CN108498536B - The purposes of sulfated heparin disaccharides grafting polymethyl acyl ethanol amine - Google Patents
The purposes of sulfated heparin disaccharides grafting polymethyl acyl ethanol amine Download PDFInfo
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- CN108498536B CN108498536B CN201810399166.3A CN201810399166A CN108498536B CN 108498536 B CN108498536 B CN 108498536B CN 201810399166 A CN201810399166 A CN 201810399166A CN 108498536 B CN108498536 B CN 108498536B
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- ethanol amine
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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
- A61K31/74—Synthetic polymeric materials
- A61K31/795—Polymers containing sulfur
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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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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F120/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
- C08F120/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F120/10—Esters
- C08F120/34—Esters containing nitrogen, e.g. N,N-dimethylaminoethyl (meth)acrylate
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
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 anti-tumor activity is strong, low anticoagulant active;Sulfated heparin disaccharides used in the present invention is grafted the research that polymethyl acyl ethanol amine prepares treatment anti-tumor drug for heparin and 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 technique
Heparin is usually present in mast cell, is existed in the tissue 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 other such as anti-inflammatory, anti-angiogenesis of effect and antitumor action can be also played in bioactive functions.Wherein,
The antitumor action of heparin has been concerned, and many researchs have been proven that heparin is able to suppress the invasion of tumour cell and turns
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 the strong anticoagulant active of Natural heparin may lead issue blood and thrombopenia etc. it is malicious
Side effect.Which has limited the applications of Natural heparin.In addition, the exclusive source of Natural heparin is animal tissue, having may be brought
The risk of virus pollution and adverse reaction.And heparin is also possible to be decomposed in vivo by heparinase and other enzymes in the treatment, leads
Cause loses bioactivity.
The anticoagulant active of heparin mainly 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 of being reduced with induced platelet;In addition, it was discovered by researchers that the anti-tumor 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 using heparinase two or more in heparinase I, II, III to produce low molecular weight or Ultra-low molecular weight
Heparin, however, leading to the risk of side effect very 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 anti-tumor activity of heparin is reduced.Therefore removal has five glycosylation sequences of 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 anti-tumor activity, synthesis brush have the hyparinoids from animal organs macromolecular of antitumor action.
Summary of the invention
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 mentioned effectively
High antimetastatic activity reduces anticoagulant active, so that preparing treatment anti-tumor drug for heparin provides support.
The technical solution used to solve the technical problems of the present invention 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 separate: 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 desalination;
(2) it the synthesis of polymethyl ethanol amine (PAMA): using ethanolamine hydrochloric salt, methacrylic chloride as raw material, closes
At metering system ethyl alcohol amine monomers, RAFT reaction 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, adds initiator, chain-transferring agent additive amount by control in reaction,
Reaction condition is controlled simultaneously realizes that molecular weight is controllable;
(3) heparin disaccharides, 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide (EDC) and N- hydroxyl graft reaction: are weighed
Base succimide (NHS) is dissolved in the MES buffer of pH 5.4~5.6, adjusts control pH 7.5~8.5, adds poly- first
Base propylene ethanol amine, reacts 8~12h at room temperature and dialyses after reaction solution centrifugation is except precipitating, 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, 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)
Are as follows: it weighs ethanolamine hydrochloric salt and is mixed with hydroquinone, methacrylic chloride is added at 70~80 DEG C, react 2h.
As the optimal technical scheme of the application, the synthesis specific steps of step (2) the polymethyl ethanol amine are as follows:
It is thio to weigh metering system ethanol amine, azodiisobutyronitrile (AIBN) and 4- cyanopentanoic acid two by 50~200:1:0.2 in molar ratio
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), 10~20:4 of mass ratio of heparin disaccharides and PAMA
~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), adjusting pH is 9.5~10.5, 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.
Purposes of the above-mentioned sulfated heparin disaccharides grafting polymethyl acyl ethanol amine in preparation treatment anti-tumor 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, and external anticoagulating active measurement display, base compared with heparin
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 gel
Primary filtration separation, strong anion chromatography exchange post separation are prepared natural disaccharides and are grafted disaccharides after G10 gel desalination
On the polymethyl ethanol amine long-chain of specified molecular weight, it is subject to sulphation, obtains with good chemical stability, it is low anticoagulant
Blood, the heparan macromolecular of superior bio compatibility, 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 advantage that
(1) present invention obtains disaccharides raw material from Natural heparin enzymatic hydrolysis 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 improves the charge density in lytic activity site with sulphation, 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.
Detailed description of the invention
Fig. 1 is the strong anion exchange chromatographic figure by heparin disaccharides;
Fig. 2 is the GPC molecular weight determination figure of specified molecular weight polymethyl ethanol amine;
Fig. 3 is that heparin and sulfated heparin disaccharides grafting polymethyl acyl ethanol amine are detected using scratch experiment to B16
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' scratch healing state;
Fig. 4 is that heparin and sulfated heparin disaccharides grafting polymethyl acyl ethanol amine are detected using scratch experiment to B16
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 embodiment
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
It includes 5mM CaCl that 6g heparin, which is dissolved in 120mL, and in the pH 7.4Tris buffer of 20mM NaCl, liver is added
Plain enzyme I, heparinaseⅡ, each 10IU of heparinase III are 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 inactivates enzyme, and 5000r/min is centrifuged 15min, takes supernatant to be lyophilized, obtains Heparin Oligosaccharides, the present embodiment
Enzyme is inactivated by improving temperature.
2.G25 gel primary filtration separates
Sephadex G-25 is handled, and the glass chromatography column of 1.2 × 100cm is dressed up.Freeze-drying oligosaccharides is matched using ultrapure water
It is set to 40mg/mL solution, loading 1mL is eluted using the ultrapure water flow velocity 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 method, chromatographic condition are as follows: ProPac SAX-10 chromatographic column, it is molten with the NaCl of 20mM -1.5M pH 3.5
Liquid is that eluent gradient elutes, 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 peak 1-8 is respectively eight kinds of disaccharides for including in heparin structure.
4.G10 gel desalination
After 40 DEG C of rotary evaporation concentrations of the heparin disaccharide component that will test, 1.2 × 100cm Sephadex G10 is used
Column desalination, mobile phase are ultrapure water, flow velocity 1mL/min.For desalination disaccharides again after rotary evaporation concentration, freeze-drying is stand-by.
5. the synthesis of methacryl ethyl alcohol amine monomers
The dry ethanolamine hydrochloric salt of 1g is mixed with 30mg hydroquinone, is placed in 25mL round-bottomed flask, 80 DEG C of heating
Under stirring, 2mL methacrylic chloride is instilled, 70~80 DEG C of condensing refluxes are stirred to react 2h;3mL is added to the product dissolved
Tetrahydrofuran dissolution, is precipitated using 100mL ether 8000r/min and is centrifuged;Precipitating 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 system ethanol amine, 4.24mg AIBN, 0.821mg4- cyanopentanoic acid dithiobenzoic acid are dissolved in
Polymerization pipe is added in 5mL anhydrous DMF.Polymerization pipe is cooling using liquid nitrogen, thaws 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 precipitation, reuses ethyl alcohol and wash three times, by what is be settled out
Polymer vacuum drying.Polymer molecular weight is using GPC measurement (Fig. 2), and polymer is monodispersed group of molecular weight as the result is shown
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, room temperature
Lower stirring 30min.PH to 8 is adjusted using triethylamine, adds 50mg polymethyl ethanol amine, reaction 8h is stirred at room temperature.Instead
It answers liquid to be centrifuged off precipitating, 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. the sulphation of heparin disaccharides grafting polymethyl acyl ethanol amine
Disaccharides is taken to be grafted polymethyl acyl ethanol amine 50mg, sulfur trioxide pyridine 75mg is dissolved in 5mL ultrapure water, makes
Adjusting pH with sodium carbonate is 9.5~10.5, and reaction solution is stirred to react molten using 0.1M hydrochloric acid afterwards for 24 hours under 50~80 DEG C of nitrogen atmosphere
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.It is close to cell in hole
After degree is greater than 90%, using 200 μ L pipette tips in drawing scratch in parallel on every hole cellular layer.Twice using PBS cleaning, 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 scratch healing state of taking pictures.
As a result such as Fig. 3 shows that the B16 melanoma cells layer scratch of agent-feeding treatment does not heal substantially after for 24 hours, says
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 grafting polymethyl acyl ethanol amine is to B16 melanoma
The rejection ability of cell migration is stronger.
2. the inhibition that sulfated heparin disaccharides grafting polymethyl acyl ethanol amine wears film ability to tumour cell in vitro is made
With
The heparin that 700 μ L contain various concentration is separately added into 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 cell 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 for passing through 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 measurement of polymethyl acyl ethanol amine
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
40 μ L 2mM factor Xas are added after 37 DEG C of water-bath 60s in object and excessive antithrombase AT- III and 20 μ L human serums
(S-2765) or II a (S-2238) chromogenic substrate, 10-30s period measure absorption at 405nm.Use Heparin Standard product
(220U/mg) measures anti-Xa or II a activity of various concentration heparin according to the above method, 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 be used as anti-tumor drug when, 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 Zone 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 inhibition B16 cell migration, 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 anti-tumor drug with application.
Protection content of the invention is not limited to above embodiments.Without departing from the spirit and scope of the invention, originally
Field technical staff it is conceivable that variation and advantage be all included in the present invention, and with the attached claims be protection
Range.
Claims (1)
1. sulfated heparin disaccharides is grafted polymethyl acyl ethanol amine in preparation treatment tumor migration, the drug of intrusion and adherency
In purposes, which is characterized in that the tumour is melanoma;The sulfated heparin disaccharides is grafted polymethyl acyl second
The preparation method of hydramine includes the following steps:
(1) preparation of heparin disaccharides with separate: be firstly added excessive heparinase I, heparinaseⅡ and heparinase III for Natural heparin
Enzymatic hydrolysis completely;Then post separation is exchanged using G25, strong anion chromatography, G10 gel desalination obtains heparin disaccharides;
(2) synthesis of polymethyl acyl ethanol amine: using ethanolamine hydrochloric salt, methacrylic chloride as raw material, synthesizing methyl third
Alkene acyl ethyl alcohol amine monomers recycle RAFT reaction to prepare the polymethyl acyl ethanol amine of specified molecular weight, the specific molecular
Amount is 17469;
(3) heparin disaccharides, 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide and N- obtained by step (1) graft reaction: are weighed
Hydroxysuccinimide is dissolved in the MES buffer of pH5.4~5.6, adjusts control pH 7.5~8.5, adds step (2) institute
Polymethyl acyl ethanol amine is obtained, reacts 8~12h at room temperature, after reaction solution centrifugation is except precipitating, dialysis, freeze-drying obtains heparin disaccharides
It is grafted polymethyl acyl ethanol amine;
(4) heparin disaccharides obtained by step (3) grafting polymethyl acyl ethanol amine, sulfur trioxide pyridine sulfating reaction: are weighed
Be dissolved in ultrapure water, adjust pH to alkalinity, 50~80 DEG C of reactions for 24 hours, then with hydrochloric acid solution neutralize, dialyse, freeze-drying to get;
In the step (3), mass ratio 10~20:4~5 of heparin disaccharides and polymethyl acyl ethanol amine, heparin disaccharides, 1-
The mass ratio of (3- dimethylamino-propyl) -3- ethyl carbodiimide and N- hydroxysuccinimide be 1:1.25~3:0.2~
1.5。
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PCT/CN2018/091470 WO2019205255A1 (en) | 2018-04-28 | 2018-06-15 | Use of sulfated heparin disaccharide-grafted polymethylacryloyl ethanolamine |
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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 |
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