CN108785666A - A kind of DC targeted nanometer vaccines and preparation method thereof applied to liver cancer immunity treatment - Google Patents
A kind of DC targeted nanometer vaccines and preparation method thereof applied to liver cancer immunity treatment Download PDFInfo
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- CN108785666A CN108785666A CN201810563337.1A CN201810563337A CN108785666A CN 108785666 A CN108785666 A CN 108785666A CN 201810563337 A CN201810563337 A CN 201810563337A CN 108785666 A CN108785666 A CN 108785666A
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- liver cancer
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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
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention relates to a kind of DC targeted nanometer vaccines and preparation method thereof applied to liver cancer immunity treatment, are using mannose-modified glycol-chitosan as carrier material, with liver cancer-specific polypeptide antigen Monophosphoinositideproteoglycans proteoglycans-3144‑152Peptide（GPC-3144‑152, FVGEFFTDV）For immunizing antigen, the nano vaccine and preparation method thereof prepared by electrostatic interaction.Such nano vaccine can increase Dendritic Cells（Dendritic cell, DC）To the endocytosis amount of antigen, protects antigen not by fast degradation and remove, extend the action time of antigen, be conducive to excitating organism and generate effective immune response.Nano vaccine raw material prepared by the present invention is cheap and easy to get, preparation method simply easily repeats, is easy to large-scale processing production, can enhance the immunotherapeutic effects of liver cancer, have a good application prospect.
Description
Technical field
The invention belongs to biomedicine field, more particularly, to a kind of nano vaccine applied to liver cancer immunity treatment and its
Preparation method.
Background technology
With Dendritic Cells（Dendritic cell, DC）For tumor vaccine core specific tumour immunization therapy by
More and more concerns, DC is the strongest professional antigen presenting cells of internal known function, is to start, regulate and control and maintain immune to answer
The key link answered.
Antigen enters body with free state, can be degraded by body fluid dilution, enzyme so that and DC is extremely low to the intake of antigen,
It is difficult to that body is induced to generate effective immune response.Nano vaccine can protect antigen not by fast degradation and removing, by right
Nano particle structure is designed targeting conveying and the control release that can also be realized to antigen, and then improves DC and taken the photograph to antigen
Taken amount, the action time for extending antigen are conducive to excitating organism and generate effective immune response.
In order to further increase the Targeting Effect of nano vaccine, the ligand molecular of DC surface receptors is selected to modify to nanometer epidemic disease
Seedling surface can be prepared with active targeting nano vaccine.Mannose receptor belongs to c-type agglutinin superfamily, can Rapid Circulation
Between DC cell membranes and early stage endosome, it can be internalized by a large amount of antigens in a relatively short period of time, induce immune response.
Currently, the application in the immunization therapy of liver cancer based on DC vaccines is less, one of the main reasons is a lack of effectively
Liver tumour antigen.Monophosphoinositideproteoglycans proteoglycans-3（Glypican-3, GPC-3）It is a kind of liver Cancer embryo protein, by exempting from
The detection of epidemic disease groupization finds that GPC-3 is overexpressed in most of Primary hepatic carcinoma cells in protein level, but in normal liver and good
Property hepatic disease can't detect.GPC-3 is apparent in the differential expression of liver cancer and benign hepatopathy, is provided to expand liver cancer treatment means
New thinking, can be used as tumour antigen or therapy target.GPC-3144-152Polypeptide can equally induce generation cytotoxic T thin
Born of the same parents（CTL）Reaction, does not generate autoimmune response, can be used as liver cancer-specific antigen.And the purity higher of polypeptide, it is more easy to industry
Change, compared with albumen, price is also less expensive.
Natural polysaccharide has good biocompatibility and biodegradability, nontoxic to human body non-stimulated, cheap and easy to get.
Chitosan is a large amount of existing unique a kind of alkaline polysaccharides in nature, has an excellent biocompatibility, biodegradability,
It is widely used in fields such as food, medical treatment, biotechnology and pharmacy.But dissolubility is poor in water for chitosan, and
Glycol-chitosan increases dissolubility in water, it is easier to experimental implementation while keeping chitosan characteristic.
Invention content
In order to further increase the Targeting Effect of nano vaccine, increase endocytosis amounts of the DC to antigen, while can protect anti-
Original is not diluted by premature breakdown and by body fluid, increases immunotherapeutic effects, and the present invention devises one kind and controlled applied to liver cancer immunity
DC targeted nanometer vaccines for the treatment of and preparation method thereof.
A kind of DC targeted nanometer vaccines applied to liver cancer immunity treatment, it is characterised in that：With mannose-modified second two
Alcohol chitosan is carrier material, with liver cancer-specific polypeptide antigen Monophosphoinositideproteoglycans proteoglycans-3144-152Peptide（GPC-3144-152,
FVGEFFTDV）For immunizing antigen, the nano vaccine prepared by electrostatic interaction；Wherein, the degree of substitution of the mannose
It is 3%~20%；According to mass fraction meter, the GPC-3144-152The amount of containing be 3%~10%.
Further, the DC targeted nanometer vaccine grain sizes for being applied to liver cancer immunity treatment are 100nm~1000nm.
The preparation method of a kind of DC targeted nanometer vaccines applied to liver cancer immunity treatment, it is characterised in that comprising following
Step：
Step 1: the preparation of mannose-modified glycol-chitosan：
Glycol-chitosan and the different sulphur hydracid phenyl-alpha-D- mannosides of 4- are dissolved in water, reaction is stirred at room temperature
For 24 hours, it dialyses to water, freeze-drying obtains mannose-modified glycol-chitosan, obtains product and be denoted as MAN-GCTS;
Step 2: the preparation of nano vaccine：
By GPC-3144-152It is dissolved in phosphate buffered saline solution（PBS）In, the pH value of phosphate buffered saline solution is 7.4；；By step
One preparation gained MAN-GCTS is soluble in water, then is added drop-wise to dissolved with GPC-3144-152PBS in, stir 0.5h after, freeze-drying, obtain
Nano vaccine.
Further, a concentration of mg/mL of 0.5 mg/mL~2 of the glycol-chitosan in the step 1, molecular weight are
5000~50000, deacetylation is 80%~100%.
Further, the glycol-chitosan structural unit in the step 1 and the different sulphur hydracid phenyl-alpha-D- of 4- are sweet
The molar ratio for revealing glucosides is 1:0.03~0.3.
Further, described in step 2 in MAN-GCTS and GPC-3144-152 mass ratio be 1:0.1~0.15.
The DC targeted nanometer vaccines and preparation method thereof that the present invention is applied to liver cancer immunity treatment have below beneficial to effect
Fruit：
（1）The present invention is applied in DC targeted nanometer vaccines of liver cancer immunity treatment and preparation method thereof, and nano vaccine can
It is acted on by active targeting, increases endocytosis amounts of the DC to antigen, while antigen can be protected dilute not by premature breakdown and by body fluid
It releases, increases immunotherapeutic effects.
（2）The present invention is applied in DC targeted nanometer vaccines of liver cancer immunity treatment and preparation method thereof, and preparation is received
Rice corpuscles raw material is cheap and easy to get, preparation method simply easily repeats, is easy to large-scale processing production, has a good application prospect.
Description of the drawings
Fig. 1 is the nuclear-magnetism figure for the MAN-GCTS that the embodiment of the present invention is prepared；
Fig. 2 is the grain size distribution for the nano vaccine that the embodiment of the present invention 1 obtains；
Fig. 3 is that the nano vaccine that the embodiment of the present invention 1 obtains is bent to the tumor killing effect of Hepa1-6 liver cancer cells tumor model mouse
Line chart；
Fig. 4 is the grain size distribution for the nano vaccine that the embodiment of the present invention 2 obtains；
Fig. 5 is that the nano vaccine that the embodiment of the present invention 2 obtains is bent to the tumor killing effect of Hepa1-6 liver cancer cells tumor model mouse
Line chart.
Specific implementation mode
The DC targeted nanometer vaccines and preparation method thereof that the invention discloses a kind of to treat applied to liver cancer immunity, below
In conjunction with specific embodiments, the present invention will be further described：
Embodiment 1
Step 1: the preparation of mannose-modified glycol-chitosan：
By glycol-chitosan（205 mg, molecular weight 50000）With the different sulphur hydracid phenyl-alpha-D- mannosides of 4-（91
mg）It is dissolved in water, at this time mole of glycol-chitosan structural unit and the different sulphur hydracid phenyl-alpha-D- mannosides of 4-
Than being 1:0.3, it is added after water so that a concentration of 2mg/ml of glycol-chitosan, is stirred at room temperature reaction for 24 hours, to water dialysis, jelly
It is dry, mannose-modified glycol-chitosan is obtained, product is obtained and is denoted as MAN-GCTS, nuclear-magnetism characterization is shown in Fig. 1, can be with by Fig. 1
Find out and successfully MAN is introduced into GCTS.
Step 2: the preparation of nano vaccine：
By GPC-3144-152（1 mg）It is dissolved in 1 mL phosphate buffered saline solutions（PBS, pH=7.4）In；It prepared by step 1
Gained MAN-GCTS（10 mg）It is dissolved in 5 ml water, then is added drop-wise to dissolved with GPC-3144-152Phosphate buffered saline solution PBS in,
After stirring 0.5 h, freeze-drying obtains nano vaccine, and particle diameter distribution is shown in Fig. 2, as seen from Figure 2 the particle diameter distribution of nano vaccine
More uniform, average grain diameter is 224 nm.
The immunization therapy of liver cancer is tested using nano vaccine of the present invention：
（1）The foundation of the transplantable tumor animal model of liver cancer
In vitro culture Hepa1-6 liver cancer cell lines, it is respectively that cell inoculation is subcutaneous in the C57 mouse armpits of 8 week old or so, it connects
The number of kind of cell is：1x106A cell, is divided into control group and treatment group by mouse at random after inoculation, establishes Hepa1-6 liver cancer
Mouse tumor model.
（2）Study immunotherapeutic effects of the nano vaccine to liver cancer
After mouse subcutaneous injection cell 10 days, nano vaccine or independent GPC-3 are begun to use to treatment group144-152Peptide is treated
（100 μ g/ of polypeptide dosage are only）, it is immunized 3 times, every minor tick 1 week, control group injects phosphate buffered saline solution PBS.Measure tumour
Knurl product, compare the therapeutic effect of each group, see Fig. 3.As seen from Figure 3, nano vaccine can inhibit the growth of tumour.
Embodiment 2
Step 1: the preparation of mannose-modified glycol-chitosan：
By glycol-chitosan（205 mg, molecular weight 5000）With the different sulphur hydracid phenyl-alpha-D- mannosides of 4-（9.1
mg）It is dissolved in water, at this point, glycol-chitosan structural unit and the different sulphur hydracid phenyl-alpha-D- mannosides of 4- rub
You are than being 1:0.03, be added water after so that glycol-chitosan a concentration of 0.5mg/ml, be stirred at room temperature reaction for 24 hours, it is saturating to water
Analysis, freeze-drying, obtains mannose-modified glycol-chitosan, obtains product and is denoted as MAN-GCTS, nuclear-magnetism characterization result and Fig. 1 mono-
It causes.It can be seen that successfully MAN is introduced into GCTS.
Step 2: the preparation of nano vaccine：
By GPC-3144-152（1.5 mg）It is dissolved in 1 mL phosphate buffered saline solutions（PBS, pH=7.4）In；It prepared by step 1
Gained MAN-GCTS（10 mg）It is dissolved in 5 ml water, then is added drop-wise to dissolved with GPC-3144-152Phosphate buffered saline solution PBS in,
After stirring 0.5 h, freeze-drying obtains nano vaccine, and particle diameter distribution is shown in Fig. 4.The particle diameter distribution of nano vaccine as seen from Figure 4
More uniform, average grain diameter is 167.4 nm.
The immunization therapy of liver cancer is tested using nano vaccine of the present invention：
（1）The foundation of the transplantable tumor animal model of liver cancer
In vitro culture Hepa1-6 liver cancer cell lines, it is respectively that cell inoculation is subcutaneous in the C57 mouse armpits of 8 week old or so, it connects
The number of kind of cell is：1x106A cell, is divided into control group and treatment group by mouse at random after inoculation, establishes Hepa1-6 liver cancer
Mouse tumor model.
（2）Study immunotherapeutic effects of the nano vaccine to liver cancer
After mouse subcutaneous injection cell 10 days, nano vaccine or independent GPC-3 are begun to use to treatment group144-152Peptide is treated
（100 μ g/ of polypeptide dosage are only）, it is immunized 3 times, every minor tick 1 week, control group injects phosphate buffered saline solution PBS.Measure tumour
Knurl product, compare the therapeutic effect of each group, see Fig. 5.As seen from Figure 5, nano vaccine can inhibit the growth of tumour.
The present invention is applied in DC targeted nanometer vaccines of liver cancer immunity treatment and preparation method thereof, and nano vaccine can
It is acted on by active targeting, increases endocytosis amounts of the DC to antigen, while antigen can be protected dilute not by premature breakdown and by body fluid
It releases, increases immunotherapeutic effects.The present invention is applied in DC targeted nanometer vaccines of liver cancer immunity treatment and preparation method thereof,
The nano-particle raw material of preparation is cheap and easy to get, preparation method simply easily repeats, is easy to large-scale processing production, has good answer
Use foreground.
Illustrative description is carried out to the present invention above in conjunction with specific embodiment, it is clear that realization of the invention is not by upper
The limitation of mode is stated, if the various improvement of inventive concept and technical scheme of the present invention progress are used, or not improved general
The design and technical solution of the present invention directly applies to other occasions, is within the scope of the invention.
Claims (6)
1. a kind of DC targeted nanometer vaccines applied to liver cancer immunity treatment, it is characterised in that：With mannose-modified ethylene glycol
Chitosan is carrier material, with liver cancer-specific polypeptide antigen Monophosphoinositideproteoglycans proteoglycans-3144-152Peptide（GPC-3144-152,
FVGEFFTDV）For immunizing antigen, the nano vaccine prepared by electrostatic interaction；Wherein, the degree of substitution of the mannose
It is 3%~20%；According to mass fraction meter, the GPC-3144-152The amount of containing be 3%~10%.
2. the DC targeted nanometer vaccines according to claim 1 applied to liver cancer immunity treatment, it is characterised in that：It is described
Be applied to liver cancer immunity treatment DC targeted nanometer vaccine grain sizes be 100nm~1000nm.
3. a kind of preparation side of DC targeted nanometer vaccines for being applied to liver cancer immunity treatment according to claim 1-2
Method, it is characterised in that comprise the steps of：
Step 1: the preparation of mannose-modified glycol-chitosan：
Glycol-chitosan and the different sulphur hydracid phenyl-alpha-D- mannosides of 4- are dissolved in water, reaction is stirred at room temperature
For 24 hours, it dialyses to water, freeze-drying obtains mannose-modified glycol-chitosan, obtains product and be denoted as MAN-GCTS;
Step 2: the preparation of nano vaccine：
By GPC-3144-152It is dissolved in phosphate buffered saline solution（PBS）In, the pH value of phosphate buffered saline solution is 7.4；By step 1
It is soluble in water to prepare gained MAN-GCTS, then is added drop-wise to dissolved with GPC-3144-152PBS in, stir 0.5h after, freeze-drying, received
Rice vaccine.
4. the preparation method of the DC targeted nanometer vaccines according to claim 3 applied to liver cancer immunity treatment, special
Sign is：A concentration of mg/mL of 0.5 mg/mL~2 of glycol-chitosan in the step 1, molecular weight be 5000~
50000, deacetylation is 80%~100%.
5. the preparation method of the DC targeted nanometer vaccines according to claim 3 applied to liver cancer immunity treatment, special
Sign is：Glycol-chitosan structural unit in the step 1 and the different sulphur hydracid phenyl-alpha-D- mannosides of 4-
Molar ratio is 1:0.03~0.3.
6. the preparation method of the DC targeted nanometer vaccines according to claim 3 applied to liver cancer immunity treatment, special
Sign is：MAN-GCTS in described in step 2 and GPC-3144-152Mass ratio be 1:0.1~0.15.
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Cited By (4)
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| CN110585426A (en) * | 2019-08-19 | 2019-12-20 | 中国医学科学院生物医学工程研究所 | Antigen and adjuvant co-delivery nano vaccine applied to liver cancer immunotherapy |
| CN110585425A (en) * | 2019-08-19 | 2019-12-20 | 中国医学科学院生物医学工程研究所 | Preparation method of antigen and adjuvant co-delivery nano vaccine applied to liver cancer immunotherapy |
| CN111298128A (en) * | 2019-12-25 | 2020-06-19 | 中国科学院长春应用化学研究所 | Efficient targeting nano vaccine carrier and preparation method thereof, and targeting nano vaccine and preparation method thereof |
| CN112245574A (en) * | 2020-10-23 | 2021-01-22 | 苏州大学 | Targeting conveying system loaded with whole-cell components and application thereof |
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|---|---|---|---|---|
| CN110585426A (en) * | 2019-08-19 | 2019-12-20 | 中国医学科学院生物医学工程研究所 | Antigen and adjuvant co-delivery nano vaccine applied to liver cancer immunotherapy |
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| CN110585425B (en) * | 2019-08-19 | 2023-03-21 | 中国医学科学院生物医学工程研究所 | Preparation method of antigen and adjuvant co-delivery nano vaccine applied to liver cancer immunotherapy |
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| CN111298128A (en) * | 2019-12-25 | 2020-06-19 | 中国科学院长春应用化学研究所 | Efficient targeting nano vaccine carrier and preparation method thereof, and targeting nano vaccine and preparation method thereof |
| CN111298128B (en) * | 2019-12-25 | 2021-07-02 | 中国科学院长春应用化学研究所 | Efficient targeting nano vaccine carrier and preparation method thereof, and targeting nano vaccine and preparation method thereof |
| CN112245574A (en) * | 2020-10-23 | 2021-01-22 | 苏州大学 | Targeting conveying system loaded with whole-cell components and application thereof |
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Application publication date: 20181113 |