CN104758945B - A kind of the thrombolytic drug targeted nano gel and its preparation method and use of pH responses - Google Patents
A kind of the thrombolytic drug targeted nano gel and its preparation method and use of pH responses Download PDFInfo
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Abstract
A kind of thrombolytic drug targeted nano gel and its preparation method and use with pH responses.The nanogel is to be covalently attached thrombolytic drug and oxidized dextran by the imine linkage of pH sensitivities, and introduce thrombus target ligand on oxidized dextran strand and formed.Imine linkage is relatively stablized under normal physiological pH value, but it can be hydrolyzed under faintly acid pH value, thrombus target ligand makes nanogel have thrombus active targeting ability, stablizes in the circulatory system, drug molecule is released again after reaching embolism position, reduces body bleeding risk caused by thrombolytic drug.This nanogel has reversible biological property, by the molecular weight, reaction ratio and the functional group that regulate and control polymer, thrombolytic drug protein molecular can either be adjusted to the resistant to hydrolysis degree of hydrolase and opportunity, it can be controlled again to discharge the activity of drug molecule, this microbody system can be used as thrombolytic drug carrier, for conveying protein or peptide medicament, the synergistic treatment of drug is realized.
Description
Technical field
The invention belongs to biomedicine technical fields, and in particular to it is a kind of based on imine linkage link with pH responses
The application of thrombolytic drug targeted nano gel and its synthetic method and the nanogel as thrombolytic drug carrier.
Background technology
In recent years, thrombotic diseases (such as acute myocardial infarction, ishemic stroke) are clinically to lead to dead and deformity
Main cause.Wherein cerebral apoplexy becomes the three big diseases of human death with its high incidence, disability rate, lethality and recurrence rate
One of [Lancet Neurology 2004,3,391-393；Lancet 2005,365,2160-2161.], seriously endanger the mankind
Health, to family and society bring heavy financial burden.With the continuous development of Chinese national economy, people's lives side
The incidence of formula, the change of dietary structure and the quickening of aging of population trend, cerebrovascular disease increases year by year, and
There is apparent rejuvenation trend.About 2,000,000 people of number of annual new hair cerebrovascular disease according to statistics, dies of cerebrovascular patient about every year
1500000 people, about 600~7,000,000 people of Cerebrovascular Disease Patients of survival, wherein 75% still has different degrees of deformity.It was predicted that
The year two thousand twenty ischemic cerebrovascular disease will become the main reason that disables of developing country.Cranial vascular disease is divided into hemorrhagic cerebrovaseular
Disease and ischemic cerebrovascular disease, wherein ischemic cerebrovascular disease account for about entire palsy 3/4ths [Lancet 2004,363,
768-774.], animal experiment shows that it is more than that will produce irreversibility cerebral lesion in 4~5 minutes to block the cerebrovascular completely, it is seen that brain
Tissue is extremely sensitive to ischemic, and recovery organization blood supply is to save key point [the Lancet Neurology of ischemic tissue as early as possible
2004,3,391-393.].
Currently, it is thromboembolism treatment to be directed to the most effective therapeutic modality that ischemic cerebrovascular disease acute stage generally acknowledges in the world.
The thromboembolism treatment drug overwhelming majority clinically used is plasminogen activator, including rtPA (recombinant tissue-type plasminogens
Activator, Recombinant Tissue Plasminogen Activator), urokinase, streptokinase and p- anisoyl
Plasminogen streptokinase compound etc. [Radiology 1990,174,993-1001.].Although these thrombolytic drugs are extensive
It uses, but it is to be solved clinically to also have many unfavorable factors to have, including allergic reaction risk, hemorrhage complication and half-life short
The problems such as [British Medical Journal 2002,325,762-765；British Medical Journal 2002,
325,948-950.].Since the half-life period of thrombolytic drug only has a few minutes, and without thrombus target specificity, curative effect to be increased
Must incremental dose, thrombus while also increases the risk of body bleeding.May be used also in addition, penetrating into extravascular drug
To participate in blood-brain barrier disruption, the reaction process such as oedema is formed, aggravate nervous system injury [New England Journal of
Medicine.1995,333,1581-1587.].
The drawbacks of to solve the problems, such as thrombolytic drug, is badly in need of developing a kind of drug delivery system, can be in thrombus localized site
It discharges drug and generates thrombolytic effect, and reduce the hemorrhage complication of the threat to life caused by " thrombus explosion " medicament at present.
The strategy taken of the drawbacks of researchers is solve the problems, such as thrombolytic drug at present includes the PEGylated of drug, binding fiber albumen
Specific antibodies and construct drug delivery system.It can be extended partly using the method for polyvinyl alcohol (PEG) covalent bonding thrombolytic drug
Decline the phase [Blood.1988,71,1641-1647.], however since the substrate of thrombolytic drug is all macromolecular (such as plasminogen),
Irreversible PEG bondings make the activity of thrombolytic drug reduce because of space repulsion.Using fibrin specific antibodies (such as polypeptide RGD,
RGDS, KEAGDV etc.) it is another strategy [Nanomedicine (Lond) for realizing thrombolytic drug part/targeting thrombolytic effect
2007,2,533-543；Journal of Control Release.2005,101,35-45.].Absar et al. by tPA with it is more
Polyglutamic acid is bonded, and is then formed with the human serum albumins for being connected with protamine and target polypeptide by electrostatic interaction compound
Object.In the circulatory system, the activity of tPA is hidden by the steric hindrance of albumin, it is lived after the heparin of therapeutic dose is added
Performance recovery~97% [Thrombosis Research 2013,131, e91-e99.].Drug delivery system includes nanometer
Grain, hydrogel and liposome etc. can also control releasing for drug by extraneous chemically or mechanically stimulation (such as heparin, ultrasonic wave)
It puts [Journal of Control Release.2002,78,67-79.].Absar et al. is by tPA with low molecular weight heparin phase
In conjunction with, then with human serum albumins compound being formed, drug forerunner physical efficiency hides enzymatic activity well, and usual agent is being added
It can restore its activity [Journal of Control Release.2012,157,46-54.] after the heparin of amount completely.Uesugi
Et al. be prepared for a kind of novel ultrasonic response nano rtPA delivery systmes, they are by rtPA and cationized gelatin and PEGylated
Gelatin forms compound, and the thrombolysis activity of rtPA is suppressed in compound, lives performance recovery [Journal in supersonic induced lower its
Of Control Release.2010,147,269-277.].
However, these methods all have some limitations.First, covalent bonding antibody or albumen can reduce the life of drug
Object activity；Secondly, the inhomogeneity of drug-antibody coupling agent, unstability and immunogenicity in long-term preservation are that chemistry is repaiied
Adorn the main problem of drug；In addition, low release/low activity of the thrombolytic drug in the circulatory system how is preferably controlled, and
Its accurate quick release/activity recovery reached after thrombi, occurs thrombolytic effect, to reduce body bleeding risk.Cause
This, develops a kind of biological responding thrombolytic drug targeted nano gel, can solve simultaneously its half-life period, intelligent control activity and
Sex chromosome mosaicism is targeted, will above have huge potential value in the application of thrombolytic drug.
Invention content
For deficiency in the prior art, the object of the present invention is to provide the thrombolytic drug being keyed based on imines targetings to receive
Rice gel.The second object of the present invention is to provide the synthetic method for the thrombolytic drug targeted nano gel being keyed based on imines.
The third object of the present invention is to provide the above-mentioned thrombolytic drug targeted nano gel being keyed based on imines as thrombolytic drug system
Agent or the application of pharmaceutical carrier.
The invention is realized by the following technical scheme：
A kind of thrombolytic drug targeted nano gel with pH responses, the thrombolytic drug target with pH responses
It is had following structure to nanogel：
Wherein, R3 is thrombolytic drug molecule；R is ester group or ether；R1 be KEAGDV, CQQHHLGGAKQAGDV, RGD or
RGDS, wherein RGD is
RGDS is
Preferably, the thrombolytic drug molecule be the rtPA containing lysine base residue, urokinase, streptokinase or
P- anisoyl plasminogen streptokinase compound.
A kind of thrombolytic drug targeted nano gel with pH responses of the present invention, is to lead to thrombolytic drug and polymer
The imines key connection of pH sensitivities is crossed, and thrombus target ligand is introduced on polymer chain.Wherein, the thrombolytic drug be containing
There is a plasminogen activator of lysine amino residue, including rtPA (rt-PA,
Recombinant Tissue Plasminogen Activator), urokinase, streptokinase and p- anisoyl fibrinolysin
Former streptokinase compound etc.；The polymer is the oxidized dextran containing aldehyde radical and hydroxyl Liang Zhong functional groups, oxidizability
It can be by reaction controlling；The imine linkage is dynamic covalent bond, is relatively stablized under normal physiological pH value, but in faintly acid pH value
Under can hydrolyze, i.e., to pH value from 7.4 to 6.5 or the variation of lower small pH value has sensibility；The thrombus target
Ligand be to thrombus have specific binding effect targeting group, including polypeptide RGD, RGDS, KEAGDV and
CQQHHLGGAKQAGDV etc..One imine linkage of sensitive chemical key in the nanogel is in thrombotic tissue etc. and normal structure acidity
It hydrolyzes and is broken under discrepant weak acid pH value physiological environment.
The thrombolytic drug targeted nano gel is sent out by thrombolytic drug molecule by the aldehyde radical of amino and oxidized dextran
Raw schiff base reaction forms thrombolytic drug-polymer-bound object；Thrombus target is introduced using the hydroxy functional group on oxidized dextran
To ligand, targeted nano gel is formed.The oxidizability (aldehyde group content) of oxidized dextran can be adjusted by reaction, thrombolysis
The ratio that drug is connected with targeting ligand can also regulate and control, and the thrombolytic drug targeting to prepare different sizes and three-dimensional structure is received
Rice gel.In view of thrombosis mechanism and porous physiological structure, the characteristics such as the low pH in surface and polyspecific binding site, this is molten
Bolt medicine target has the ability to thrombus active targeting with nanogel, and since imine linkage is in low pH after reaching thrombi
Under fracture release thrombolytic drug, generate thrombolytic effect, reduce the body bleeding caused by thrombolytic drug and other complication
Risk.
A kind of synthetic method of the thrombolytic drug targeted nano gel with pH responses, includes the following steps：A. will
One kind in KEAGDV, CQQHHLGGAKQAGDV, RGD, RGDS arbitrary several is dissolved in solvent；Oxidized dextran or by its
It is added in above-mentioned solvent after being dissolved in solvent；EDC/DMA or PDCC/DMAP is added to after being dissolved in solvent in above-mentioned solvent,
Reaction temperature is to be reacted at 4~100 DEG C；B. the reaction product solution or dispersion liquid obtained, passes through separation, purifying, drying
The oxidized dextran of introducing thrombus target ligands specific is obtained after removing solvent；C. it is urokinase, streptokinase, again by material medicine
Group tissue-type plasminogen activator, one kind in p- anisoyl plasminogen streptokinase compound or arbitrary several molten
In solvent；By the oxidized dextran for introducing thrombus target ligands specific or it is dissolved in being added to said medicine after solvent molten
In liquid, its pH value is controlled between 7~10, is reacted at being 4~100 DEG C in reaction temperature；D. the reaction product obtained is molten
Liquid or dispersion liquid pass through separation, purifying, the dry thrombolytic drug target with pH responses for going after solvent to obtain above structure
To nanogel.
Preferably, the solvent is selected from water, formic acid, acetic acid, hydrochloric acid solution, N, N '-dimethyl formamide, dimethyl are sub-
At least one of sulfone, methanol, ethylene glycol, ethyl alcohol, dichloromethane, acetonitrile；The pH value control phosphoric acid disodium hydrogen-lemon
Lemon acid buffer, potassium dihydrogen phosphate-sodium hydrate buffer solution, disodium hydrogen phosphate-phosphate sodium dihydrogen buffer solution, calmine-salt
Acid, Tris-HCl buffer solutions, boric acid-borate buffer solution, Glycine-NaOH buffer solution, borax-sodium hydroxid buffer solution,
At least one of groups formed such as sodium carbonate-bicarbonate buffer solution；The reaction temperature is 4~60 DEG C；Described
Reaction time is 24~48 hours；It is described isolate and purify, solvent precipitation can be used in drying process, solvent extraction, ties again
Crystallization, gel chromatographic columns partition method, preparation solution phase separation method, dialysis, freeze-drying, boulton process, natural seasoning,
Or any combination of the above method；Its oxidizability (content of aldehyde radical) of the oxidized dextran can pass through the amount of addition oxidant
To control.
A kind of purposes of the thrombolytic drug targeted nano gel with pH responses, by the thrombolytic drug targeted nano
Gel is as pharmaceutical preparation.Specifically, the pH response thrombolytic drug targeted nano gels of the present invention can be used as pharmaceutical preparation.It is made
Preparation Method using dialysis commonly used in the art, gel chromatography separation method, freeze-drying, direct dissolution method, solvent evaporation method,
Ultrasonic method or their arbitrary combination.The thrombolytic drug is urokinase, streptokinase, recombinant tissue-type plasminogen activation
Agent, p- their any mixture etc. of anisoyl plasminogen streptokinase compound.
The thrombolytic drug targeted nano gel can be used as thrombolytic drug preparation, be used for the treatment of thrombotic diseases,
Also pharmaceutical carrier is can be used as, for loading thrombolytic drug such as rtPA, urokinase, streptokinase and p- anisoyl plasminogen
Streptokinase compound etc., to form the nano-carrier for coating a variety of drugs, and by the physiological responses of imine linkage and ligand
Targeting, the speed and drug release position that intelligently control drug is discharged from nanogel carrier on a molecular scale are real
The synergistic treatment of existing drug.
Compared with prior art, the invention has the advantages that：
1, thrombolytic drug is connected on oxidized dextran strand by the present invention by imine linkage, while being drawn on polymer
Enter the selectively targeted group of thrombus, prepares the thrombolytic drug targeted nano gel with pH responses.The nanogel can prolong
Long protein molecule resists the time of chymotrypsin hydrolysis, simultaneously because there is existing chemical bonding between drug and polymer support again
Physical interaction stabilizes structure to a certain extent so that the blood circulatory half-life of pharmaceutical carrier extends.
2, it is dynamic covalent bond as the imine linkage of linking group, stablizes under normal physiological conditions, but it can be in weak acid
It is broken under environment, releases active drug molecule, on a molecular scale the intelligently speed of Drug controlled release, imines
The Drug Carrier Systems that key can sensitively respond structure small pH fluctuations in physiological environment are significant.
3, the introducing of the selectively targeted group of thrombus makes nanogel have the function of active targeting thrombus, reaches thrombus
Thrombolytic drug is released at position, generates thrombolytic effect, to reducing body bleeding and other complication caused by thrombolytic drug
Risk have a very important significance.
4, the nano-scale microbody system in the present invention can be used as pharmaceutical carrier, swash as urinated for protein thrombolytic drug
Enzyme, streptokinase, rt-PA, p- anisoyl plasminogen streptokinase compound their one
Kind is a variety of, to form the nano-carrier for coating a variety of drugs, realizes the synergistic treatment of drug.
5, the nano-scale microbody system in the present invention can be used as pharmaceutical carrier, can be by controlling dividing for oxidized dextran
Son amount and oxidizability are realized to hydrolase by space steric effect or selectively show bioactivity to protein substrate.
6, the preparation method of pH of the invention response thrombolytic drug targeted nano gel is simple and convenient to operate.
Specific implementation mode
The present invention is described in detail with reference to embodiments, but not limited to the examples disclosure of that.
Embodiment 1
(1) synthesis of oxidized dextran
1g glucans (Mn 40000) are dissolved in 30mL water, 0.956g sodium metaperiodates (being dissolved in 20mL water), room is added
After being protected from light for 24 hours under temperature, 0.411g glycerine is added, continues to stir 15min, reaction mixed liquor is transferred in bag filter,
Dialyse 48h in deionized water, replaces a water within every four hours.By the sample freeze-drying after dialysis, white powder is obtained
Product.The molar ratio for changing glucan and sodium metaperiodate, can prepare the different oxidized dextran of aldehyde group content.
(2) synthesis of oxidized dextran-RGD
By 0.0382g RGD, 0.5g oxidized dextrans (oxidizability 0.5) and 0.1227g 4-dimethylaminopyridine (DMAP)
It is added in the single-necked flask of 100ml, the dissolving of 30ml dichloromethane is added, single port bottle is put into 37 DEG C of water-baths, stirring is equal
It is even.0.1917g 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDC.HCl) are weighed, 20ml dichloromethanes are added
Alkane dissolves.After mixture stirs evenly in single port bottle, the dichloromethane solution of EDC.HCl is added drop-wise in single port bottle, is continued
After stirring for 24 hours, reactant is transferred in the bag filter that molecular cut off is 12000, in the mixing dialyzate (body of ethyl alcohol and water
Product is than being 4: 1) dialysis for 24 hours, replaces a dialyzate in every four hours in.Bag filter is transferred in water later and continues dialysis for 24 hours,
Replace a water within every six hours.Sample after dialysis is freeze-dried, white powder product is obtained.
(3) synthesis of urokinase-oxidized dextran-RGD nanogels
25mg urokinases are dissolved in 2mL PBS (0.01M, pH8.0), 15mg oxidized dextrans-RGD is dissolved in 2mL PBS
In (0.01M, pH 8.0), the two is mixed, after stirring for 24 hours at room temperature, with G75 sephadex chromatography post separations.Collect sample
Product obtain white powder product after freeze-drying.The molar ratio for changing urokinase and oxidized dextran-RGD, can prepare different medicines
The compound of object grafting rate.
Embodiment 2
(4) synthesis of oxidized dextran
1g glucans (Mn 40000) are dissolved in 30mL water, 0.956g sodium metaperiodates (being dissolved in 20mL water), room is added
After being protected from light for 24 hours under temperature, 0.411g glycerine is added, continues to stir 15min, reaction mixed liquor is transferred in bag filter,
It dialyses in deionized water for 24 hours, replaces a water within every four hours.By the sample freeze-drying after dialysis, white powder is obtained
Product.The molar ratio for changing glucan and sodium metaperiodate, can prepare the different oxidized dextran of aldehyde group content.
(5) synthesis of oxidized dextran-RGD
By 0.0382g RGD, 0.5g oxidized dextrans (oxidizability 0.5) and 0.1227g 4-dimethylaminopyridine (DMAP)
It is added in the single-necked flask of 100ml, the dissolving of 30ml dichloromethane is added, single port bottle is put into 60 DEG C of water-baths, stirring is equal
It is even.0.1917g 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDC.HCl) are weighed, 20ml dichloromethanes are added
Alkane dissolves.After mixture stirs evenly in single port bottle, the dichloromethane solution of EDC.HCl is added drop-wise in single port bottle, is continued
After stirring for 24 hours, reactant is transferred in the bag filter that molecular cut off is 12000, in the mixing dialyzate (body of ethyl alcohol and water
Product is than being 4: 1) dialysis for 24 hours, replaces a dialyzate in every four hours in.Bag filter is transferred in water later and continues dialysis for 24 hours,
Replace a water within every six hours.Sample after dialysis is freeze-dried, white powder product is obtained.
(6) synthesis of urokinase-oxidized dextran-RGD nanogels
25mg urokinases are dissolved in 2mL PBS (0.01M, pH 8.0), 15mg oxidized dextrans-RGD is dissolved in 2mL PBS
In (0.01M, pH 8.0), the two is mixed, after stirring for 24 hours at room temperature, with G75 sephadex chromatography post separations.Collect sample
Product obtain white powder product after freeze-drying.The molar ratio for changing urokinase and oxidized dextran-RGD, can prepare different medicines
The compound of object grafting rate.
Embodiment 3
(7) synthesis of oxidized dextran
1g glucans (Mn 40000) are dissolved in 30mL water, 0.956g sodium metaperiodates (being dissolved in 20mL water), room is added
After being protected from light 48h under temperature, 0.411g glycerine is added, continues to stir 15min, reaction mixed liquor is transferred in bag filter,
Dialyse 48h in deionized water, replaces a water within every four hours.By the sample freeze-drying after dialysis, white powder is obtained
Product.The molar ratio for changing glucan and sodium metaperiodate, can prepare the different oxidized dextran of aldehyde group content.
(8) synthesis of oxidized dextran-RGD
By 0.0382g RGD, 0.5g oxidized dextrans (oxidizability 0.5) and 0.1227g 4-dimethylaminopyridine (DMAP)
It is added in the single-necked flask of 100ml, the dissolving of 30ml dichloromethane is added, single port bottle is put into 4 DEG C of water-baths, stirring is equal
It is even.0.1917g 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDC.HCl) are weighed, 20ml dichloromethanes are added
Alkane dissolves.After mixture stirs evenly in single port bottle, the dichloromethane solution of EDC.HCl is added drop-wise in single port bottle, is continued
After stirring 48h, reactant is transferred in the bag filter that molecular cut off is 12000, in the mixing dialyzate (body of ethyl alcohol and water
Product is than being 4: 1) dialysis for 24 hours, replaces a dialyzate in every four hours in.Bag filter is transferred in water later and continues dialysis for 24 hours,
Replace a water within every six hours.Sample after dialysis is freeze-dried, white powder product is obtained.
(9) synthesis of urokinase-oxidized dextran-RGD nanogels
25mg urokinases are dissolved in 2mL PBS (0.01M, pH 8.0), 15mg oxidized dextrans-RGD is dissolved in 2mL PBS
In (0.01M, pH 8.0), the two is mixed, after stirring for 24 hours at room temperature, with G75 sephadex chromatography post separations.Collect sample
Product obtain white powder product after freeze-drying.The molar ratio for changing urokinase and oxidized dextran-RGD, can prepare different medicines
The compound of object grafting rate.
Claims (4)
1. a kind of thrombolytic drug targeted nano gel with pH responses, characterized in that described is molten with pH responses
Bolt drug targeting nanogel has following structure：
Wherein, R3For urokinase；R is ester group or ether；R1For KEAGDV, CQQHHLGGAKQAGDV, RGD or RGDS.
2. a kind of synthetic method of thrombolytic drug targeted nano gel with pH responses described in claim 1, feature
It is to include the following steps：A. by KEAGDV, CQQHHLGGAKQAGDV, RGD, RGDS one kind or arbitrary several be dissolved in solvent
In；Oxidized dextran is added in above-mentioned solvent after being dissolved in solvent；After EDC/DMA or PDCC/DMAP is dissolved in solvent
It is added in above-mentioned solvent, is reacted at being 4~100 DEG C in reaction temperature；B. the reaction product solution or dispersion liquid obtained,
Pass through separation, purifying, the dry oxidized dextran for going after solvent to obtain introducing thrombus target ligands specific；C. by material medicine
Urokinase is dissolved in solvent；By the oxidized dextran for introducing thrombus target ligands specific or it is dissolved in being added to after solvent
It states in drug solution, controls its pH value between 7~10, reacted at being 4~100 DEG C in reaction temperature；D. what is obtained is anti-
Reaction mixture or dispersion liquid are answered, goes after solvent to obtain the molten with pH responses of above structure by separation, purifying, drying
Bolt drug targeting nanogel.
3. a kind of synthetic method of thrombolytic drug targeted nano gel with pH responses according to claim 2,
It is characterized in, the solvent is selected from water, formic acid, acetic acid, hydrochloric acid solution, N, N '-dimethyl formamide, dimethyl sulfoxide (DMSO), methanol, second
At least one of glycol, ethyl alcohol, dichloromethane, acetonitrile；The pH value control phosphoric acid disodium hydrogen-lemon acid buffering
Liquid, potassium dihydrogen phosphate-sodium hydrate buffer solution, disodium hydrogen phosphate-phosphate sodium dihydrogen buffer solution, calmine-hydrochloric acid, Tris-
HCl buffer solutions, boric acid-borate buffer solution, Glycine-NaOH buffer solution, borax-sodium hydroxid buffer solution, sodium carbonate-carbon
At least one of the group that sour hydrogen sodium buffer solution is formed；The reaction temperature is 4~60 DEG C.
4. a kind of thrombolytic drug targeted nano gel with pH responses described in claim 1, which is characterized in that described molten
Bolt drug targeting nanogel is as the application for preparing treatment thrombus drug.
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| US3639213A (en) * | 1969-12-02 | 1972-02-01 | Baxter Laboratories Inc | Streptokinase chemically bonded to a carbohydrate matrix |
| CN101045033A (en) * | 2007-04-30 | 2007-10-03 | 中国人民解放军第四军医大学 | Ply-glycosyl modified acid-sensitive nanometer gel |
| WO2009155705A1 (en) * | 2008-06-26 | 2009-12-30 | Therapure Biopharma Inc. | Polysaccharide-protein conjugates reversibly coupled via imine bonds |
| CN101745119A (en) * | 2010-01-25 | 2010-06-23 | 中国药科大学 | Polysaccharide conjugate of carboxylic acid drug, preparation method thereof and application thereof |
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