CN106279678B - A kind of preparation for the reduction-sensitive nano-micelle that can covalently carry medicine - Google Patents
A kind of preparation for the reduction-sensitive nano-micelle that can covalently carry medicine Download PDFInfo
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- CN106279678B CN106279678B CN201610642642.0A CN201610642642A CN106279678B CN 106279678 B CN106279678 B CN 106279678B CN 201610642642 A CN201610642642 A CN 201610642642A CN 106279678 B CN106279678 B CN 106279678B
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
- C08G73/02—Polyamines
- C08G73/0246—Polyamines containing other atoms than carbon, hydrogen, nitrogen or oxygen in the main chain
- C08G73/0253—Polyamines containing sulfur in the main chain
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
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Abstract
The present invention relates to biomedical material technology more particularly to a kind of preparation methods for the reduction-sensitive nano-micelle that can covalently carry medicine：First with N; bis- (acryloyl group) cystamines of N and amino acid containing hydrophobic grouping carry out total sudden reaction by Michael's addition method; using esterification and hydrazidesization reaction; synthesis obtains terpolymer, finally by being self-assembly of poly- amphoteric ion nano-micelle in selective solvent.Due to containing cystine linkage and amphoteric ion in copolymer segment, thus nano-micelle has reduction-sensitive and excellent anti-protein non-specific adsorption performance；The nano-micelle can covalently load adriamycin drug.The nano-micelle good biocompatibility of the present invention, can be degradable in vivo, is expected to be used as anti-cancer medicament carrier.
Description
Technical field
The present invention relates to biomedical material technology more particularly to a kind of reduction-sensitive nanometers that can covalently carry medicine
The preparation method of micella.
Background technology
Malignant tumour seriously threatens the health of the mankind, and according to the report of the World Health Organization, cancer is a global master
Want the cause of death.The method for the treatment of cancer is mainly controlled including surgical resection, chemotherapy (chemotherapy) and radiation at present
It treats.All there is very big defect in these treatment means, such as drug generates toxic side effect, normal structure organ is damaged, for patient
For be all great pain.
In order to overcome drug to directly transport caused serious shortcomings, nanotechnology that the 1980s rises with polymerize
The combination of object material produces the administration nano-drug administration system of a series of new：Polymer micelle, vesica, liposome and microballoon, will
Drug physics is coated into carrier or is combined with support chemistry, can effectively reduce the toxic side effect of drug normal tissue；Pass through tax
The special physiological stimulation response of carrier is given, the distribution of drug in vivo can be improved, go directly lesion tissue area, and poor in diseased region
Drug is released under the action of anisotropic temperature, pH and reductant-oxidant, to improve the bioavilability of drug.
Biotechnology based on nano-particle has become drug conveying and the frontier development of other medical domains,
But as delivery system, the previous prodigious obstacle of mesh is the nonspecific proteins absorption of nano-particle in vivo, this meeting
Causing carrier to interact with blood protein leads to aggregation and immune response, these problems are serious to limit drug-carrying nanometer particle
The application of son clinically.
In order to ensure that the cyclical stability of nano-particle, PEG are usually utilized to modification carrier outer layer.PEG is superior hydrophilic
Performance, it is possible to reduce protein adsorption avoids carrier from being removed by reticuloendothelial system.However thering is relevant report to point out, PEG is in oxygen
With can occur autoxidation in the presence of transition metal ions, i.e. the hydroxyl of the ends PEG quilt under the action of alcohol dehydrogenase in vivo
It is oxidized to aldehyde radical, to make it lose anti-protein adsorption performance.In addition, " stealthy " shielding action of PEG itself can equally make cancer
Cell identifies difficulty to it, and cancer cell is made to substantially reduce the uptake ratio of carrier.
Based on the bionics Study to membrane structure, it is found that the amphoteric ion structure of cell membrane surface Phosphorylcholine has
Excellent anti-protein adsorption effect.Common amphoteric ion structure has carboxybetaine class (CBMA), sulfonic group betaines
(SBMA), Phosphorylcholine class (MPC) and amino acids, these structures act on forming fine and close hydration layer by ionic bond,
While anti-protein adsorption, pharmaceutical carrier can be stablized, therefore the alternative PEG of amphoteric ion polymer is used for modifying nano-particle
Surface.
Glutathione (GSH) is a kind of tripeptides containing sulfydryl, is a kind of important reducing agent, energy in biochemical reaction
Enough restore cystine linkage.Reduced glutathione in cytoplasm compared with horn of plenty, a concentration of 1-10mM, but in blood content compared with
It is few, general a concentration of 2 μ Μ；For normal structure, concentration of the GSH in tumour cell is about up to 4~10 times.Utilize this
One feature can design the pharmaceutical carrier containing cystine linkage, make its in tumour cell GSH generate response, have target
Intracellular release anti-cancer medicine.
Usually there are two types of modes when poly- amphoteric ion nano-micelle carrying medicament：First, connecting section and drug point by polymer
The hydrophobic interaction of son；Second is that being interacted by the counter ions in the charged ion and drug in pharmaceutical carrier.But
It is that both modes are easy that drug is brought to reveal and be difficult to condition control release problem.
Invention content
For reason given above, the object of the present invention is to provide a kind of systems for the reduction-sensitive nano-micelle that can covalently carry medicine
Preparation Method.First by N, three kinds of bis- (acryloyl group) cystamines of N-, lysine and other hydrophobic amino acids monomers pass through Michael
Addition synthesis of ternary copolymer, then by the carboxyl of hydrophobic amino acid in copolymer pass through esterification, then with hydration hydrazine reaction
Poly- (bis- (acryloyl group) cystamine-co- alpha-amido phenylpropyl alcohols hydrazides of lysine-co-N, N-) terpolymer is obtained, finally water-soluble
The reduction-sensitive nano-micelle of medicine can be covalently carried in liquid by being self-assembly of.
Solvent selected by Michael addition reaction in addition to water, also needs the polarity that dissolvable hydrophobic components are added in the present invention
Organic solvent, such as dimethyl sulfoxide, n,N-Dimethylformamide, tetrahydrofuran, methanol or ethyl alcohol；Reaction temperature is controlled at 50 DEG C
Left and right, the temperature contribute to secondary amine to be reacted with double bond, to the larger copolymer of smooth shape molecular weight.Three kinds of monomeric units are being received
There is respective function in rice glue beam：1) contain cystine linkage in bis- (acryloyl group) the cystamine molecules of N, N-, carrier is made to have
Restore response, can glutathione effect under chain rupture, so that carrier is destroyed；2) lysine be essential amino acid it
One, human development, enhancing immune function can be promoted, contain carboxyl and amino simultaneously in molecule, form poly- amphoteric ion, assign medicine
Object carrier anti-protein non-specific adsorption performance and pH sensibility；3) amino acid is human endogenous's property substance, hydrophobicity
Group is that the self assembly of polymer and drug carrying ability lay the foundation；And the carboxyl in amino acid can be with hydrazine hydrate after esterification
Reaction generates hydrazides, convenient for, with hydrazone bond covalent bond, hydrazone bond fracture in acid condition can control drug release with adriamycin.
The first step synthesized in the present invention is Michael's addition copolymerization, and the raw material of use is N, bis- (acryloyl group) Guangs of N-
Amine, lysine and hydrophobic amino acid, high polymer, N, mole of bis- (acryloyl group) cystamines of N- are controlled in charging in order to obtain
Number is equal with the sum of the molal quantity of amino acid.
Specifically in the synthesis step 1) in, solvent selected by Michael addition reaction is polar organic solvent and deionized water
Mixed liquor, volume ratio 2:1, polar organic solvent includes dimethyl sulfoxide, n,N-Dimethylformamide, tetrahydrofuran, Isosorbide-5-Nitrae-
Dioxane, ethyl alcohol or methanol；Selected catalyst is 0.1Wt% sodium hydrate aqueous solutions, adjusts pH in 10.5~12.0 ranges
It is interior, it is conducive to increase the nucleophilicity of amino；
After the completion of Michael addition reaction, in the synthesis step 2) in, by the carboxyl ester in amino acid, with right
Toluenesulfonic acid is catalyst, is heated to 60 DEG C, is reacted 4.5 hours, then ester bond and hydration hydrazine reaction generate hydrazide structure；Water
A concentration of 10Wt% of hydrazine is closed, molal quantity is 2~3 times of the sum of amino acid molal quantity, and back flow reaction 8 is small at a temperature of 65 DEG C
When.
The present invention also provides a kind of application of reduction-sensitive nano-micelle that can covalently carry medicine in preparing pharmaceutical carrier
Nano-micelle dry powder and doxorubicin hydrochloride is added in DMF solvent in method, in the case where triethylamine coexists, reacts at room temperature 24 hours；
Then the bag filter for being 3500 with molecular cut off is dialysed in deionized water, is finally freeze-dried.
Using N, bis- (acryloyl group) cystamines of N-, lysine are polymerize with hydrophobic amino acid by what Michael's addition obtained
Object contains the multi-functional response groups such as cystine linkage, amino and carboxyl simultaneously.In human body, tumor tissues and normal structure phase
Than temperature, pH and redox environment etc. have larger difference, and that is designed using these differences has stimulating responsive
Nano-carrier, release of the drug in targeting moiety may be implemented.In vivo in cyclic process, the cystine linkage in carrier is in cell
Outer low glutathione concentrations (2 μm of olL-1) under can keep stable, and once enter it is intracellular, high concentration glutathione (2~
Can 10mM) cystine linkage be made to destroy rapidly, drug is promoted therefrom to release；Meanwhile tumor tissues pH (<6.5) than normal group
Knit that pH (≈ 7.4) is low, and in tumour cell amidos of the pH of lysosome and endosome in 4.5~6, carrier in acid condition
Lower protonation can be such that carrier is swollen, and to further destroy carrier structure, drug is fully discharged.
According to the above aspect of the present invention, the present invention has at least the following advantages：
1. utilizing Michael's addition synthetic polymer, easy to operate, reaction condition is mild, and reaction is more thorough, without other
By-product generates.
2. due to containing the structural units such as cystine linkage, amino and carboxyl in the polymer segment simultaneously, thus imparting and receiving
The sensitive pH of rice glue beam and reduction response, in inside tumor cells faintly acid and reproducibility environment, micellar structure is destroyed,
So as to smoothly discharge drug.
3. cystine linkage is located at main polymer chain, under high concentration glutathione effect inside cancer cell, the fracture of cystine linkage
Entire polymer degradation, no macromolecular residual can be made to can avoid the side effect of material residual and initiation in practical applications.
4. the amino in polymer and carboxyl, PEG can be not only substituted as the hydrophilic segment for stablizing micella, but also micella
The charge on surface assigns micella excellent anti-protein adsorption effect, can extend carrier circulation time in vivo.
5. the nano-micelle containing hydrazide structure is easy and adriamycin covalent bond, increases load drug stabilisation and control discharges
Possibility.
6. being the polymer of Material synthesis using amino acid and alkaloid, there is good biocompatibility.
Above description is only the general introduction of technical solution of the present invention, in order to better understand the technical means of the present invention,
And can be implemented in accordance with the contents of the specification, below with presently preferred embodiments of the present invention and after coordinating attached drawing to be described in detail such as.
Description of the drawings
The structural schematic diagram of nano-micelle load adriamycin drug in Fig. 1 present invention；
Bis- (acryloyl group) cystamines of Fig. 2 N, N-, lysine and phenylalanine are with molar ratio：1:0.9:It is synthesized when 0.1
Nano-micelle scanning electron microscope (SEM) photograph；
Particle diameter distribution of the nano-micelle at pH 7.4, N in Fig. 3 present invention1、N2、N3、N4Molar ratio is indicated in table 1；
Change of size of the nano-micelle in 10mM glutathione solutions under different time in Fig. 4 present invention.
Specific implementation mode
With reference to the accompanying drawings and examples, the specific implementation mode of the present invention is described in further detail.Implement below
Example is not limited to the scope of the present invention for illustrating the present invention.
Embodiment 1
1) synthesis of bis- (acryloyl group) cystamines of N, N-：
In 250mL three-necked flasks, 5.630g 2-aminoethyl disulfide dihydrochlorides are dissolved in 25mL deionized waters, are placed in ice-water bath
Stirring.It weighs 4g sodium hydroxides and is dissolved in 10mL deionized waters, the sodium hydroxide solution dissolved is added in dropping funel；It weighs
4.526g acryloyl chlorides are dissolved in 5mL dichloromethane, are placed in constant pressure funnel, and two kinds of solution are added drop-wise to Guang dropwise simultaneously
In amine dihydrochloride aqueous solution, ice-water bath is kept to stir 5 hours.Solution is filtered after reaction, obtained white solid is used
Deionization is washed three times.Then obtained material re-crystallizing in ethyl acetate after cleaning, dry 24 in 30 DEG C of vacuum drying chambers
Hour obtains product.
2) conjunction of poly- (bis- (acryloyl group) cystamine-co- alpha-amido phenylpropyl alcohols hydrazides of lysine-co-N, N-) terpolymer
At：
In the three-necked flask of 50mL, by N, bis- (acryloyl group) cystamines of N-, lysine and phenylalanine are matched as shown in table 1
One of side is dissolved in the mixed solution of 4mL n,N-Dimethylformamide (DMF) and 2mL deionized waters, and the pH value for adjusting solution is
11, it reacts 5 days for 48 DEG C under nitrogen protection；Methanol 2.5mL and 0.1g p-methyl benzenesulfonic acid is added in reaction solution, is heated to 60
DEG C, it reacts 4.5 hours.It uses the sodium hydroxide solution of 2wt% to adjust pH to 7 again, the hydrazine hydrate solution 1.5mL of 10W% is added
It is added in above-mentioned solution, the back flow reaction 8 hours at a temperature of 65 DEG C.
Solution is transferred in the bag filter that molecular cut off is 3500 after reaction, in first alcohol and water (V:V=2:1)
It dialyses 3 days in mixing extracellular fluid dialysis, freeze-drying obtains pale yellow powder product.Bis- (acryloyl group) cystamines of N, N-, lysine
As shown in table 1 with rate of charge of the phenylalanine in mixed solution, the present invention provides 4 kinds of terpolymer synthesizing formulas, can root
It is needed according to application, passes through the proportioning different adjustment nano-micelle grain size of three kinds of monomers.
1 Michael addition reaction synthesizing formula list of table
3) preparation of nano-micelle:
By poly- (bis- (acryloyl group) cystamine-co- alpha-amido phenylpropyl alcohols hydrazides of lysine-co-N, the N-) terpolymers of 10mg
It is dissolved in 1mL dimethyl sulfoxide (DMSO)s, 8mL ultra-pure waters is slowly added dropwise into solution during lasting stirring.It is molten after completion of dropwise addition
Liquid continues stirring 3 hours, is then transferred to solution in the bag filter that molecular cut off is 3500, and dialysis obtains nanometre glue in 24 hours
Beam.By scanning electron microscope (SEM) photograph as it can be seen that regular spherical morphology is presented in the nano-micelle, particle diameter distribution is than more uniform.
Different nano-micelle sizes is needed according to application, the proportioning of three kinds of monomers can be adjusted, to obtain different-grain diameter
Nano-micelle.
Embodiment 2
With embodiment 1, but phenylalanine is replaced with tryptophan, remaining reaction condition is such as embodiment 1.
Embodiment 3
With embodiment 1, but phenylalanine is replaced with methionine, remaining reaction condition is such as embodiment 1.
Embodiment 4
With embodiment 1, but phenylalanine is replaced with leucine, remaining reaction condition is such as embodiment 1.
Embodiment 5
With embodiment 1, but phenylalanine is replaced with para hydroxybenzene alanine, remaining reaction condition is such as embodiment 1.
Embodiment 6
The measurement of nano-micelle critical micelle concentration (CMC)：
Gained nano micellar solution in embodiment 1 is diluted to a series of various concentrations, takes receiving for various concentration polymer
Rice micellar solution 4mL, is separately added into 30 μ L a concentration of 1.622 × 10-5The acetone soln of g/mL pyrenes is protected from light and is put in 25 DEG C of nitrogen atmosphere
In the isothermal vibration case enclosed, it is incubated a period of time, waits for that acetone is all evaporated completely, with fluorescent spectrophotometer assay emission spectrum,
Fluorescence exciting wavelength λ=333nm is set, scanning range λ=350~500nm, excitation and transmite slit width are 5nm, sample
Pond thickness 1cm.By measuring a series of various concentration nano-particle solutions in 373nm and 383nm (i.e. I1、I3) fluorescence intensity, and
Using log concentration as X-axis, I1/I3It maps for Y-axis, the CMC value of polymer nano micelle is found out by the catastrophe point of curve.As a result it shows
Show：The nano-micelle of four kinds of formulas has smaller CMC value, respectively 22.5mg/L, 27.3mg/L, 33.7mg/L, 39.3mg/
L has stronger anti-dilution stability.
Embodiment 7
The pH sensibility of nano-micelle：
Gained nano-micelle in embodiment 1 is placed in the PBS buffer solutions that pH is respectively 7.4,6.5 and 5.0, by dynamic
Laser light scattering system detectio micella grain size changes with time, and as a result shows that micella has certain pH sensibility, with acidity
Enhancing grain size increase.
Embodiment 8
The reduction-sensitive of nano-micelle：
Gained nano-micelle in embodiment 1 is placed in a concentration of 10mM glutathione solutions, in different time laser
Light scattering apparatus tests the change of size of nano-micelle, observation reduction response.In 10mM glutathione solutions, grain after 12 hours
Diameter increases, and after illustrating that the cystine linkage being located in main chain is broken under glutathione effect, hydrophobic part can re-assembly, with
The volume of the increase of time, aggregation increases, and grain size is caused to increase.
Embodiment 9
The anti-albumen non-specific adsorption performance of nano-micelle：
Gained nano-micelle in embodiment 1 is mixed with the culture medium of the RPMI-1640 containing 10% fetal calf serum, or
It is mixed with the BSA solution of 4.5wt%, pH 7.4.Above-mentioned mixed solution be incubated at 37 DEG C for 24 hours, using laser light scattering instrument come
The change of size of nano-micelle is detected, micella anti-protein non-specific adsorption performance is observed.As a result it shows：Nano micellar solution
After contacting 24 hours with different proteins, grain size is not substantially change, with its in protein-free buffer solution, do not have
There are aggregation or disintegration phenomenon, this result illustrates to realize in human body without mutual suction-operated between nano-micelle and protein
The cycle of long period.
Embodiment 10
The biocompatibility of nano-micelle：
With gained nano-micelle N in embodiment 14For research object.The cytotoxicity of nano-micelle is carried out using mtt assay
Test, the cervical cancer cell (Hela cells) or l cell (3T3 cells) for taking logarithmic phase to grow, through 0.25% pancreas
After protease digestion, cell is blown and beaten with the RPMI-1640 culture mediums containing 10% fetal calf serum, after with culture medium by cell
It is diluted to a concentration of 1.2 × 104The cell suspension of a/mL is inoculated in 96 orifice plates, per 100 μ L of hole, is placed in constant incubator and trains
It supports and discards culture medium afterwards for 24 hours, it is 0,80,160,240,320 μ g/mL that experimental group, which is separately added into 100 μ L containing polymer concentration gradient,
RPMI-1640 complete mediums, every group sets 4 multiple holes, continues to be placed in constant incubator and cultivates 48h, every after culture
20 μ L MTT (5mg/mL) solution are added in hole, continue after cultivating 4h, discard the solution in culture plate, 150 μ L are added per hole
DMSO, concussion shake up, and absorbance are measured at 570nm with microplate reader, and calculate cell survival rate.As a result it shows：3T3 and Hela
Cell survival rate of two kinds of cells in the nano micellar solution of various concentration between 96%~100%, in conjunction with table 2 it is found that
The cytotoxicity grade of nano-micelle is 1 grade, on cell growth without influence, thus has good biocompatibility.
Relationship of 2 cell of table with respect to appreciation rate and cytotoxicity
Embodiment 11
The preparation of medicament-carried nano micelle：
In 25 milliliters of fine taper bottles, 8 milliliters of DMF solvents are added, add 200 milligrams of nano-micelle dry powder and 50 milligrams of salt
Sour adriamycin adds 0.5 milliliter of triethylamine, reacts at room temperature 24 hours；Reaction solution is transferred to the dialysis that molecular cut off is 3500
Bag, is dialysis medium with deionized water, dialyses 3 days at room temperature, replaces dialysis medium for every eight hours, and finally freeze-drying is carried
Medicine nano-micelle.
The above is only a preferred embodiment of the present invention, it is not intended to restrict the invention, it is noted that for this skill
For the those of ordinary skill in art field, without departing from the technical principles of the invention, can also make it is several improvement and
Modification, these improvements and modifications also should be regarded as protection scope of the present invention.
Claims (7)
1. a kind of preparation method for the reduction-sensitive nano-micelle that can covalently carry medicine, includes the following steps successively：
1) by lysine, N, bis- (acryloyl group) cystamines of N- and three kinds of monomers of amino acid containing hydrophobic grouping under base catalysis,
The in the mixed solvent of water and polar organic solvent obtains terpolymer by Michael addition reaction；
2) this terpolymer is obtained by the reaction to the copolymer solution of the group containing hydrazides through over-churning, again with hydrazine hydrate；
3) copolymer solution obtains solid powder after dialysis purification, freeze-drying, and powder is dissolved in dimethyl sulfoxide, holds
Ultra-pure water is slowly added dropwise into terpolymer solution under continuous stirring；
4) after dripping, solution is transferred in bag filter by stirring a period of time, and dialysis treatment obtains nano-micelle.
2. the preparation method of a kind of reduction-sensitive nano-micelle that can covalently carry medicine according to claim 1, described
In step 1), the amino acid containing hydrophobic grouping includes phenylalanine, tryptophan, the third ammonia of methionine, leucine and para hydroxybenzene
Acid.
3. the preparation method of a kind of reduction-sensitive nano-micelle that can covalently carry medicine according to claim 1, described
In step 1), the molar ratio of bis- (acryloyl group) cystamines of N, N-, lysine and three kinds of monomers of amino acid containing hydrophobic grouping is 1:
0.9:0.1、1:0.8:0.2、1:0.7:0.3、1:0.6:0.4、1:0.5:0.5、1:0.4:0.6、1:0.3:0.7、1:0.2:0.8
Or 1:0.1:0.9.
4. the preparation method of a kind of reduction-sensitive nano-micelle that can covalently carry medicine according to claim 1, described
In step 1), solvent selected by Michael addition reaction is the mixed liquor of polar organic solvent and deionized water, volume ratio 2:1,
Polar organic solvent includes dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, 1,4- dioxane, ethyl alcohol or methanol.
5. the preparation method of a kind of reduction-sensitive nano-micelle that can covalently carry medicine according to claim 1, described
In step 1), catalyst selected by Michael's addition is 0.1Wt% sodium hydrate aqueous solutions, adjusts pH in 10.5~12.0 ranges
It is interior.
6. the preparation method of a kind of reduction-sensitive nano-micelle that can covalently carry medicine according to claim 1, described
In step 2), esterification is esterifying reagent with methanol, using p-methyl benzenesulfonic acid as catalyst, is heated to 60 DEG C, reaction 4.5 is small
When.
7. the preparation method of a kind of reduction-sensitive nano-micelle that can covalently carry medicine according to claim 1, described
In step 2), a concentration of 10Wt% of hydrazine hydrate, molal quantity is the sum of the molal quantity of lysine and the amino acid containing hydrophobic grouping
2~3 times, the back flow reaction 8 hours at a temperature of 65 DEG C.
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| EP1970400A1 (en) * | 2005-11-24 | 2008-09-17 | Mitsuru Akashi | Stimuli-responsive degradable gel |
| CN105820334A (en) * | 2016-05-19 | 2016-08-03 | 江南大学 | Preparing method for poly-zwitter-ion nanoparticles based on amino acid |
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| EP1970400A1 (en) * | 2005-11-24 | 2008-09-17 | Mitsuru Akashi | Stimuli-responsive degradable gel |
| CN105820334A (en) * | 2016-05-19 | 2016-08-03 | 江南大学 | Preparing method for poly-zwitter-ion nanoparticles based on amino acid |
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