CN108403704A - Heparin disaccharides is grafted the purposes of sulphation polymethyl acyl ethanol amine - Google Patents
Heparin disaccharides is grafted the purposes of sulphation polymethyl acyl ethanol amine Download PDFInfo
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- CN108403704A CN108403704A CN201810552288.1A CN201810552288A CN108403704A CN 108403704 A CN108403704 A CN 108403704A CN 201810552288 A CN201810552288 A CN 201810552288A CN 108403704 A CN108403704 A CN 108403704A
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- heparin
- sulphation
- ethanol amine
- disaccharides
- grafted
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7016—Disaccharides, e.g. lactose, lactulose
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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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/58—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
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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
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- Medicinal Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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Abstract
The invention belongs to biomedical materials fields, specifically disclose a kind of purposes of heparin disaccharides grafting sulphation polymethyl acyl ethanol amine, the heparin disaccharides grafting sulphation polymethyl acyl ethanol amine puts on display out higher toxicity to 7 cells of MCF, and highly selective and efficiency potentiality are shown to MCF 7.
Description
Technical field
The invention belongs to biomedical materials fields, and in particular to heparin disaccharides is grafted sulphation polymethyl acyl ethyl alcohol
The purposes of amine.
Background technology
The cause of the death more than 90% cancer patient is cancer metastasis diffusion, and the method that anti-rotation is moved has become treatment of cancer and grinds
An important direction in studying carefully, but up to the present, few researchs move field in chemotherapy or immunotherapy anti-rotation
Obtain important breakthrough.Searching can inhibit the therapy of metastases committed step to be still very important.
Heparin is a kind of traditional antithrombotic reagent, in recent study, is equally also applied to through a variety of ways
Fight the advanced cancer transfer in animal model and clinical research.In general, heparin, which has had become one kind, has development latent
The anti-metastasis drug of power.However, heparin is since its heterogeneous structure composition has the bioactivity for being difficult to assess, which increase it
Cause the risk of side effect.
In the recent period, it is a series of synthesized using oligosaccharides graft polymerization skeleton contain sugar high molecular, provide a kind of new thinking
To improve the homogenieity of hyparinoids from animal organs.Compared to natural polysaccharide, this family macromolecule passes through design and rational, contains regulatable knot
Structure can enhance its activity by " sugared cluster effect ".Some are such to be proved to possess and natural polysaecharides containing sugar high molecular
Like or stronger anticoagulation, it is anti-inflammatory, combined with common cold virus, the activity of anti-alzheimer syndrome.This illustrates that heparin is similar
Object possesses huge potentiality containing sugar high molecular in terms of antitumor application thereof.
On the other hand, it in the evolution of medicine or biomaterial, is improved under the premise of not dramatically increasing toxicity
Activity is main research direction.For this angle, hyparinoids from animal organs is containing the significant challenge that sugar high molecular rationally designs
Selected high molecular material and grafting oligosaccharides need while having high degree of biocompatibility.For more detailed, in addition to low thin
Other than cellular toxicity, this high molecular design also needs to include the following：(1) main chain has high flexibility as heparin
And water solubility；(2) chemical constitution of main chain is conducive to the graft reaction of oligosaccharides；(3) it is selected according to the standard of biological safety
The oligosaccharides type of grafting.
Poly- aminoethyl methacrylate (PAMA) being easy to water-soluble cationic polymer as a kind of, can use atom
Transfer base polymerization (ATRP) method carrys out controllable polymerization.It is most of such to prepare polymer drug/vaccine transmits and tumour in vivo
In the research of model, the cytotoxicity of very little is all shown.On the other hand, the safety of Natural heparin disaccharides early has been found super
Spend 80 years.Research explanation has compared the oligosaccharides being chemically synthesized, and natural heparin disaccharides reduces in practical application
Security risk.Therefore we have proposed a kind of new strategies --- the Natural heparin disaccharides that enzymolysis obtains is connected to PAMA skeletons
On, by more similar to the structure of heparin, so that this kind of hyparinoids from animal organs is obtained more bioactivity containing sugar high molecular enhances.
Invention content
For the deficiency of existing issue, the object of the present invention is to provide heparin disaccharides to be grafted sulphation polymethyl acyl second
The purposes of hydramine, it is right that result of study of the present invention shows that heparin disaccharides is grafted sulphation polymethyl acyl ethanol amine (SGPHD)
MCF-7 cells show higher toxicity, and highly selective and efficiency potentiality are shown to MCF-7, to be controlled for heparin preparation
It treats anti-breast cancer medicines and support is provided.
The present invention solve its technical problem the technical solution adopted is that：
Heparin disaccharides is grafted sulphation polymethyl acyl ethanol amine and is preparing the purposes in treating anti-breast cancer medicines.
Preferably, it is activity that the anti-breast cancer medicines, which are with heparin disaccharides grafting sulphation polymethyl acyl ethanol amine,
Ingredient, in addition pharmaceutically acceptable auxiliary material is prepared.
Above-mentioned heparin disaccharides is grafted sulphation polymethyl acyl ethanol amine, by being combined excessive heparinase I, heparinaseⅡ
And heparinase III, Natural heparin is degradable, and natural disaccharides is prepared in separation, and disaccharides is grafted on the poly- of specified molecular weight
On methacryl ethanol amine long-chain, be subject to sulphation to get.
The preparation method of above-mentioned heparin disaccharides grafting sulphation polymethyl acyl ethanol amine, includes the following steps：
(1) preparation of heparin disaccharides with detach：Being firstly added excessive heparinase I, heparinaseⅡ and heparinase III will be natural
Heparin digests completely；Then heparin disaccharides is obtained using G25, strong anion chromatography exchange column, G10 gel desalinations；
(2) synthesis of polymethyl ethanol amine：Using ethanolamine hydrochloric salt, methacrylic chloride as raw material, synthesizing methyl
Propylene ethyl alcohol amine monomers recycle RAFT reactions to prepare the polymethyl ethanol amine of specified molecular weight；
(3) graft reaction：Weigh heparin disaccharides, 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides and N- hydroxyl fourths
Imidodicarbonic diamide, is dissolved in the MES buffer solutions of pH 5.4~5.6, and adjusting control pH adds polymethyl ethyl alcohol 7.5~8.5
Amine reacts 8~12h and dialyses after reaction solution centrifugation is except precipitation at room temperature, and freeze-drying obtains heparin disaccharides grafting polymethyl ethyl alcohol
Amine；
(4) sulfating reaction：Weigh heparin disaccharides grafting polymethyl acyl ethanol amine, sulfur trioxide pyridine be dissolved in it is ultrapure
In water, adjust pH to alkalinity, 50~80 DEG C of reactions for 24 hours, then with hydrochloric acid solution neutralize, and dialyse, freeze-drying to get.
Synthetic route is as follows：
Heparin disaccharides grafting sulphation polymethyl acyl ethanol amine provided by the invention and preparation method, with existing skill
Art is compared, and is had the following advantages：(1) heparin disaccharides used in is natural disaccharides rather than artificial synthesized disaccharides, has safety,
The selection of macromolecule and heparin does premise with the biological safety of height；(2) heparin disaccharides is structure with high molecular combine
The material of innovation and optimization；(3) heparin disaccharides grafting sulphation polymethyl acyl ethanol amine has selective killing to MCF-7
Effect is had a good application prospect with its preparation treatment anti-breast cancer medicines.
Description of the drawings
Fig. 1 is by SGPHD for the cytotoxicity result of different tumour cells；
Fig. 2 is SGPHD200Influence to B16 cells；
Fig. 3 is SGPHD200Influence to COS7 cells.
Specific implementation mode
The present invention is described in further details with reference to embodiments.Production is not specified in agents useful for same or instrument and equipment
Manufacturer, being accordingly to be regarded as can be by commercially available conventional products.
1. experimental method
SGPHD detects the cytotoxicity of MCF-7, B16, MGC80-3, Hela and COS7 using MTT experiment, SGPHD
The cell survival rate of each concentration processing group and blank group uses 570nm UV absorbance detections.
2. experimental result
SGPHD is as shown in Figure 1 for the cytotoxicity result of several different tumour cells.SGPHD200Generation as SGPHD
Table all shows several tumour cells certain cytotoxicity.
Heparin disaccharides is grafted polymethyl acyl ethanol amine (GPHD) and is carried out using B16 cells and COS7 cells with SGPHD
The assessment of toxicity, as Figure 2-3, GPHD200Two kinds of cells of representative pair as GPHD all show higher cytotoxicity,
It is a kind of defect that this High Fragmentation to cancer cell non-selectivity, which acts in drug development,；And SGPHD200As a contrast
The heparin of group has not significant impact cell survival rate.
In conjunction with Fig. 1-3 it is recognized that while SGPHD200B16 and COS7 cell Proliferations are not influenced significantly, but to MCF-7
Cell but shows higher toxicity, prepares anti-breast cancer medicines with it, has a good application prospect.
The protection content of the present invention is not limited to above example.Without departing from the spirit and scope of the invention, originally
Field technology personnel it is conceivable that variation and advantage be all included in the present invention, and with the attached claims be protection
Range.
Claims (2)
1. heparin disaccharides is grafted sulphation polymethyl acyl ethanol amine and is preparing the purposes in treating anti-breast cancer medicines.
2. purposes according to claim 1, which is characterized in that the anti-breast cancer medicines are to be grafted sulfuric acid with heparin disaccharides
Change polymethyl acyl ethanol amine is active constituent, in addition pharmaceutically acceptable auxiliary material is prepared.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810552288.1A CN108403704A (en) | 2018-05-31 | 2018-05-31 | Heparin disaccharides is grafted the purposes of sulphation polymethyl acyl ethanol amine |
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| CN201810552288.1A CN108403704A (en) | 2018-05-31 | 2018-05-31 | Heparin disaccharides is grafted the purposes of sulphation polymethyl acyl ethanol amine |
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| CN201810552288.1A Pending CN108403704A (en) | 2018-05-31 | 2018-05-31 | Heparin disaccharides is grafted the purposes of sulphation polymethyl acyl ethanol amine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019205255A1 (en) * | 2018-04-28 | 2019-10-31 | 江南大学 | Use of sulfated heparin disaccharide-grafted polymethylacryloyl ethanolamine |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101491835A (en) * | 2009-02-27 | 2009-07-29 | 江南大学 | Preparation method of heparin modified gold nano-particles |
| CN104892807A (en) * | 2015-06-02 | 2015-09-09 | 江南大学 | Surface saccharide-modified polymer micelle, and preparation method and application thereof |
| CN105504097A (en) * | 2015-12-30 | 2016-04-20 | 深圳市海普瑞药业股份有限公司 | Sulfated heparin oligosaccharide as well as preparation method and application thereof |
| CN105891343A (en) * | 2014-12-06 | 2016-08-24 | 烟台东诚药业集团股份有限公司 | Analysis and detection method for fine structures of components of sulodexide |
| WO2017113197A1 (en) * | 2015-12-30 | 2017-07-06 | 深圳市海普瑞药业集团股份有限公司 | Sulfated heparin oligosaccharide and preparation method and application thereof |
-
2018
- 2018-05-31 CN CN201810552288.1A patent/CN108403704A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101491835A (en) * | 2009-02-27 | 2009-07-29 | 江南大学 | Preparation method of heparin modified gold nano-particles |
| CN105891343A (en) * | 2014-12-06 | 2016-08-24 | 烟台东诚药业集团股份有限公司 | Analysis and detection method for fine structures of components of sulodexide |
| CN104892807A (en) * | 2015-06-02 | 2015-09-09 | 江南大学 | Surface saccharide-modified polymer micelle, and preparation method and application thereof |
| CN105504097A (en) * | 2015-12-30 | 2016-04-20 | 深圳市海普瑞药业股份有限公司 | Sulfated heparin oligosaccharide as well as preparation method and application thereof |
| WO2017113197A1 (en) * | 2015-12-30 | 2017-07-06 | 深圳市海普瑞药业集团股份有限公司 | Sulfated heparin oligosaccharide and preparation method and application thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019205255A1 (en) * | 2018-04-28 | 2019-10-31 | 江南大学 | Use of sulfated heparin disaccharide-grafted polymethylacryloyl ethanolamine |
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