CN103893813B - Polymeric composition and high molecular material - Google Patents
Polymeric composition and high molecular material Download PDFInfo
- Publication number
- CN103893813B CN103893813B CN201210586655.2A CN201210586655A CN103893813B CN 103893813 B CN103893813 B CN 103893813B CN 201210586655 A CN201210586655 A CN 201210586655A CN 103893813 B CN103893813 B CN 103893813B
- Authority
- CN
- China
- Prior art keywords
- histidine
- matrix metalloproteinase
- polymeric composition
- activity
- medical equipment
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 CC(C)(C)CCOC(C(CCc1cnc[n]1)NC(*C(C)(C)C)=O)O Chemical compound CC(C)(C)CCOC(C(CCc1cnc[n]1)NC(*C(C)(C)C)=O)O 0.000 description 1
Abstract
The present invention provides polymeric composition and high molecular material.A kind of polymeric composition, including：Macromolecule with hydroxyl；And the derivatives graft of histidine or histidine is on the macromolecule with hydroxyl.
Description
Technical field
The present disclosure generally relates to a kind of polymeric composition, and especially in regard to a kind of high score subgroup with zinc ion affinity
Compound, and there is this polymeric composition matrix metalloproteinase (matrixmetallopoateinases, MMPs) to suppress work(
Effect, can be directly using bulk form as chronic wounds dressing or the surface that can be used to handle medical equipment, so that sufferer uses this
Tissue inflammation's symptom can be improved when chronic wounds dressing or medical equipment and/or promote wound healing.
Background technology
Being currently known the matrix metalloproteinase (matrixmetallopoateinases, MMPs) of high activity and concentration is
Cause the main cause of chronic wounds slowly not more.The infection and inflammation of wound can cause a large amount of secretion of MMPs of tissue with
Decompose with remove wound bed death cell and bacterium, but matrix metal proteinase activity it is excessive also can cambium decomposition with
The damage of growth factor, makes wound return to the inflammation phase once again, and forming vicious circle can not heal.Said circumstances is in patient of diabetes
Or the wound of other chronic sufferers of pathogenic is very common, or even cause the wound deterioration even amputation of sufferer.There is base at this time
The dressing of matter metalloproteinases inhibition can reduce local host metal proteinase activity, promote wound healing.
Also, in various inflammatory reaction, such as rheumatoid arthritis (rheumatoid arthritis) and Osteoarthritis
(osteoarthritis) the also equal situation of a large amount of secretion of MMPs in a organized way.The matrix metalloproteinase of high activity
One of performance often starts a variety of biochemical mechanisms, turn for the machine that causes a disease, cause cartilage destruction.In addition in coronary artery disease（Such as hat
Worry）During with myocardial damage, produced active matrix metalloproteinase often lead by further degradation of cell epimatrix
Cause patch and vascular wall it is thinning so that rupture.The material with matrix metalloproteinase inhibition, which can be used as, at this time alleviates illness
The effect of.
In addition, usually in angiogenesis, cell migration, tissue is newborn rebuild when must have the generation of matrix metalloproteinase with
The degraded of helper cell extracellular matrix materials.But when tumour generates, the activities present of excess matrix metalloproteinases can cause
Extracellular basement membrane degradation, and therefore promote the infringement ability of tumour and transfer ability to rise therewith, cause the expansion of tumour cell
Dissipate.There is the exploitation of the inhibitor and material that suppress matrix metal proteinase activity can help to reduce neonate tumour blood vessel at this time
With transfer.
Matrix metalloproteinase contains zinc ion, the endopeptidease of decomposable asymmetric choice net most cells epimatrix for a group.Its
Containing proparea (prodomain), catalytic center, erythrocruorin associated proteins (hemopexin) effect section and cross-film in structure
(transmembrane) four effect sections (domain) are formed.Now it has been found that matrix metalloprotease more than 25 kinds
Enzyme, it rough can be divided into four types, including (1) Collagenase；(2) gelatinase；(3) stromelysin；With (4) membrane type matrix metal
Protease.The gelatin being rich in tissue, collagen can effectively be decomposed, with proteoglycan etc., and with organizing the formation of, group
Knit metabolism and inflammatory response is related.Matrix metalloproteinase is in the zinc atom in secretion generation period, at this time its activated positions
Combined with cystine, be disactivation state, when polypeptide is cut after open, matrix metalloproteinase then as it is active it
Form.
Research mainly has three kinds of methods for the suppressing method of matrix metalloproteinase at present：(1) metalloproteinases is used
Tissue inhibiting (tissue inhibitor ofmetalloproteinase) and matrix metalloproteinase ferroheme knot
Hop protein, which forms the compound that reversible, non-covalent bond combines, makes it lose activity；(2) matrix is directly suppressed with peptide or antibody format
The activities present of metalloproteinases；And (3) inactivate enzyme using the molecule for having high-affinity between zinc ion to be bonded.Its
Chelated zinc ions and then make the deactivated mechanism of matrix metalloproteinase, be with not being bonded electricity by phosphorus, nitrogen, sulphur, oxygen etc.
Son is very easy to the atom of (lone pairelectrons) to form coordination (coordination) shape with transition metal
Formula.
Shown by document and in recent years Related product R＆D direction, the advanced dressing of chronic wounds starts demand and suppresses matrix metal
Proteinase activity is healed with promoting wound bed to rebuild.Such product can inhibit matrix metalloproteinase to develop with wound bed contact
Raw doctor's material of activity is the third suppressing method.By taking the Promogran chronic wounds dressing of Systagenix companies as an example, its
Oxycellulose and collagen combine base material and can effectively absorb wound bed diffusate, and by oxycellulose acid group and zinc
The affinity inhibitory enzyme activity of ion.Smith ＆Nephew companies also release chronic wounds dressing Biostep its suppression mechanism
It is EDTA of the addition with chelated zinc ions effect in base material, since matrix metalloproteinase must be by the knot with zinc ion
Close to maintain the state of its activation, therefore the EDTA to dissociate in base material can effectively reduce zinc ion concentration, even absorption contain zinc it
Matrix metalloproteinase is allowed to inactivate.But this chelating molecule be free state exist, therefore action time be easily restricted with efficiency.
Therefore at present there is an urgent need for a kind of new material, it can the long-acting activity for suppressing matrix metalloproteinase.
The content of the invention
The present invention provides a kind of polymeric composition, including：Macromolecule with hydroxyl；And histidine or histidine it
Derivatives graft is on the macromolecule with hydroxyl.
The present invention also provides a kind of high molecular material, including：Polymeric composition, it includes：Macromolecule with hydroxyl；
And the derivatives graft of histidine or histidine is on the macromolecule with hydroxyl.
The present invention further provides a kind of medical equipment, including：Polymeric composition, it includes：High score with hydroxyl
Son；And the derivatives graft of histidine or histidine is on the macromolecule with hydroxyl.
Above and other purpose, feature and advantage in order to allow the present invention can become apparent, cited below particularly preferably to implement
Example, and coordinate appended diagram, it is described in detail below：
Brief description of the drawings
Fig. 1 shows to form one of polymeric composition of the present invention embodiment；
Fig. 2 shows the application mode of polymeric composition of the present invention；
Fig. 3 shows inhibiting rate of the Boc histidines to Matrix Metalloproteinase-9 of various concentrations；
Fig. 4 shows the polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " of various concentrations（Embodiment 1 it
Lot1）To the inhibiting rate of Matrix Metalloproteinase-9；
Fig. 5 shows polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis "（The Lot1 of embodiment 1）Form it
Inhibiting rate of the film to Matrix Metalloproteinase-9；
Fig. 6 shows polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis "（The Lot2 of embodiment 1）Form it
Inhibiting rate of the film to Matrix Metalloproteinase-9；
Fig. 7 shows polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis "（The Lot2 of embodiment 1）Form it
Inhibiting rates of the film Lot1-1 and Lot1-2 to Matrix Metalloproteinase-9；
Fig. 8 shows poly ethylene vinyl alcohol grafting histidine derivative " EVOH-g-BocHis "（The Lot3 of embodiment 2 with
Lot4）Inhibiting rate of the film formed to Matrix Metalloproteinase-9；
Fig. 9 shows hydroxypropyl methyl cellulose grafting histidine derivative " HPMC-g-BocHis "（The Lot5 of embodiment 3）
Inhibiting rate of the film formed to Matrix Metalloproteinase-9；
Figure 10 shows hydroxypropyl methyl cellulose grafting histidine derivative " HPMC-g-BocHis "（Embodiment 3 it
Lot6）Inhibiting rate of the film formed to Matrix Metalloproteinase-9；
Figure 11 shows hydroxypropyl methyl cellulose grafting histidine derivative " HPMC-g-BocHis "（The Lot6 of embodiment 3
With Lot7）Inhibiting rate of the film formed to Matrix Metalloproteinase-9；
Figure 12 shows poly ethylene vinyl alcohol grafting histidine derivative film sample (Lot 3) to Matrix Metalloproteinase-9
It is long-acting suppression measures of effectiveness result；
Figure 13 shows base material (EVOH-c-BocHis) and poly ethylene vinyl alcohol grafting group ammonia through histidine impregnation processing
The result of the long-acting suppression measures of effectiveness of acid derivative film sample (Lot 4).
Figure 14 displays grafting histidine derivative film sample is to zoopery diabetic mice wound fluid mesostroma gold
The Activity Assessment result of Proteases -9.
【Primary clustering symbol description】
101~the macromolecule with hydroxyl；
The derivative of 103~histidine or histidine；
105~base material；
S1~mix, be coated with, be impregnated with processing procedure.
Embodiment
In an embodiment of the present invention, the present invention provides polymeric composition, it has suppression with zinc ion affinity
The effect of activity of matrix metalloproteinase (matrix metallopoateinases, MMPs) processed.Referring to Fig. 1.Fig. 1 is shown
Form one of polymeric composition of the present invention embodiment.Shown in Fig. 1, the derivative 103 of histidine or histidine is grafted
In formation polymeric composition of the present invention on the macromolecule 101 with hydroxyl.
As shown in Figure 1, the polymeric composition of the present invention may include the macromolecule 101 and histidine or group ammonia with hydroxyl
The derivative 103 of acid is grafted on the macromolecule 101 with hydroxyl.Polymeric composition of the present invention has zinc ion affinity,
And have effects that to suppress the activity of matrix metalloproteinase.In one embodiment, can be pressed down by polymeric composition of the present invention
The matrix metalloproteinase of system may include, but be not limited to Fibroblast collagenase, MMP-2, matrix metal egg
White enzyme -8, Matrix Metalloproteinase-9 and/or MMP-13.
In the polymeric composition of the present invention, the derivative of histidine or histidine is about 0.1 ~ 99wt%.
In the polymeric composition of the present invention, the macromolecule of hydroxyl may include to synthesize macromolecule or natural polymer, and
Above-mentioned synthesis macromolecule or natural polymer may include linear polymeric or the macromolecule with side chain.
In one embodiment, above-mentioned synthesis macromolecule can be linear synthesis macromolecule.The example of above-mentioned linear synthesis macromolecule
Son may include polyolefin-based glycol (polyalkylene glycol), polyvinyl alcohol (polyvinyl alcohol, PVA), gather
Vinylacetate (polyvinyl acetate, PVAc), vinyl alcohol-vinyl acetate co-polymer (poly (vinyl
Alcohol-co-vinylacetate)), ethylene-vinyl alcohol copolymer (poly (ethylene vinyl-co-alcohol,
EVOH)) its derivative is combined with above-mentioned, but not limited to this.
Also, in one embodiment, in polymeric composition of the present invention, the macromolecule of above-mentioned hydroxyl can be natural polymer
Son, and natural polymer may include polysaccharide polymer.It may include suitable for the polysaccharide polymer of polymeric composition of the present invention, but
It is not limited to, hyaluronic acid (hyaluronic acid), starch (starch), cellulose (cellulose), methylcellulose
(methylcellulose), hydroxypropyl cellulose (hydroxypropyl cellulose), hydroxypropyl methyl cellulose
(hydroxypropyl methylcellulose), oxycellulose (oxidizedcellulose), glucan
(dextran), scleroglucan (scleroglucan), chitin (chitin), spherical chitosan (chitosan), card Derain glue
(crudlan), algin (alginate), carrageenin (carrageenan), pectin (pectin), gum arabic (gum
Arabic magnificent bean gum (guar gum), the blue glue (gellan) of knot, Pu Lulan (pullulan), chondroitin (chondroitin), are closed
Sulfate), heparin (heparin) or keratin sulfate (keratin sulfate) or derivatives thereof etc..
And in polymeric composition of the present invention, histidine and its histidine derivative possess lone electron pair because it has
The nitrogen of (lone pair), so the effect of chelated zinc ions can be carried out.The derivative of above-mentioned histidine may include Nα- protection group
Threonine derivative, but not limited to this.Above-mentioned NαThe example of-protection histidine derivative may include, but be not limited to Nα- Boc- organizes ammonia
Acid (Nα-Boc-histidine)、Nα- Cbz- histidines (Nα-Cbz-histidine)、Nα- Fmoc- histidines (Nα-Fmoc-
) and N histidineα- Ac- histidines (Nα- Ac-histidine) etc..
In polymeric composition of the present invention, the derivative of the above-mentioned histidine or histidine can be grafted on directly with hydroxyl
On the macromolecule of base, or it can be grafted on by agent is connected on the macromolecule with hydroxyl.
In one embodiment, the derivative of histidine or histidine is directly to graft on the macromolecule with hydroxyl.In
In this embodiment, the derivative of above-mentioned histidine or histidine can be bonded with chemical covalent directly grafts on the high score with hydroxyl
On son, and above-mentioned chemical covalent bond may include ester bond or urethane, but not limited to this.Ester bond bond by histidine or
The protonated functional group of histidine is replaced in the high molecular hydroxyl with hydroxyl.
In a specific embodiment, polymeric composition of the present invention includes the derivative of macromolecule and histidine with hydroxyl
Thing is directly grafted on the above-mentioned macromolecule with hydroxyl, wherein the above-mentioned macromolecule with hydroxyl include polyvinyl alcohol, ethene-
Ethenol copolymer, hyaluronic acid, cellulose or hydroxypropyl methyl cellulose, and the derivative of above-mentioned histidine is Nα-Boc-
Histidine.
In another embodiment, the derivative of above-mentioned histidine or histidine can graft on tool by agent (spacer) is connected
Have on the macromolecule of hydroxyl, and suitable for connecting the example of agent between the present invention, it may include polyethylene glycol class, alkanes carbochain
Deng, but not limited to this.
The matrix metalloproteinase inhibiting rate of polymeric composition of the present invention is up to 10-100%.In one embodiment, this hair
Bright polymeric composition can be of about 20.39%-62.15% to the inhibiting rate of Matrix Metalloproteinase-9.
The application mode of polymeric composition of the present invention can be found in Fig. 2, but not limited to this.Fig. 2 is shown, comprising with hydroxyl
Macromolecule 101 and graft on the high score of the present invention of the histidine of the macromolecule 101 with hydroxyl or the derivative 103 of histidine
Subgroup compound is by mixing, be coated with, be impregnated with processing procedure S1 and be used in combination with base material 105.
Polymeric composition of the present invention can be distributed in promiscuous mode in base material or the surface and/or inside of medical equipment.
Alternatively, polymeric composition of the present invention can form solution.In one embodiment, above-mentioned solution can be machined directly to
Bulk, and this bulk can be used for medical application, but not limited to this.
In another embodiment, above-mentioned solution can be used to processing base material or medical equipment with physical absorption in the base material or
The surface of medical equipment.In this embodiment, the material of base material may include, but be not limited to, polysaccharide（For example, cellulose and its
Derivative, hyaluronic acid and its derivative etc.）, polyurethanes, polyvinyl alcohol, ethylene-vinyl alcohol copolymer, poly- third
Alkenes etc., or above-mentioned combination, and the example of medical equipment may include, such as wound dressing, tissue substituent, organizational project branch
Frame, contacting blood device and conduit etc., but not limited to this.
In an alternative embodiment of the invention, the present invention also provides a kind of high molecular material, it includes the height of the invention described above
Molecular composition, and the polymeric composition of the invention described above has zinc ion affinity, and with suppression matrix metalloprotease
The effect of activity of enzyme.Have effects that to suppress the activity of matrix metalloproteinase since the high molecular material of the present invention includes
Polymeric composition, therefore its can be used for medical treatment with to improve the symptom of sufferer tissue inflammation and/or promote wound healing,
But not limited to this.
In one embodiment, high molecular material high molecular material of the present invention can further include base material.In this embodiment, Yu Ben
In invention high molecular material, polymeric composition can mix either polymeric composition physical absorption in the table of base material with base material
Face is interior to form medical equipment.
The example of the material of above-mentioned base material, can be polysaccharide（For example, cellulose and its derivates, hyaluronic acid and its spreading out
Biology etc.）, polyurethanes, polyvinyl alcohol, ethylene-vinyl alcohol copolymer, PP type etc., or above-mentioned combination,
But not limited to this.In addition, above-mentioned medical equipment may include, but be not limited to wound dressing, tissue substituent, tissue engineering bracket,
Contacting blood device or conduit etc..
【Embodiment】
Embodiment 1
The synthesis of polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis "
Shown in the structure following manner (I) of polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis "：
Formula (I).
Boc-His-OH (4.48g, 17.57mmol) and DMAP (1.95g, 15.97mmol) are placed in double equipped with magnetite
In neck bottle.Two-neck bottle is vacuumized 3 minutes to remove air in bottle and fill drying nitrogen afterwards.It is subsequently added into DMAc (35ml)
In two-neck bottle and stirring makes content even suspension in 10 minutes.EDC solids (3.06g, 15.97mmol) are taken to be quickly poured into double necks
Bottle in, with 30 DEG C of water-baths 3 it is small when with activated b oc-His-OH.By PVA10k（Molecular weight is 10000）（2.79g,
53.24mmol, 80% hydrolysis (hydrolyzed)）Add in DMAc (28ml) and stirred in 80 DEG C to being completely dissolved to form PVA
Solution, and be cooled to afterwards 45 DEG C it is spare.Boc-His-LG solution (LG=Leaving Group after activating（Leaving group）)
Rapidly join above-mentioned PVA solution, and to form a reaction solution when 45 DEG C of sustained responses 24 are small., will be above-mentioned after Temperature fall
Reaction solution is loaded on bag filter (MWCO:6-8,000), with DMAc (1.5L, 20X) dialysis 40 it is small when（Replaced when the 16th is small saturating
Analyse liquid once）, then with DIW (7.5L, 100X) dialysis 48 it is small when（Replaced when the 3rd, 6,9,12,24,27,30,33 and 36 are small saturating
Analyse liquid）.Solid is collected, is freeze-dried and obtains product PVA-g-BocHis.
Root experimental method mentioned above, the reaction equivalent being adjusted by between PVA and Boc-His-OH and obtain difference
The high molecular material PVA-g-BocHis of the difference BocHis grafting degree of batch, and with nuclear magnetic resonance spectrometer (Nuclear
Magnetic ResonanceSpectroscopy) determine its grafting rate.The results are shown in Table 1.
Table 1, PVA-g-BocHis material specifications
Embodiment 2
The synthesis of poly ethylene vinyl alcohol grafting histidine derivative " EVOH-g-BocHis "
Shown in the structure following manner (II) of poly ethylene vinyl alcohol grafting histidine derivative " EVOH-g-BocHis "：
Formula (II).
Boc-His-OH (11.46g, 44.88mmol) and DMAP (4.98g, 40.8mmol) are placed in double equipped with magnetite
In neck bottle.Two-neck bottle is vacuumized 3 minutes to remove air in bottle and fill drying nitrogen afterwards.It is subsequently added into DMAc (90ml)
In two-neck bottle and stirring makes content even suspension in 10 minutes.EDC solids (7.82g, 40.8mmol) are taken to be quickly poured into double necks
Bottle in, with 30 DEG C of water-baths 3 it is small when with activated b oc-His-OH.By EVOH (5.84g, 150mmol, 32mol%ethylene
Unit) add in DMAc (58ml) and in 80 DEG C of stirrings to being completely dissolved to form EVOH solution, and be cooled to afterwards 45 DEG C it is standby
With.Boc-His-LG solution (LG=Leaving Group after activating（Leaving group）) above-mentioned EVOH solution is rapidly joined, and
To form a reaction solution when 45 DEG C of sustained responses 24 are small.After Temperature fall, above-mentioned reaction solution is loaded on bag filter
(MWCO:6-8,000), with DMAc (3.0L, 20X) dialysis 40 it is small when（Dialyzate is replaced when the 16th is small once）.Afterwards, will be saturating
Liquid pours into DIW (5.0L, 25X) and carries out first time reprecipitation in analysis bag.Solid is collected with MeOH back dissolvings (10%w/v), then is poured into
DIW (7.0L, 35X) carries out second of reprecipitation.Collect solid and solid is unfolded with DIW cleanings three times.It is freeze-dried and obtains
To product EVOH-g-BocHis.
Root experimental method mentioned above, the reaction equivalent being adjusted by between EVOH and Boc-His-OH and obtain difference
BocHis is grafted the high molecular material EVOH-g-BocHis of degree, and determines its grafting rate with nuclear magnetic resonance spectrometer.As a result such as
Shown in table 2.
Table 2, EVOH-g-BocHis material specifications
Embodiment 3
The synthesis of hydroxypropyl methyl cellulose grafting histidine derivative " HPMC-g-BocHis "
Structure following manner (III) institute of hydroxypropyl methyl cellulose grafting histidine derivative " HPMC-g-BocHis "
Show：
Formula (III).
Boc-His-OH (2.92g, 11.44mmol) and DMAP (1.27g, 10.4mmol) are placed in double necks equipped with magnetite
In bottle.Two-neck bottle is vacuumized 3 minutes to remove air in bottle and fill drying nitrogen afterwards.It is subsequently added into DMAc (22.9ml)
In two-neck bottle and stirring makes content even suspension in 10 minutes.EDC solids (1.99g, 10.4mmol) are taken to be quickly poured into double necks
Bottle in, with 30 DEG C of water-baths 3 it is small when with activated b oc-His-OH.By HPMC（2.0g, 10.4mmol, Mn120,000, methoxy
The substitution degree (degree of substitution, DS) of base (methoxy):1.1-1.6mol, propylene oxide
(propyleneoxide) mole substitution degree (molar degree of substitution, MS):0.1-0.3mol）Add
Enter in DMAc (40ml) and in 80 DEG C of stirrings to being completely dissolved to form HPMC solution, and be cooled to afterwards 50 DEG C it is spare.Will be living
Boc-His-LG solution (LG=Leaving Group after change（Leaving group）) above-mentioned HPMC solution is rapidly joined, and held in 50 DEG C
To form a reaction solution when continuous reaction 24 is small.After Temperature fall, above-mentioned reaction solution is loaded on bag filter (MWCO:6-8,
000), with DMAc (1.4L, 20X) dialysis 40 it is small when（Dialyzate is replaced when the 16th is small once）, then with DIW (7.0L, 100X)
Dialyse 72 it is small when（Dialyzate is replaced when the 3rd, 6,9,12,24,27,30,33,36,48,52 and 56 are small）.Collect solid, freezing
Dry and obtain product HPMC-g-BocHis.
Root experimental method mentioned above, the reaction equivalent being adjusted by between HPMC and Boc-His-OH and obtain difference
BocHis is grafted the high molecular material HPMC-g-BocHis of degree, and determines its grafting rate with nuclear magnetic resonance spectrometer.As a result such as
Shown in table 3.
Table 3, HPMC-g-BocHis material specifications
Embodiment 4
The synthesis of hyaluronic acid grafting histidine derivative " HA-g-BocHis "
Shown in the structure following manner (IV) of hyaluronic acid grafting histidine derivative " HA-g-BocHis "：
Formula (IV).
Boc-His-OH (8.42g, 33.0mmol) and DMAP (3.67g, 30.0mmol) are placed in double necks equipped with magnetite
In bottle.Two-neck bottle is vacuumized 3 minutes to remove air in bottle and fill drying nitrogen afterwards.Be subsequently added into DMAc (66ml) in
In two-neck bottle and stirring makes content even suspension in 10 minutes.EDC solids (5.75g, 30.0mmol) are taken to be quickly poured into two-neck bottle
In, with 30 DEG C of water-baths 3 it is small when with activated b oc-His-OH.HATBA (18.6g, 30.0mmol) is poured into glass reaction groove
It is interior.10 minutes are vacuumized to remove air in bottle after glass reaction truss is set mechanical stirring device, afterwards and with drying nitrogen
Backfill.It will be added with the DMAc (186ml) that molecular sieve removed water in glass reaction groove, and be placed in 45 DEG C of circulator baths and with rotating speed
More than when 250rpm mechanical agitations 2 are small, so that HA16000TBA（Molecular weight is 16000）Or HA350000TBA（Molecular weight is 350,
000）Uniform dissolution is to form HA solution.Boc-His-LG solution (LG=Leaving Group after activating（Leaving group）) fast
Speed is added in the glass reaction groove containing above-mentioned HATBA solution.Mechanical agitation rotating speed after 30 minutes in raising glass reaction groove is extremely
300rpm, and make in reactive tank solution when 45 DEG C of sustained responses 24 are small to form reaction solution.After Temperature fall, it will react molten
Liquid is transferred to bag filter (MWCO:12-14,000), with DMAc (6.0L, 20X) dialysis 40 it is small when（16th replaces dialyzate when small
Once）, then with DIW (18.0L, 100X) dialysis 72 it is small when（When 3rd, 6,9,12,24,27,30,33,36,48,52 and 56 are small more
Change dialyzate）.Then, collect aqueous solution in bag filter and pass through sodium ion exchange resin（ROHM HAAS, food-grade, 520g）, will
TBA is replaced into sodium ion, and it is about 1-1.5wt% to be concentrated in vacuo to concentration of aqueous solution.Afterwards, adjusted with 0.1M NaOH molten
Liquid pH value is dried to obtain product HA-g-BocHis to 7.6 ± 0.2, using freeze-drying.
Root experimental method mentioned above, the reaction equivalent being adjusted by between HA and Boc-His-OH and obtain difference
BocHis is grafted the high molecular material HA-g-BocHis of degree, and determines its grafting rate with nuclear magnetic resonance spectrometer.As a result such as table
Shown in 4.
Table 4, HA-g-BocHis material specifications
Embodiment 5
The synthesis of cellulose graft histidine derivative " Cellulose-g-BocHis "
Shown in the structure following manner (V) of cellulose graft histidine derivative " Cellulose-g-BocHis "：
Formula (V).
Boc-His-OH (1.39g, 5.34mmol) and DMAP (0.6g, 4.94mmol) are placed in the two-neck bottle equipped with magnetite
In.Two-neck bottle is vacuumized 3 minutes to remove air in bottle and fill drying nitrogen afterwards.Be subsequently added into DMAc (10.9ml) in
In two-neck bottle and stirring makes content even suspension in 10 minutes.EDC solids (0.95g, 4.94mmol) are taken to be quickly poured into two-neck bottle
In, with 30 DEG C of water-baths 3 it is small when with activated b oc-His-OH.Cellulose cloth (2.00g, 12.34mmol) is put into 150ml
In glass reaction groove, be impregnated in the DMAc (20ml) that molecular sieve removed water, and when 45 DEG C small with rotating speed 100rpm stirrings 2 with
On.Boc-His-LG solution (LG=Leaving Group after activating（Leaving group）) rapidly join in glass reaction groove, make
Cloth is with Boc-His-LG solution when 45 DEG C of sustained responses 24 are small.After Temperature fall, the cellulose cloth after reaction immerses
In DMAc (0.5L, 20X) and stir 0.5 it is small when, when placing into that stirring 1 is small in DIW (1.0L, 100X), it is clear to reuse DIW afterwards
Wash three times, to remove the impurity after reacting.Finally Cellulos-g-BocHis is drying to obtain.
Embodiment 6
Different samples suppress to test to activity of matrix metalloproteinase-9
Analysis method
Step 1：Before (pro)-Matrix Metalloproteinase-9 activate
Before 10 μ g/ml-Matrix Metalloproteinase-9 (R＆D) solution addition 100mMAPMA（Final concentration 1mM）, and in
In the past-Matrix Metalloproteinase-9 is transformed into Matrix Metalloproteinase-9 before activation when effect 2 is small in 37 DEG C of incubators
(activatedpro-matrix metallopoateinases)
Step 2：Test sample
Matrix Metalloproteinase-9 analyzes buffer solution with activity of matrix metalloproteinase-9 before activating（50mM
Tris,10mM CaCl2,150mM NaCl,0.05%Brij-35(w/v),pH7.5）It is 100ng/ml to be diluted to concentration.It is each
Test sample is separately added into Matrix Metalloproteinase-9 before activation, be placed in 37 DEG C of incubators reaction 2 or 24 it is small when.It is negative right
Matrix Metalloproteinase-9 solution before being the activation without test sample reaction according to group, positive controls matrix before activation
Add activity of matrix metalloproteinase-9 inhibitor 1,10- phenanthroline (1,10- in matrix metalloproteinases-9 solution
Phenanthroline,1,10-PT)（Final concentration 0.1mM）.
Step 3：Activity of matrix metalloproteinase-9 is analyzed
Take out with Matrix Metalloproteinase-9 solution before the activation after material reaction in the black disk (black in 96- holes
plate).Add isometric Matrix Metalloproteinase-9 matrix（Final concentration 10uM）When reaction 0.5-1 is small in 37 DEG C of incubators,
In high sensitivity fluor tester (Flexstation3) measure fluorescence readings (Ex/Em=320/405nm).
Experimental result
Influence of the A.Boc- histidine concentrations on activity of matrix metalloproteinase-9 suppression
During by the Boc histidines of known various concentrations and small activated Matrix Metalloproteinase-9 effect 2, matrix is measured
Matrix metalloproteinases-9 activity is influenced change be subject to various concentrations histidine.The results are shown in Figure 3.When histidine concentrations reach
There is more than 50% inhibition during 2.64mg/ml to Matrix Metalloproteinase-9.y=21.83ln(x)+28.06.
B. polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " powder concn lives Matrix Metalloproteinase-9
Property suppress efficiency assessment
By grafting rate be 13.3% polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " (embodiment 1 it
Lot1) powder matches somebody with somebody the test sample as various concentrations, and tests its influence to activity of matrix metalloproteinase-9.As a result such as
Shown in 5 and the 4th figure of table.
The suppression effect of table 5, the polyvinyl alcohol graft copolymerized histidine derivative of various concentrations to Matrix Metalloproteinase-9
The results show that PVA-g-His grafting rates are 13.3%, PVA-g-His concentration when being 2% ~ 10% to matrix metalloprotease
The inhibiting rate of enzyme -9 is to have 47.78%；PVA-g-His concentration has 62.15% to suppress to imitate for 20% Matrix Metalloproteinase-9
Fruit.
C. the film of the polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " of the Lot1 of embodiment 1 is to matrix gold
The activity suppression measures of effectiveness of Proteases -9
Polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " powder that the Lot1 of embodiment 1 is obtained（Connect
Branch rate 13.3%）Add in DMAC, and dissolving is stirred at room temperature（500rpm, 6 it is small when）, mould is inserted after dissolving with 60 DEG C of progress
Dry 72 it is small when with into diaphragm.By membrane cutting be diameter 1cm film sample carry out 24 it is small when Matrix Metalloproteinase-9 live
Property test, and respectively using BocHis and PVA film as control group.The results show is in table 6 and Fig. 5.
The suppression effect of the film that table 6, polyvinyl alcohol graft copolymerized histidine derivative are formed to Matrix Metalloproteinase-9
The results show that the film of Lots1 can reach 33.27% inhibiting rate to the inhibiting rate of Matrix Metalloproteinase-9 and
PVA film in comparison（Control group）Slow mechanism dissolved only has 16.89% decay of activity situation.
D. the film of the polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " of the Lot2 of embodiment 1 is to matrix gold
The activity suppression measures of effectiveness of Proteases -9
Polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " powder that the Lot2 of embodiment 1 is obtained（Connect
Branch rate 19.0%）Add in DMAC, and dissolving is stirred at room temperature（500rpm, 6 it is small when）, mould is inserted after dissolving with 60 DEG C of progress
Dry 72 it is small when with into diaphragm.By membrane cutting be diameter 1cm film sample carry out 24 it is small when Matrix Metalloproteinase-9 live
Property test, and to be crosslinked PVA (cPVA) films as control group.The results show is in table 7 and Fig. 6.
The suppression effect of table 7, polyvinyl alcohol graft copolymerized histidine derivative film to Matrix Metalloproteinase-9
-:Without histidine
Since film size is fixed, the group of its grafting of the Lot2 of embodiment 1 according to film weight and grafting rate
Propylhomoserin is about 19.4mg/ml relative to the concentration of matrix metal proteinase activity analytical solution, and the Lots2 films are to matrix metal
Protease -9 can reach 41.04% inhibiting rate.In comparison be crosslinked PVA (cPVA) film to Matrix Metalloproteinase-9 not
Active inhibition.
E. the film of the polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " of the Lot1 of embodiment 1 is to matrix gold
The activity suppression measures of effectiveness of Proteases -9
Polyvinyl alcohol graft copolymerized histidine derivative " PVA-g-BocHis " powder that the Lot1 of embodiment 1 is obtained（Connect
Branch rate 13.3%）Add in DMAC, and dissolving is stirred at room temperature（500rpm, 6 it is small when）, mould is inserted after dissolving with 60 DEG C of progress
Dry 72 it is small when with into diaphragm.By membrane cutting be diameter 1cm film sample carry out 24 it is small when Matrix Metalloproteinase-9 live
Property test, and to be crosslinked PVA film (cPVA) as control group.The results show is in table 8 and Fig. 7.
The suppression effect of table 8, polyvinyl alcohol graft copolymerized histidine derivative film to Matrix Metalloproteinase-9
-:Without histidine
Since film size is fixed, and batch difference causes between PVA-g-BocHis sample Lot1-1 and Lot1-2 batches it
Difference in thickness, thus PVA-g-BocHis films according to weight and grafting rate PVA-g-BocHis films Lot1-1 with
The histidine of its grafting of Lot1-2 relative to the concentration of matrix metal proteinase activity analytical solution be respectively 21.64mg/ml with
12.4mg/ml.From result, Lots1-1 and 1-2 films have respectively to Matrix Metalloproteinase-9 29.26% and 44.97% it
Maximum inhibition.PVA film (cPVA) not active inhibition is crosslinked in comparison.
F. the poly ethylene vinyl alcohol of the Lot3 and Lot4 of embodiment 2 are grafted histidine derivative " EVOH-g-BocHis "
Film suppresses measures of effectiveness to activity of matrix metalloproteinase-9
The poly ethylene vinyl alcohol grafting histidine derivative " EVOH-g- that the Lot3 of embodiment 2 and Lot4 are obtained
BocHis " powder is added in DMAC, and dissolving is stirred at room temperature（500rpm, 6 it is small when）, mould is inserted after dissolving with 60 DEG C of progress
Dry 72 it is small when with into diaphragm.By membrane cutting be diameter 1cm film sample carry out 24 it is small when Matrix Metalloproteinase-9 live
Property test, and using EVOH films as control group.The results show is in table 9 and Fig. 8.
The suppression effect of table 9, poly ethylene vinyl alcohol grafting histidine derivative film to Matrix Metalloproteinase-9
- be free of histidine
Since film size is fixed but difference in thickness between sample Lot1-1 and Lot1-2 batch, according to weight and connect
Branch rate understands that the histidine of its grafting of EVOH-g-BocHis films Lot3 and Lot4 is analyzed relative to matrix metal proteinase activity
The concentration of solution is respectively 17.7mg/ml and 24.03mg/ml.From result, the activity suppression efficiency of Lots3 and 4 films because
Its histidine weight percent rises the maximum inhibition Lots3 for having 43.68% and 38.25% respectively and 4 films to matrix metal
Protease -9 has 43.68% and 38.25% maximum inhibition respectively.The not active inhibition of EVOH films in comparison.
G. the hydroxypropyl methyl cellulose grafting histidine derivative " HPMC-g-BocHis " of the Lot5 of embodiment 3 is thin
Film suppresses measures of effectiveness to activity of matrix metalloproteinase-9
The poly- hydroxypropyl methyl cellulose grafting histidine derivative " HPMC-g- that the Lot5 of embodiment 3 is obtained
BocHis " powder be dissolved in after DMAC insert mould with 60 DEG C carry out drying 72 it is small when with into diaphragm.It is diameter by membrane cutting
Activity of matrix metalloproteinase-9 is tested when the film sample progress 3 of 1cm is small, and using HPMC films as control group.The results show
In table 10 and Fig. 9.
The suppression effect of table 10, hydroxypropyl methyl cellulose grafting histidine derivative film to Matrix Metalloproteinase-9
-:Without histidine
The histidine of its grafting of HPMC-g-BocHis Lot5 films is relative to matrix gold according to weight and grafting rate
The concentration of Proteases activity analysis solution is 2.4mg/ml.From result, Lot5 films have Matrix Metalloproteinase-9
33.2% maximum inhibition.The not active inhibition of HPMC films in comparison.
H. the hydroxypropyl methyl cellulose grafting histidine derivative " HPMC-g-BocHis " of the Lot6 of embodiment 3 is thin
Film suppresses measures of effectiveness to activity of matrix metalloproteinase-9
The poly- hydroxypropyl methyl cellulose grafting histidine derivative " HPMC-g- that the Lot6 of embodiment 3 is obtained
BocHis " powder be dissolved in after DMAC insert mould with 60 DEG C carry out drying 72 it is small when with into diaphragm.It is diameter by membrane cutting
The film sample of 1cm carry out 24 it is small when activity of matrix metalloproteinase-9 test, and using HPMC (cHPMC) films of crosslinking as pair
According to group.The results show is in table 11 and Figure 10.
The suppression effect of table 11, hydroxypropyl methyl cellulose grafting histidine derivative film to Matrix Metalloproteinase-9
-:Without histidine
The histidine of its grafting of HPMC-g-BocHis Lot6 films is relative to matrix gold according to weight and grafting rate
The concentration of Proteases activity analysis solution is 10.15mg/ml.From result, Lot6 films are to Matrix Metalloproteinase-9
There is 42.41% maximum inhibition, in comparison the not active inhibition of cHPMC films.
I. the hydroxypropyl methyl cellulose grafting histidine derivative " HPMC-g- of the Lot6 and Lot7 of embodiment 3
The film of BocHis " suppresses measures of effectiveness to activity of matrix metalloproteinase-9
The hydroxypropyl methyl cellulose grafting histidine derivative " HPMC-g- that the Lot6 of embodiment 3 and Lot7 are obtained
BocHis " powder is added in DMAC, and dissolving is stirred at room temperature（500rpm, 6 it is small when）, mould is inserted after dissolving with 60 DEG C of progress
Dry 72 it is small when with into diaphragm.By membrane cutting be diameter 1cm film sample carry out 2 it is small when activity of matrix metalloproteinase-9
Test, and using HPMC (cHPMC) films of crosslinking as control group.The results show is in table 12 and Figure 11.
The suppression effect of table 12, hydroxypropyl methyl cellulose grafting histidine derivative film to Matrix Metalloproteinase-9
-:Without histidine
Since film size is fixed but difference in thickness between Lot6 and Lot7 batches, according to weight and grafting rate
The histidine of its grafting of HPMC-g-BocHis films Lot6 and Lot7 is relative to the dense of matrix metal proteinase activity analytical solution
Degree is respectively 5.52mg/ml and 8.71mg/ml.From result, Lots6 and 7 films are to Matrix Metalloproteinase-9 because by it
The influence of hydrophilic nmature change has 37.26% and 36.37% maximum inhibition respectively.CHPMC films do not have work in comparison
Property inhibition.
Embodiment 7
Long-acting suppression measures of effectiveness experiment
It is prepared by laboratory sample
A. poly ethylene vinyl alcohol grafting histidine derivative film sample is prepared (EVOH-g-BocHis)：
The poly ethylene vinyl alcohol grafting histidine derivative powder of Lot3 and Lot4 is added in DMAC, and is stirred at room temperature
Dissolving, inserted after dissolving mould with 60 DEG C carry out drying 72 it is small when with into diaphragm.
B. film sample is impregnated with to prepare（Coat Boc histidines EVOH films (BocHiscoated EVOH Film,
EVOH-c-Bochis)）：
Take appropriate Boc histidines concussion to be dissolved in 10ml and be total to solution (co-solvent) (DMAc/MeOH5:95) so that its
Dissolving.Taken out after poly ethylene vinyl alcohol film is immersed this Boc histidines (Boc-Histidine) solution after the completion of dissolving, it
Afterwards by film be positioned in 60 DEG C of baking ovens 24 it is small when, remove complete after the solvent in solution coating Boc histidines EVOH it is thin
Film.EVOH thin film coated Boc histidine contents are using nuclear magnetic resonance spectrometer and determination of elemental analysis as about 9.18%.
Experimental method and result
A. poly ethylene vinyl alcohol grafting histidine derivative film sample (Lot3) is to the long-acting of Matrix Metalloproteinase-9
Suppress measures of effectiveness experiment
Poly ethylene vinyl alcohol grafting histidine derivative film sample (Lot3) is positioned in PBS buffer solutions in 37 DEG C
Shaken with 150rpm, and it is every 2 it is small when replace fresh PBS buffer solutions with simulated body fluid physiology situation.Every 4,8 is small with 24
When sampling carry out activity of matrix metalloproteinase-9 test.With poly ethylene vinyl alcohol film as control group.As a result as table 13 with
Shown in Figure 12.
Table 13, poly ethylene vinyl alcohol are grafted length of the histidine derivative film sample (Lot3) to Matrix Metalloproteinase-9
Effect suppresses the result of measures of effectiveness
From table 13 and Figure 12, poly ethylene vinyl alcohol is grafted histidine derivative film sample to matrix metalloprotease
The inhibition of enzyme -9 is effectively maintained between 20.39% to 27.84%.
B. the base material only through histidine impregnation processing (EVOH-c-BocHis) and poly ethylene vinyl alcohol grafting histidine spread out
The long-acting suppression measures of effectiveness of biofilm sample (Lot4)
Base material (EVOH-c-BocHis) and poly ethylene vinyl alcohol that respectively will be through histidine impregnation processing be grafted histidine
Derivative film sample (EVOH-g-His, Lot4) sample is positioned in PBS buffer solutions to be shaken in 37 DEG C with 150rpm,
And it is every 2 it is small when replace fresh PBS buffer solutions with simulated body fluid physiology situation.Separately sampled progress when starting and the 24th are small
Activity of matrix metalloproteinase-9 is tested.As a result as shown in table 14 and Figure 13.
Table 14, the base material (EVOH-c-BocHis) through histidine impregnation processing and poly ethylene vinyl alcohol grafting histidine
The result of the long-acting suppression measures of effectiveness of derivative film sample (Lot4)
The results show poly ethylene vinyl alcohol grafting histidine derivative film sample (Lot4), not only to matrix metalloprotease
Enzyme -9 has inhibition, more long-acting this can be maintained to suppress function.Otherwise coating histidine derivative solution weight percentage reaches
9.18% EVOH-c-BocHis, though there is good suppression efficiency to Matrix Metalloproteinase-9, when 24 is small during starting
But almost lose afterwards and suppress function.
Embodiment 8
Diabetic mice wound fluid matrix metalloproteinase Activity determination
It is prepared by laboratory sample
A. prepared by poly ethylene vinyl alcohol grafting histidine derivative film sample (EVOH-g-BocHis)：
The poly ethylene vinyl alcohol of embodiment 2 is grafted histidine derivative (EVOH-g-BocHis) powder with solid component 15%
Ratio add in DMAC, and dissolving is stirred at room temperature, inserted after dissolving mould with 60 DEG C carry out drying 72 it is small when with into diaphragm.
B. poly- hydroxypropyl methyl cellulose grafting histidine derivative film sample is prepared (HPMC-g-BocHis)：
The poly- hydroxypropyl methyl cellulose that embodiment 3 is obtained is grafted histidine derivative (HPMC-g-BocHis) powder
End be dissolved in solid 15% ratio of component after DMAC insert mould with 60 DEG C carry out drying 72 it is small when with into diaphragm.
C. diabetic mice；Rat is continuously injected with streptozocin (streptozotocin, STZ)（Strain：Sprague-
Dawley(SD)）4 weeks, make zootype of the generation similar to the second patients with type Ⅰ DM.
Experimental method and result
A. the big wounds of 5cm X6cm are outputed into six diabetes rats behind that numbering is 1 to 6 respectively.Numbering 1 is with compiling
Numbers 2 mouse is that the rat of EVOH treatment groups, numbering 3 and numbering 4 is that poly ethylene vinyl alcohol is grafted histidine derivative film
(EVOH-g-BocHis) treatment group, and the rat of numbering 5 and numbering 6 is grafted histidine for poly- hydroxypropyl methyl cellulose and derives
Thing film (HPMC-g-BocHis) treatment group.
B. by sample thin film mulching in wound surface, on film plus last layer waterproof and breathable dressing, and stitched with perform the operation
Dressing is fixed on wound surrounding by line.The 1st day and the 3rd day after operation, wound fluid is extracted respectively, carries out wound fluid mesostroma
Metal proteinase activity detects.
C. matrix metal proteinase activity is analyzed：Wound fluid is to analyze buffer solution（50mM Tris,10mM
CaCl2,150mM NaCl,0.05%Brij-35(w/v),pH7.5）50 times of dilution.Take the body such as wound fluid addition after diluting
Product Matrix Metalloproteinase-9 matrix（Final concentration 10uM）When reaction 0.5-1 is small in 37 DEG C of incubators, surveyed in high sensitivity fluorescence
Determine instrument (Flexstation3) measure fluorescence readings (Ex/Em=320/405nm).
Table 15, grafting histidine derivative film sample are to zoopery diabetic mice wound fluid mesostroma metal egg
The Activity Assessment result of white enzyme -9
From table 15 and Figure 14, the 3rd day after surgery, histidine derivative film dressing is grafted（Poly ethylene vinyl alcohol
It is grafted histidine derivative film (EVOH-g-BocHis) and poly- hydroxypropyl methyl cellulose grafting histidine derivative film
(HPMC-g-BocHis)）, its wound fluid matrix metalloproteinase activity substantially compared with the 1st day when reduce, wherein again with poly-
Hydroxypropyl methyl cellulose grafting histidine derivative material result is preferred.
Although the present invention is disclosed above with preferred embodiment, so it is not limited to the present invention, any to be familiar with this skill
Skill person, without departing from the spirit and scope of the invention, when can make it is a little change and retouch, therefore the protection domain of the present invention
When regarding after attached claim institute defender subject to.
Claims (17)
1. a kind of polymeric composition be used to prepare have effects that suppress matrix metalloproteinase activity medical equipment or
The purposes of inhibitor, the wherein polymeric composition include：
Macromolecule with hydroxyl, wherein should macromolecule with hydroxyl be polyvinyl alcohol, it is ethylene-vinyl alcohol copolymer, transparent
Matter acid, cellulose or hydroxypropyl methyl cellulose；And
The derivatives graft of histidine or histidine is on the macromolecule with hydroxyl.
2. polymeric composition as claimed in claim 1, which is used to prepare, to be had effects that to suppress the activity of matrix metalloproteinase
Medical equipment or inhibitor purposes, wherein the derivative of the histidine or the histidine be the polymeric composition 0.1
~99wt%.
3. polymeric composition as claimed in claim 1, which is used to prepare, to be had effects that to suppress the activity of matrix metalloproteinase
Medical equipment or inhibitor purposes, the wherein derivative of the histidine is Nα- protection histidine derivative.
4. polymeric composition as claimed in claim 3, which is used to prepare, to be had effects that to suppress the activity of matrix metalloproteinase
Medical equipment or inhibitor purposes, the wherein Nα- protection histidine derivative includes Nα- Boc- histidines (Nα-Boc-
histidine)、Nα- Cbz- histidines (Nα-Cbz-histidine)、Nα- Fmoc- histidines (Nα- Fmoc-histidine) or
Nα- Ac- histidines (Nα-Ac-histidine)。
5. polymeric composition as claimed in claim 1, which is used to prepare, to be had effects that to suppress the activity of matrix metalloproteinase
Medical equipment or inhibitor purposes, the wherein derivative of the histidine or the histidine has hydroxyl directly to graft on this
Macromolecule on, or graft on the macromolecule with hydroxyl by agent is connected.
6. polymeric composition as claimed in claim 5, which is used to prepare, to be had effects that to suppress the activity of matrix metalloproteinase
Medical equipment or inhibitor purposes, the wherein derivative of the histidine or the histidine has hydroxyl directly to graft on this
Macromolecule on.
7. polymeric composition as claimed in claim 6, which is used to prepare, to be had effects that to suppress the activity of matrix metalloproteinase
Medical equipment or inhibitor purposes, wherein the derivative of the histidine or the histidine be with chemical covalent bond directly connect
Branch is on the macromolecule with hydroxyl.
8. polymeric composition as claimed in claim 7, which is used to prepare, to be had effects that to suppress the activity of matrix metalloproteinase
Medical equipment or inhibitor purposes, wherein the chemical covalent bond include ester bond or urethane.
9. polymeric composition as claimed in claim 6, which is used to prepare, to be had effects that to suppress the activity of matrix metalloproteinase
Medical equipment or inhibitor purposes, the wherein histidine derivative Nα- Boc- histidines.
10. polymeric composition as claimed in claim 5 is used to prepare the work(with the activity for suppressing matrix metalloproteinase
The medical equipment of effect or the purposes of inhibitor, the wherein derivative of the histidine or the histidine are to be grafted on by the agent of this company
On the macromolecule with hydroxyl.
11. polymeric composition as claimed in claim 10 is used to prepare the work(with the activity for suppressing matrix metalloproteinase
The medical equipment of effect or the purposes of inhibitor, the wherein agent of this company include polyethylene glycol class or alkanes carbochain.
12. polymeric composition as claimed in claim 1 is used to prepare the work(with the activity for suppressing matrix metalloproteinase
The medical equipment of effect or the purposes of inhibitor, the wherein polymeric composition are distributed in promiscuous mode in base material or medical equipment
Surface and/or inside.
13. polymeric composition as claimed in claim 1 is used to prepare the work(with the activity for suppressing matrix metalloproteinase
The medical equipment of effect or the purposes of inhibitor, the wherein polymeric composition form solution.
14. polymeric composition as claimed in claim 13 is used to prepare the work(with the activity for suppressing matrix metalloproteinase
The medical equipment of effect or the purposes of inhibitor, the wherein solution are machined directly to bulk.
15. polymeric composition as claimed in claim 13 is used to prepare the work(with the activity for suppressing matrix metalloproteinase
The medical equipment of effect or the purposes of inhibitor, the wherein solution are used to processing base material or medical equipment with physical absorption in the base
The surface of material or medical equipment.
16. the polymeric composition as described in claim 12 or 15 is used to prepare with the activity for suppressing matrix metalloproteinase
The effect of medical equipment or inhibitor purposes, wherein the material of the base material for polysaccharide, polyurethanes, polyethylene
Alcohols, ethylene-vinyl alcohol copolymer, PP type or above-mentioned combination.
17. the polymeric composition as described in claim 12 or 15 is used to prepare with the activity for suppressing matrix metalloproteinase
The effect of medical equipment or inhibitor purposes, wherein the medical equipment include wound dressing, tissue substituent, organizational project
Stent, contacting blood device or conduit.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210586655.2A CN103893813B (en) | 2012-12-28 | 2012-12-28 | Polymeric composition and high molecular material |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210586655.2A CN103893813B (en) | 2012-12-28 | 2012-12-28 | Polymeric composition and high molecular material |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103893813A CN103893813A (en) | 2014-07-02 |
| CN103893813B true CN103893813B (en) | 2018-04-17 |
Family
ID=50985591
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210586655.2A Active CN103893813B (en) | 2012-12-28 | 2012-12-28 | Polymeric composition and high molecular material |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103893813B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI482634B (en) * | 2013-10-24 | 2015-05-01 | Ind Tech Res Inst | Biomedical composition |
| CN109852574B (en) * | 2017-11-30 | 2021-11-16 | 山西加乐医疗科技有限责任公司 | Cell scaffold and preparation method thereof |
| TWI760992B (en) | 2019-12-26 | 2022-04-11 | 財團法人工業技術研究院 | Graft polymer and composite material containing the same |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1302066B (en) * | 1963-06-10 | 1969-11-13 | Avny Yair | Method for grafting polypeptide chains onto polyhydroxy polymers |
| US6174999B1 (en) * | 1987-09-18 | 2001-01-16 | Genzyme Corporation | Water insoluble derivatives of polyanionic polysaccharides |
| JP3637892B2 (en) * | 2001-11-16 | 2005-04-13 | 味の素株式会社 | Antibacterial packaging material |
| FR2892725B1 (en) * | 2005-10-31 | 2011-03-04 | Flamel Tech Sa | POLYGLUTAMIC ACIDS FUNCTIONALIZED BY DERIVATIVES OF HISTIDINE AND HYDROPHOBIC GROUPS AND THEIR PARTICULARLY THERAPEUTIC APPLICATIONS |
| JP2011511091A (en) * | 2008-02-08 | 2011-04-07 | コルゲート・パーモリブ・カンパニー | Compositions and methods comprising peptides of basic amino acids and proteases |
| CN101481325B (en) * | 2009-01-21 | 2013-06-12 | 山东大学 | Basic amino acid metalloproteinase inhibitor and use thereof |
| CN101787119A (en) * | 2010-03-25 | 2010-07-28 | 复旦大学 | Polymer with tumor organization pH responsiveness and micelle thereof |
| JP2013523827A (en) * | 2010-04-06 | 2013-06-17 | シネジェン， インコーポレイテッド | Methods and compositions for treating wounds using chitosan compounds |
-
2012
- 2012-12-28 CN CN201210586655.2A patent/CN103893813B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN103893813A (en) | 2014-07-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Yu et al. | A self-healing and injectable oxidized quaternized guar gum/carboxymethyl chitosan hydrogel with efficient hemostatic and antibacterial properties for wound dressing | |
| CN104056300B (en) | A kind of polysaccharide-dopamine compound bio glue and application | |
| JPH10502665A (en) | Wound healing agent | |
| Hasan et al. | Cellulose-based superabsorbent hydrogels | |
| CN106492279A (en) | A kind of fast preparation method of fibroin albumen hyaluronic acid pluralgel | |
| US11787922B2 (en) | Hydrophobically modified chitosan compositions | |
| CN103893813B (en) | Polymeric composition and high molecular material | |
| US20160113905A1 (en) | Polymer composition and polymer material | |
| US6476204B1 (en) | Dextran-maleic acid monoesters and hydrogels based thereon | |
| CN109796606A (en) | A kind of self-healing hydrogel and preparation method thereof based on MULTIPLE DYNAMIC chemical bond | |
| WO2008072379A1 (en) | Method for producing modified biopolymer and method for crosslinking biopolymers | |
| CN109157669B (en) | Cellulose-reinforced glucan-based injectable antibacterial hydrogel dressing and preparation method thereof | |
| CN107118373A (en) | A kind of POSS PEG hybridized hydrogels, its preparation method and application | |
| US6773703B1 (en) | Protein-containing hydrogels | |
| CN102604149B (en) | Three-dimensional chitosan hydrogel and preparation method thereof | |
| CN110215536B (en) | Bacterial cellulose hydrogel dressing for diabetic wound and preparation method thereof | |
| CN101530629A (en) | Method for preparing photo-crosslinking chitosan hydrogel film | |
| CN106750416A (en) | A kind of injection aquagel for possessing self-healing and pH response performances and its preparation method and application | |
| CN107254460B (en) | Carboxymethyl chitosan/sodium alginate composite sponge immobilized papain and application thereof | |
| Qiu et al. | Biocompatible and biodegradable Bletilla striata polysaccharides hydrogels crosslinked by BDDE for wound healing through the regulating of macrophage polarization | |
| CN105820267B (en) | A kind of skin wound preparation for repairing and its preparation method and application | |
| Chen et al. | Mussel-inspired self-healing hydrogel form pectin and cellulose for hemostasis and diabetic wound repairing | |
| CN114652743A (en) | Sodium alginate-based nitric oxide donor, and synthesis method and application thereof | |
| Fekete et al. | Polysaccharide-based polymer gels | |
| EP1025860B1 (en) | Protein-containing hydrogels |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |