advance pre-cooling; Take 10 g of dry MPEG2000-PCL6000 and dissolve with anhydrous 100 mL dichloromethane, after adding 5 triethylamines in advance, dropwise adding the acryloyl of 0.16g, 35 DEG C, reaction 6 hours under anhydrous, nitrogen protection condition, petroleum ether precipitation synthetic product; The MPEG-PCL being connected to-C=C-double bond is dissolved in dichloromethane, instill the dichloromethane solution (ensureing that PEI is excessive) of the polymine (PEI) of excessive (molecular weight MW=2000Da), 45 DEG C, under magnetic agitation condition, react 27 hours, after pre-cooling petroleum ether precipitation several, oven dry, dialysis purification reaction product; MPEG is obtained after lyophilization
2000-PCL
6000-PEI
2000triblock polymer.
embodiment 3
Anhydrous for 10g MPEG (molecular weight MW=2000Da) is added in there-necked flask, take 12g caprolactone, the stannous octoate of instillation 0.5%w/w, oil bath is heated to 160 DEG C, magnetic agitation is also reacted 12 hours under nitrogen protection condition, vacuum cooled, uses dichloromethane solubilizing reaction mixture, wash, purification, nuclear-magnetism identification of M PEG-PCL molecular weight by the petroleum ether repeated precipitation of in advance pre-cooling; Take 10 g of dry MPEG2000-PCL2000 and dissolve with anhydrous 100 mL dichloromethane, after adding 5 triethylamines in advance, dropwise adding the acryloyl of 0.16g, 35 DEG C, reaction 8 hours under anhydrous, nitrogen protection condition, petroleum ether precipitation synthetic product; The MPEG-PCL being connected to-C=C-double bond is dissolved in dichloromethane, instill the dichloromethane solution (ensureing that PEI is excessive) of the polymine (PEI) of excessive (molecular weight MW=2000Da), 45 DEG C, under magnetic agitation condition, react 28 hours, after pre-cooling petroleum ether precipitation several, oven dry, dialysis purification reaction product; MPEG is obtained after lyophilization
2000-PCL
2000-PEI
2000triblock polymer.
nuclear-magnetism result:
By Fig. 1 different molecular weight MPEG-PCL-PEI polymer nucleus magnetic hydrogen spectrum (
1h-NMR) figure, can find out that each block molecule amount of obtained MPEG-PCL-PEI is respectively (A) MW
mPEG2000Da, MW
pCL2000Da, MW
pEI2000Da; (B) MW
mPEG2000Da, MW
pCL6000Da, MW
pEI2000Da; (C) MW
mPEG5000Da, MW
pCL2000Da, MW
pEI2000Da.
in Mice Body, immune effect detects
Take a certain amount of polymer, be made into 5mg/mL aqueous solution and be heated to 55 DEG C, adding corresponding dosage albumen, to 6 to 8 all female C57BL/6J mices (5 mice/groups) with the OVA vaccine of the Immunity at intervals OVA of 2 weeks or micelles encapsulate, by subcutaneous injection twice.The dosage of OVA and micelle is respectively 20 micrograms/mice and 100 μ g/ mices.The matched group (injection Alumen, Pierce Inc. approval be used for the adjuvant of human vaccination) of Alumen group as adjuvant is added in test.Within after last immune antibody 7 days, collect blood and analyze, the IgG antibody (comprising IgG1, IgG2a, IgG2b) in blood plasma is determined by using ELISA.Anti ova antibody titer is by the OD(450 nm of ELISA after minimum serum-dilution) reading is greater than 0.1 for positive criterion.
As shown in Figure 2, wherein OVA represents chicken ovalbumin to result, and M2 represents MPEG
2000-PCL
2000-PEI
2000, M5 represents MPEG
5000-PCL
2000-PEI
2000, M6 represents MPEG
2000-PCL
6000-PEI
2000, Alum is aluminium hydroxide matched group, can find out compared to, after adding subject cationic polymer nanocomposite immunological adjuvant, enhancing body is to the specific immune response of this antigen, and effect is better than aluminium hydroxide matched group.
cell in vitro assessment of levels immunostimulating effect:
T cell proliferation assay is used to evaluate ion vitro immunization effect, by splenocyte (2 × 10
6cell/ml) be inoculated in 96 orifice plates in (100 μ L/ hole), cultivation solubility OVA(50 mcg/ml) and establish blank group, at 37 DEG C and 5%CO
2the solution (genebio, Shanghai, China) of 10 μ L Cell counting Kit (CCK-8), after 72 hours, joins in each hole by lower cultivation.Plate is cultivated 4 hours again at 37 DEG C, uses microplate reader to measure absorbance at 450 nm.MPLA adjuvant is Monophosphoryl lipid A matched group.
As shown in Figure 3, wherein OVA represents chicken ovalbumin to result, and M2 represents MPEG
2000-PCL
2000-PEI
2000, M5 represents MPEG
5000-PCL
2000-PEI
2000, M6 represents MPEG
2000-PCL
6000-PEI
2000, MPLA adjuvant is Monophosphoryl lipid A matched group, can find out that subject cationic polymer nanocomposite immunological adjuvant also has the function of enhancing body to the specific immune response of this antigen in vitro.
Claims (6)
1. a preparation method for cationic polymer nano immune adjuvant, is characterized in that, described preparation method comprises the following steps:
(1) anhydrous poly glycol monomethyl ether is added in container, take caprolactone, instill the stannous octoate of 0.5% w/w, oil bath is heated to 120-160 DEG C, stir and react 4-12h, vacuum cooled under nitrogen protection condition, adding dichloromethane solubilizing reaction mixture, wash by the petroleum ether repeated precipitation of in advance pre-cooling, obtain MPEG-PCL;
(2) obtained MPEG-PCL is dry and dissolve with anhydrous methylene chloride, after first adding 5 triethylamines, dropwise add acryloyl chloride, 35 DEG C, react 4-8 hour under anhydrous, nitrogen protection condition, must MPEG-PCL containing carbon-carbon double bond with petroleum ether precipitation;
(3) MPEG-PCL containing carbon-carbon double bond is dissolved in dichloromethane, instill the dichloromethane solution of excessive polymine, 45 DEG C, under magnetic agitation condition, react more than 24 hours, after the petroleum ether precipitation several of pre-cooling, oven dry, dialysis purification reaction product, obtain MPEG-PCL-PEI triblock polymer after lyophilization.
2. the preparation method of a kind of cationic polymer nano immune adjuvant according to claim 1, is characterized in that, in described step (1), the mol ratio of caprolactone and poly glycol monomethyl ether is 1.2:1.
3. the preparation method of a kind of cationic polymer nano immune adjuvant according to claim 1, is characterized in that, the mol ratio 1.2:1 of acryloyl chloride and MPEG-PCL in described step (2).
4. the preparation method of a kind of cationic polymer nano immune adjuvant according to claim 1, it is characterized in that, in described step (3), the excessive dichloromethane solution of polymine of instillation is greater than 1 with the ratio of the MPEG-PCL amount of substance containing carbon-carbon double bond.
5. the preparation method of a kind of cationic polymer nano immune adjuvant according to claim 1, is characterized in that, MW in described MPEG-PCL-PEI triblock polymer
mPEG=2000-5000, MW
pCL=2000-6000, MW
pEI=2000.
6. cationic polymer is as the application preparing nano immune adjuvant, it is characterized in that, described cationic polymer is MPEG-PCL-PEI triblock polymer.
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Cited By (5)
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| CN104922694A (en) * | 2015-07-20 | 2015-09-23 | 南方医科大学 | Insulin controlled-release nanometer particle and preparing method thereof |
| CN105194670A (en) * | 2015-10-28 | 2015-12-30 | 温州医科大学 | Cationic polymer-loaded paclitaxel/indocyanine green co-delivery micelle and preparation method thereof |
| CN108727599A (en) * | 2017-04-24 | 2018-11-02 | 暨南大学 | A kind of glutathione response type target polymer micella and the preparation method and application thereof |
| CN112089833A (en) * | 2020-08-14 | 2020-12-18 | 中山大学 | Universal CpG ODN nano-particle adjuvant and preparation method and application thereof |
| CN113577263A (en) * | 2021-07-21 | 2021-11-02 | 四川大学 | Cationic nanoemulsion adjuvant capable of encapsulating antigen and preparation method and application thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104922694A (en) * | 2015-07-20 | 2015-09-23 | 南方医科大学 | Insulin controlled-release nanometer particle and preparing method thereof |
| CN104922694B (en) * | 2015-07-20 | 2018-09-21 | 南方医科大学 | A kind of insulin slow release nano particle and preparation method thereof |
| CN105194670A (en) * | 2015-10-28 | 2015-12-30 | 温州医科大学 | Cationic polymer-loaded paclitaxel/indocyanine green co-delivery micelle and preparation method thereof |
| CN108727599A (en) * | 2017-04-24 | 2018-11-02 | 暨南大学 | A kind of glutathione response type target polymer micella and the preparation method and application thereof |
| CN108727599B (en) * | 2017-04-24 | 2020-03-17 | 暨南大学 | Glutathione-responsive targeted polymer micelle and preparation method and application thereof |
| CN112089833A (en) * | 2020-08-14 | 2020-12-18 | 中山大学 | Universal CpG ODN nano-particle adjuvant and preparation method and application thereof |
| CN113577263A (en) * | 2021-07-21 | 2021-11-02 | 四川大学 | Cationic nanoemulsion adjuvant capable of encapsulating antigen and preparation method and application thereof |
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Application publication date: 20150304 |