CN108498536A - Sulfated heparin disaccharides is grafted the purposes of polymethyl acyl ethanol amine - Google Patents
Sulfated heparin disaccharides is grafted the purposes of polymethyl acyl ethanol amine Download PDFInfo
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- A61K31/74—Synthetic polymeric materials
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Abstract
The characteristics of the invention belongs to biomedical materials fields, specifically disclose a kind of purposes of sulfated heparin disaccharides grafting polymethyl acyl ethanol amine, and the sulfated heparin disaccharides grafting polymethyl acyl ethanol amine antitumor activity is strong, low anticoagulant active；The research that sulfated heparin disaccharides grafting polymethyl acyl ethanol amine used in the present invention prepares treatment antitumor drug for heparin provides a new direction.
Description
Technical field
The invention belongs to biomedical materials fields, and in particular to sulfated heparin disaccharides is grafted polymethyl acyl ethyl alcohol
The purposes of amine.
Background technology
Heparin is usually present in mast cell, is existed in the tissues such as lung, vascular wall, intestinal mucosa, since its is various
Affinity is widely used as anticoagulant in clinic.Heparin is most people it is well known that its work in Blood Coagulation Process
With, but be that can also play other such as anti-inflammatory, anti-angiogenesis of effect and antitumor action in bioactive functions.Wherein,
The antitumor action of heparin has been concerned, and many researchs have been proven that heparin can inhibit the invasion of tumour cell and turn
It moves.However Natural heparin is inhomogenous mixture in structure, and biological activity standard is caused to be difficult to define, structure-activity relationship and work
It is extremely difficult with the research of mechanism.And may to cause bleeding and thrombopenia etc. malicious for the strong anticoagulant active of Natural heparin
Side effect.Which has limited the applications of Natural heparin.In addition, the exclusive source of Natural heparin is animal tissue, having may bring
The risk of virus pollution and adverse reaction.And heparin is also possible in vivo be decomposed by heparinase and other enzymes in the treatment, leads
Cause loses bioactivity.
The anticoagulant active of heparin essentially from it includes specific pentose sequence, which can be with antithrombase
(AT- III) is combined, and activates antithrombase, due to the anticoagulant active that heparin has, so can largely be caused bleeding using heparin
The effects that being reduced with induced platelet；In addition, it was discovered by researchers that the antitumor activity of heparin and its anticoagulation ability not
It is directly linked, but since the adjoint hydrogen bond of heparin saccharide ring is formed and the effect of heparin sulfate radical negative electrical charge, so that heparin is tied
Close the result of the protein to play an important role during metastases.Therefore, the exploitation of low anticoagulation heparin causes very high point
Note, especially in terms of inhibiting growth and metastasis of tumours.
The Chinese patent application of application number CN2012103286497 discloses a kind of side of control production low molecular weight heparin
Method degrades heparin to produce low molecular weight or Ultra-low molecular weight using heparinase two or more in heparinase I, II, III
Heparin leads to the risk of side effect very however, due to heparin and its specificity and polydispersity of low molecular weight heparin structure
It is high.
Recent years, many researchers also attempt to use the specific heparin disaccharides of chemical method composite structure and heparin derivatives
To weaken anticoagulant active, however, this method is along with the high cost of production and the difficulty of synthesis, the reduction of degree
Also the antitumor activity of heparin is reduced.Therefore five glycosylation sequences of the removal with anticoagulant capacity will determine the heparin disaccharides of component
It is grafted on acrylate long-chain and is subject to sulphation, it is possible to reduce structural heterogeneity, eliminate anticoagulant active, and improve
Its antitumor activity, synthesis brush have the hyparinoids from animal organs macromolecular of antitumor action.
Invention content
For the deficiency of existing issue, the object of the present invention is to provide sulfated heparin disaccharides to be grafted polymethyl acyl second
The purposes of hydramine.Result of study of the present invention shows that sulfated heparin disaccharides grafting polymethyl acyl ethanol amine can be carried effectively
High antimetastatic activity reduces anticoagulant active, and support is provided to prepare treatment antitumor drug for heparin.
The present invention solve its technical problem the technical solution adopted is that：
A kind of sulfated heparin disaccharides grafting polymethyl acyl ethanol amine, passes through and is combined excessive heparinase I, heparinase
II, heparinase III, Natural heparin is degradable, and natural disaccharides is prepared in separation, and disaccharides is grafted on specified molecular weight
On acrylate long-chain, it is subject to sulphation, obtains with good chemical stability, low anticoagulation, superior bio compatibility resists and swells
The heparan macromolecular of tumor performance.
The preparation method of above-mentioned sulfated heparin disaccharides grafting 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 (PAMA)：Using ethanolamine hydrochloric salt, methacrylic chloride as raw material, close
At metering system ethyl alcohol amine monomers, RAFT reactions is recycled to prepare the polymethyl ethanol amine of specified molecular weight；Specific molecular
The polymethyl ethanol amine of amount is reacted by RAFT to be realized, initiator, chain-transferring agent additive amount are added by control in reaction,
Reaction condition is controlled simultaneously realizes that molecular weight is controllable；
(3) graft reaction：Weigh heparin disaccharides, 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides (EDC) and N- hydroxyls
Base succimide (NHS), is dissolved in the MES buffer solutions of pH 5.4~5.6, and adjusting control pH adds poly- first 7.5~8.5
Base propylene ethanol amine, reacts 8~12h and dialyses after reaction solution centrifugation is except precipitation at room temperature, and freeze-drying obtains heparin disaccharides and is grafted poly- first
Base propylene ethanol amine (GPHD)；
(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.
As the optimal technical scheme of the application, the enzyme of heparinase I, heparinaseⅡ and heparinase III in the step (1)
Adding proportion living is 1:1:1.
As the optimal technical scheme of the application, the synthesis specific steps of methacryl ethanol amine in the step (2)
For：It weighs ethanolamine hydrochloric salt to mix with hydroquinone, methacrylic chloride is added at 70~80 DEG C, react 2h.
As the optimal technical scheme of the application, the synthesis of step (2) the polymethyl ethanol amine the specific steps are：
In molar ratio 50~200:1:0.2 to weigh metering system ethanol amine, azodiisobutyronitrile (AIBN) and 4- cyanopentanoic acids two thio
Benzoic acid (CTA), and it is dissolved in n,N-Dimethylformamide (DMF), it is reacted for 24 hours under 70~80 DEG C of nitrogen protections, wherein AIBN makees
For initiator, CTA is as polymerizable chain transfer agents.
As the optimal technical scheme of the application, in the step (3), the mass ratio 10~20 of heparin disaccharides and PAMA:4
~5, the mass ratio of heparin disaccharides, EDC and NHS is 1:1.25~3：0.2~1.5.
As the optimal technical scheme of the application, in the step (4), it is 9.5~10.5 to adjust pH, and agents useful for same is carbon
Sour sodium.
As the optimal technical scheme of the application, in the step (2), the polymethyl ethanol amine of specified molecular weight is
The monodispersed component of molecular weight.
Above-mentioned sulfated heparin disaccharides grafting polymethyl acyl ethanol amine is preparing the purposes in treating antitumor drug.
As the optimal technical scheme of the application, the tumour is melanoma.
Macromolecular of the present invention is the heparin disaccharides degraded by heparinase, is connect with ammonium polyacrylate, one end
Reactive group is carboxyl, and one end reactive group is amino, is connected by forming amido bond, the class with antimetastatic activity of synthesis
Heparin contains sugared macromolecular.
In the embodiment of the present invention, sulfated heparin disaccharides be grafted polymethyl acyl ethanol amine to tumor cell migration, wear
The inhibiting effect of film ability all shows stronger inhibiting effect compared with heparin, and external anticoagulating active measures display, base
Originally anticoagulant active is eliminated, there is development potentiality very much.
Its specific synthetic route is as follows：
The present invention is degradable by Natural heparin by being combined heparinase I, heparinaseⅡ and heparinase III, through G25 gels
It is tentatively separated by filtration, strong anion chromatography exchange post separation is prepared natural disaccharides and is grafted disaccharides after G10 gel desalinations
On the polymethyl ethanol amine long-chain of specified molecular weight, it is subject to sulphation, obtains with good chemical stability, low anti-freezing
Blood, superior bio compatibility, the heparan macromolecular of antitumor activity energy.
Sulfated heparin disaccharides grafting polymethyl acyl ethanol amine provided by the invention and preparation method, with existing skill
Art is compared, and is had the following advantages：
(1) present invention obtains disaccharides raw material from Natural heparin enzymolysis first, eliminates chemical method synthesis heparin sugar unit
It is cumbersome, while the quantity in heparin anti-coagulating activated centre is also eliminated, significantly reduce anticoagulant active；
(2) heparin disaccharides of the invention is natural disaccharides, has safety；The selection of macromolecule and heparin all has height
Biological safety do premise；
(3) heparin disaccharides is grafted on PAMA by the present invention, is formed " sugared cluster effect ", and product is also presented hypotoxicity and can neglect
Anticoagulant active slightly；
(4) present invention sulphation improves the charge density in lytic activity site, improves antimetastatic activity；
(5) preparation method is relatively simple, has many advantages, such as that raw material is cheap, reaction condition is mildly easily-controllable.
Description of the drawings
Fig. 1 is the strong anion exchange chromatographic figure by heparin disaccharides；
Fig. 2 is the GPC molecular weight determination figures of specified molecular weight polymethyl ethanol amine；
Fig. 3 is to detect heparin and sulfated heparin disaccharides grafting polymethyl acyl ethanol amine to B16 using scratch experiment
The inhibition situation of melanoma cells migration；Wherein, Control represents the blank control group added without drug, and Heparin is represented
Heparin, SGPHD represent sulfated heparin disaccharides grafting polymethyl acyl ethanol amine；Figure be 0h with for 24 hours after in the presence of drug it is thin
The comparison of born of the same parents' cut healing state；
Fig. 4 is to detect heparin and sulfated heparin disaccharides grafting polymethyl acyl ethanol amine to B16 using scratch experiment
Melanoma cells wear the inhibition situation of film；Wherein, Control represents the blank control group added without drug, and Heparin is represented
Heparin, SGPHD represent sulfated heparin disaccharides grafting polymethyl acyl ethanol amine.
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.
Embodiment 1：
1. enzymic degradation prepares heparin disaccharides
6g heparin is dissolved in the pH 7.4Tris buffer solutions that 120mL includes 5mM CaCl, 20mM NaCl, liver is added
Each 10IU of plain enzyme I, heparinaseⅡ, heparinase III is placed in 37 DEG C of shaking tables, 150 revs/min of concussion reactions for 24 hours.After reaction, instead
Answering liquid to be boiled 3min makes enzyme inactivate, and 5000r/min centrifuges 15min, takes supernatant to be lyophilized, obtains Heparin Oligosaccharides, the present embodiment
Enzyme is set to inactivate by improving temperature.
2.G25 gel is tentatively separated by filtration
Sephadex G-25 dress up the glass chromatography column of 1.2 × 100cm through processing.Freeze-drying oligosaccharides is matched using ultra-pure water
It is set to 40mg/mL solution, loading 1mL is eluted using the ultrapure water flow velocities of 1mL/min, is absorbed using UV detector monitoring 232nm
Wavelength curve is in charge of and collects each peak and be lyophilized.
3. strong anion exchange chromatographic detects disaccharide component
Using HPLC methods, chromatographic condition is：ProPac SAX-10 chromatographic columns, it is molten with the NaCl of 20mM -1.5M pH 3.5
Liquid elutes for eluent gradient, flow velocity 0.5mL/min, 25 DEG C of column temperature.Loading is in charge of the 20 μ L of heparin disaccharides sample of collection respectively,
Elution curve is monitored, determines to include disaccharide component, as shown in Figure 1, the peaks 1-8 are respectively eight kinds of disaccharides for including in heparin structure.
4.G10 gel desalination
After the 40 DEG C of rotary evaporation concentrations of heparin disaccharide component detected, 1.2 × 100cm Sephadex G10 are used
Column desalination, mobile phase are ultra-pure water, flow velocity 1mL/min.For desalination disaccharides again after rotary evaporation concentration, freeze-drying is for use.
5. the synthesis of methacryl ethyl alcohol amine monomers
The 1g ethanolamine hydrochloric salts dried are mixed with 30mg hydroquinones, are placed in 25mL round-bottomed flasks, 80 DEG C of heating
Under stirring, 2mL methacrylic chlorides are instilled, 70~80 DEG C of condensing refluxes are stirred to react 2h；3mL is added to the product dissolved
Tetrahydrofuran dissolves, and uses the 8000r/min precipitation centrifugations of 100mL ether；Precipitation is washed three times with ether, and vacuum drying obtains methyl
Acryloyl ethyl alcohol amine monomers.
6. the synthesis of specified molecular weight polymethyl ethanol amine
662mg metering systems ethanol amine, 4.24mg AIBN, 0.821mg4- cyanopentanoic acid dithiobenzoic acids are dissolved in
Polymerization pipe is added in 5mL anhydrous DMFs.Polymerization pipe is cooled down using liquid nitrogen, is thawed after vacuumizing, and replaces high pure nitrogen, in triplicate.
After 70-80 DEG C of oil bath of polymerization pipe is stirred to react for 24 hours, using 100mL ethanol precipitations, reuses ethyl alcohol and wash three times, by what is be settled out
Polymer is dried in vacuo.Polymer molecular weight measures (Fig. 2) using GPC, as a result shows that polymer is monodispersed group of molecular weight
Point.
7. heparin disaccharides is grafted polymethyl acyl ethanol amine
200mg mixing heparin disaccharides, 47mg NHS and 257mg EDC is taken to be dissolved in 50mL pH 5.5MES buffer solutions, room temperature
Lower stirring 30min.PH to 8 is adjusted using triethylamine, adds 50mg polymethyl ethanol amines, reaction 8h is stirred at room temperature.Instead
It answers liquid to be centrifuged off precipitation, is dialysed using 3000 bag filter of molecular cut off, freeze-drying obtains product heparin disaccharides and is grafted poly- methyl
Acryloyl ethanol amine.
8. heparin disaccharides is grafted the sulphation of polymethyl acyl ethanol amine
Disaccharides grafting polymethyl acyl ethanol amine 50mg, sulfur trioxide pyridine 75mg is taken to be dissolved in 5mL ultra-pure waters, make
It is 9.5~10.5 to adjust pH with sodium carbonate, and reaction solution is stirred to react under 50~80 DEG C of nitrogen atmosphere uses 0.1M hydrochloric acid molten afterwards for 24 hours
Liquid neutralizes, and is dialysed using 3000 bag filter of molecular cut off, and freeze-drying obtains product sulfated heparin disaccharides grafting polymethyl
Acyl ethanol amine.
Performance test
The inhibition of tumor cell migration ability is made in vitro 1. sulfated heparin disaccharides is grafted polymethyl acyl ethanol amine
With
The B16 melanoma cells easily shifted are seeded on 24 orifice plates, density is 5 × 104/ hole.Wait for that cell is close in hole
After degree is more than 90%, cut is drawn in parallel on every hole cellular layer using 200 μ L pipette tips.Twice using PBS cleanings, it is changed to nothing
Blood serum medium, while being grouped and heparin (512mg/L) is added, the sulfated heparin disaccharides of various concentration is grafted polymethyl acyl
Ethanol amine (128mg/L, 256mg/L and 512mg/L) continues culture for 24 hours, observes and cut healing state of taking pictures.
As a result as Fig. 3 shows that the B16 melanoma cells layer cuts of agent-feeding treatment do not heal substantially after for 24 hours, say
The transfer ability of its bright script is very strong.And heparin and sulfated heparin disaccharides grafting polymethyl acyl ethanol amine is added to this
Kind healing has apparent inhibiting effect, and sulfated heparin disaccharides is grafted polymethyl acyl ethanol amine to B16 melanomas
The rejection ability of cell migration is stronger.
2. the inhibition that sulfated heparin disaccharides grafting polymethyl acyl ethanol amine in vitro wears tumour cell film ability is made
With
It is separately added into the heparin that 700 μ L contain various concentration in each hole of 24 orifice plates and sulfated heparin disaccharides is grafted poly- methyl
The culture medium of acryloyl ethanol amine (128mg/L, 256mg/L and 512mg/L), the cells device Transwell.To on each cell
Layer 100 μ L density of inoculation are 1 × 106The B16 melanoma cells suspension of/mL is wiped after continuing culture for 24 hours using cotton swab
The B16 melanoma cells on cell upper layer, and using 0.1% crystal violet solution to the B16 melanoma cells across cell film
Dyeing, after PBS cleans residual dye three times, sight is looked into and cell-penetrating situation of taking pictures.
As a result such as Fig. 4 is shown, heparin and sulfated heparin disaccharides grafting polymethyl acyl ethanol amine wear film to this
Movement has apparent inhibiting effect, and sulfated heparin disaccharides grafting polymethyl acyl ethanol amine shows stronger inhibition
Ability.
3. sulfated heparin disaccharides is grafted the external anticoagulating active of polymethyl acyl ethanol amine and measures
Sulfated heparin disaccharides is grafted the external anticoagulating active of polymethyl acyl ethanol amine and uses 7.0 version of European Pharmacopoeia
Substrate determination of color.6.05g/L Tris solution is used as dilution by salt acid for adjusting pH to 8.4.The medicine of 160 μ L various concentrations
After 37 DEG C of water-bath 60s, 40 μ L 2mM factor Xas are added with III and 20 μ L human serums of excessive antithrombase AT- in object
(S-2765) or II a (S-2238) chromogenic substrate, 10-30s periods measure absorption at 405nm.Use Heparin Standard product
(220U/mg) measures anti-Xa or II a activity of various concentration heparin as stated above, and draws standard curve, according to standard song
Line calculates anti-Xa or II a activity of sulfated heparin disaccharides grafting polymethyl acyl ethanol amine.
1 sulfated heparin disaccharides of table is grafted polymethyl acyl ethanol amine (SGPHD) and heparin, heparin as a control group
The external anticoagulating active of disaccharides
As can be seen from Table 1, sulfated heparin disaccharides grafting polymethyl acyl ethanol amine has suitable with heparin disaccharides
Anticoagulation ability, 50 times lower than heparin or more, therefore, when as antitumor drug, can be ignored SGPHD bleeding risk；
The anticoagulant active of heparin is mediated by single chain glycoprotein antithrombin Ⅲ, which is mainly derived from the Mixed Zones NA/NS Zhong Te
Anisotropic five glycosylation sequences that can be specifically bound with antithrombase, since the heparin disaccharides of SGPHD does not contain above-mentioned pentasaccharides structure,
So SGPHD can theoretically reduce its anticoagulant active.
SGPHD is to inhibiting B16 cell migrations, intrusion and adherency and heparin it can be seen from above performance test data
Compared to showing stronger effect, while the quantity in heparin anti-coagulating activated centre is also eliminated, significantly reduces anticoagulation
Activity, these results have an important influence on the further rational design of antitumor drug with application.
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. sulfated heparin disaccharides is grafted polymethyl acyl ethanol amine and is preparing the purposes in treating antitumor drug.
2. sulfated heparin disaccharides grafting polymethyl acyl ethanol amine described in claim 1 is preparing treatment antitumor drug
In purposes, the tumour is melanoma.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810399166.3A CN108498536B (en) | 2018-04-28 | 2018-04-28 | The purposes of sulfated heparin disaccharides grafting polymethyl acyl ethanol amine |
| PCT/CN2018/091470 WO2019205255A1 (en) | 2018-04-28 | 2018-06-15 | Use of sulfated heparin disaccharide-grafted polymethylacryloyl ethanolamine |
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| CN201810399166.3A CN108498536B (en) | 2018-04-28 | 2018-04-28 | The purposes of sulfated heparin disaccharides grafting polymethyl acyl ethanol amine |
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| CN102864191A (en) * | 2011-12-16 | 2013-01-09 | 深圳市海普瑞药业股份有限公司 | Heparin disaccharide mixture and preparation method and application thereof |
| CN103087219A (en) * | 2011-12-30 | 2013-05-08 | 北京大学 | Dentritic heparin nano-material modified biological type artificial blood vessel |
| 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 |
| CN106932494A (en) * | 2015-12-30 | 2017-07-07 | 深圳市海普瑞药业股份有限公司 | A kind of method that enzymolysis-HPLC detects Sulodexide |
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|---|---|---|---|---|
| CN103705534A (en) * | 2013-12-30 | 2014-04-09 | 中国药科大学 | Preparation of natural active substance constructed polymer composite medicine and application thereof in inhibiting angiogenesis |
| CN108641018B (en) * | 2018-04-28 | 2019-07-23 | 江南大学 | A kind of sulfated heparin disaccharides grafting polymethyl acyl ethanol amine and preparation method thereof |
| CN108403704A (en) * | 2018-05-31 | 2018-08-17 | 江南大学 | Heparin disaccharides is grafted the purposes of sulphation polymethyl acyl ethanol amine |
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- 2018-04-28 CN CN201810399166.3A patent/CN108498536B/en active Active
- 2018-06-15 WO PCT/CN2018/091470 patent/WO2019205255A1/en active Application Filing
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102864191A (en) * | 2011-12-16 | 2013-01-09 | 深圳市海普瑞药业股份有限公司 | Heparin disaccharide mixture and preparation method and application thereof |
| CN103087219A (en) * | 2011-12-30 | 2013-05-08 | 北京大学 | Dentritic heparin nano-material modified biological type artificial blood vessel |
| 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 |
| CN106932494A (en) * | 2015-12-30 | 2017-07-07 | 深圳市海普瑞药业股份有限公司 | A kind of method that enzymolysis-HPLC detects Sulodexide |
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| CN108498536B (en) | 2019-07-23 |
| WO2019205255A1 (en) | 2019-10-31 |
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