CN108938597A - A kind of chitosan graft polymer medicine-carrying nanoparticles and its preparation and application - Google Patents
A kind of chitosan graft polymer medicine-carrying nanoparticles and its preparation and application Download PDFInfo
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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Abstract
The present invention relates to a kind of chitosan graft polymer medicine-carrying nanoparticles and its preparations and application, and hyaluronic acid decorated chitosan graft poly- two (ethylene glycol) methyl ether methyl methacrylate PDEGMA nano particle is as carrier, carrying medicament.Preparation method of the present invention is easy to operate, experiment condition is easy to control；Obtained drug-loading nanoparticles can long-acting slow-release, and there is pH and responsive to temperature type to convey, release rate is high under lower ph and higher temperature environment, is suitble to the microenvironment of tumor tissues, has the potentiality for doing subsequent related experiment analysis using it.
Description
Technical field
The invention belongs to drug-loading nanoparticles and its preparation and application field, in particular to a kind of chitosan graft polymer
Drug-loading nanoparticles and its preparation and application.
Background technique
Taxol (PTX) is a kind of secondary metabolites of terpene complexity extracted from yewtree, is a kind of wide spectrum
Efficient anti-tumor drug, it, by stablizing micro-pipe and their depolymerization being inhibited to play a role, causes in fission process
The apoptosis of tumour cell, to reach antitumaous effect.Most of anti-tumor drugs all show cytotoxicity caused by high dose
And side effect caused by specificity and targeting power deficiency.Wherein, more worst to be, PTX is injected intravenously not only to disease
Becoming position cell has killing ability, and the toxicity of normal tissue is not avoided that, therefore, suitable drug is selected to carry
Body, it is particularly critical for the clinical application of this anti-tumor drug.Specifically, compared with conventional medicament, Nano medication transmitting
System can show passively/active tumor sites targeting and lasting and intelligence drug release profile.
It is worth noting that, the microenvironment of knub position is more slightly higher than the temperature of normal tissue, (1~2 DEG C is higher than normally
Tissue), slant acidity pH value (slightly below normal tissue) and the excess cell proliferation along with high enzyme concentration, these can all weaken carefully
The therapeutic effect of cytotoxic drugs.And the drug carrier system of some temperature or pH responsiveness can be synthesized according to these features,
Commonly known as " intelligent nano carrier ", because they can undergo quick, unexpected and reversible structure/attribute in knub position
Change, to cope with the minor change of ambient enviroment.Poly- two (ethylene glycol) methyl ether methacrylic acid is grafted using chitosan (CS)
The method of methyl esters (PDEGMA) can synthesize the pharmaceutical carrier with pH value and temperature response characteristics, it is micro- to realize knub position
The double response functions of environment.
However, the multi-functional drug carriers as breast cancer treatment, need to do the tumor-targeting of nano particle
It is further to improve.The important component of the hyaluronic acid extracellular matrix of tumor locus is a kind of natural polysaccharide, is had very strong
Hydrophilicity, have good biocompatibility and biological degradability (the highly expressed hyaluronidase of tumor locus can be by it
Degradation) and organism immune response will not be caused.Hyaluronic acid can specificity combination cell surface CD44, much study table
Bright tumor cell surface CD44 4-5 times of expression about higher than normal cell, therefore by hyaluronic acid decorated in drug delivery system
Surface will improve its Targeting Performance, and load upper model drug PTX, be applied to before having good research in breast cancer treatment
Scape.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of chitosan graft polymer medicine-carrying nanoparticles and its systems
Standby and application overcomes the prior art not have the defect of the double response functions of environment and specificity.The operation letter of this method preparation method
List, experiment condition are easy to control；Obtained drug-loading nanoparticles can long-acting slow-release, and there is pH and responsive to temperature type to convey,
Release rate is high under lower ph and higher temperature environment, is suitble to the microenvironment of tumor tissues, chitosan graft polymer nanocomposite
Grain average grain diameter can utmostly reach tumor locus in 180nm.
A kind of chitosan graft polymer medicine-carrying nanoparticles of the invention, the nano particle are hyaluronic acid decorated
Chitosan graft poly- two (ethylene glycol) methyl ether methyl methacrylate PDEGMA.
The load medicine of the nano particle is taxol PTX.
The preparation method of chitosan graft polymer medicine-carrying nanoparticles, step described in one kind of the invention include:
(1) chitosan graft polymer CS-g-PDEGMA solution is added in hyaluronic acid HA solution, is stirred, dialysis is cold
It is lyophilized dry, obtains hyaluronic acid decorated chitosan graft polymer nano granules HA-CS-g-PDEGMA；Wherein HA and CS-g-
The mass ratio of PDEGMA is 1:2~10；
(2) drug solution is added dropwise in the HA-CS-g-PDEGMA aqueous solution of stirring, is stirred to react 24~48h, dialysed
Be freeze-dried after purification to get；Wherein the mass ratio of HA-CS-g-PDEGMA nano particle and drug is 1:0.05~1:0.1.
The preferred embodiment of above-mentioned preparation method is as follows:
The specific preparation of chitosan graft polymer CS-g-PDEGMA in the step (1) are as follows:
Chitosan progress acetylation is obtained into the chitosan (N-CS) of acetylation；The chitosan N-CS of acetylation is taken to be dissolved in molten
In agent, chain-transferring agent dodecyl trithiocarbonic acid rouge (DDACT) is slowly added thereto, in dicyclohexylcarbodiimide
(DCC) and in the presence of 4- dimethylamino pyridine (DMAP) 40h is stirred at room temperature, dialysis is dried to obtain N-CS-RAFT；Take N-CS-
RAFT is dissolved in solvent, and initiator azodiisobutyronitrile AIBN and two polyethylene glycol monomethyl ether methyl methacrylates are added
DEGMA, stirs in 40 DEG C of oil baths, precipitates, and filtering is dried to obtain N-CS-g-PDEGMA nano particle；Wherein chitosan, DEGMA
Mass ratio be 1:0.1.
Further specifically: CS-g-PDEGMA nano particle the preparation method comprises the following steps: take 5g chitosan, a certain concentration is added
Acetum, at room temperature magnetic force for 24 hours, then be added 250mL absolute ethyl alcohol and stirring to clarify, add 0.5mL acetic anhydride,
A period of time is stirred at room temperature, 10%NaOH is added to get the chitosan (N-CS) of acetylation is arrived；N-CS 0.292g is taken to be dissolved in
Chain-transferring agent DDACT (0.37g) is slowly added thereto by 30mL DMF, in the presence of DCC (0.205g) and DMAP (0.015g)
It is stirred at room temperature 40 hours, dialysis is dried to obtain N-CS-RAFT；It takes 0.0468g N-CS-RAFT to be dissolved in 5mL DMF, is added
The DEGMA of the AIBN and 0.50g of 0.0016g, stir in 40 DEG C of oil baths, precipitate, and filtering is dried to obtain N-CS-g-PDEGMA and receives
Rice grain.
The concentration of chitosan graft polymer CS-g-PDEGMA solution is 0.5mg/ml~1mg/ml in the step (1),
Solution solvent is dimethylformamide DMF.
Hyaluronic acid HA solution in the step (1) specifically: HA is dissolved in solvent, 40 DEG C of heating water baths make it completely
Magnetic agitation 4h under EDC the and NHS ice bath that mass ratio is 2:1 is added in dissolution after cooling, wherein HA and EDC, NHS mass ratio are
2:2:1.
The solvent is dry formamide.
Stirring in the step (1) specifically: magnetic agitation first stirs 4-5h under 40 DEG C of nitrogen atmospheres, then with room
Continue stirring under temperature for 24 hours.
It is further preferred: magnetic agitation, first 5h is stirred under 40 DEG C of nitrogen atmospheres, then with continue at room temperature stirring for 24 hours.
Dialysis uses the bag filter of MWCO=3500 in the step (1).
The solvent of drug solution is dehydrated alcohol in the step (2).
In the step (2) in HA-CS-g-PDEGMA aqueous solution: the ratio of HA-CS-g-PDEGMA nano particle and water
For 0.5mg:1mL~20mg:1mL.
It is for 24 hours that the time is stirred to react in the step (2).
The revolving speed of the HA-CS-g-PDEGMA aqueous solution stirred in the step (2) is 300rmp, is stirred to react stirring for 24 hours
Mixing speed is 200rmp.
Sublimation drying is 2~4 days in the step (1), (2).
A kind of application of chitosan graft polymer medicine-carrying nanoparticles of the present invention.
Beneficial effect
(1) present invention passes through chitosan and two kinds of PDEGMA using the physisorption between chitosan and taxol
The characteristics of material itself, is self-assembled into nano particle, which can load a large amount of dewatering medicaments, and synthesis contains taxol
Breast cancer targeting the polymer drug-carried composite material of chitosan graft, this preparation method is easy to operate, experiment condition is easily-controllable
System；Obtained drug-loading nanoparticles can long-acting slow-release, and there is pH and responsive to temperature type to convey, in lower ph and higher temperatures
Release rate height (referring to Fig. 1) under environment is spent, existing nano particle some is only capable of the pH of response tumor microenvironment, changes to temperature
It is less obvious to become response, and nano particle of the invention can be more suitable for the microenvironment of tumor tissues to temperature and pH double-response；
(2) size of nano particle HA-CS-g-PDEGMA prepared by the present invention is averaged 180nm and existing nano particle phase
It is more more particularly suitable than nano particle size prepared by the present invention, tumour portion can be delivered drugs by EPR effect to the greatest extent
Position；
(3) the polymer drug-carried composite material of chitosan graft of breast cancer prepared by the present invention targeting, can long-acting slow-release,
And there is pH and temperature sensitivity to convey, release rate is high at lower pH and higher temperature value environment, is suitble to the micro- of tumor tissues
Environment has the potentiality that subsequent related experiment analysis is done using it；
(4) it may be implemented to breast cancer cancer cell in the HA in the chitosan graft polymer of breast cancer targeting of the present invention
Active targeting effect, HA can the highly expressed CD44 of target cell surface, and can further study its internal circulation and metabolism distribution.
Detailed description of the invention
Fig. 1 is the drug release profiles of HA-CS-g-PDEGMA/PTX nano particle in the embodiment of the present invention 1；
Fig. 2 is CS-g-PDEGMA nano particle in the embodiment of the present invention 11H NMR spectra；
Fig. 3 is the FT-IR figure of CS-g-PDEGMA nano particle in the embodiment of the present invention 1；Wherein A is CS, N-CS, N-CS-
The FT-IR of RAFT schemes；B is that the FT-IR of PDEGMA, CS-g-PDEGMA scheme；
Fig. 4 is CS-g-PDEGMA nano particle TEM figure in the embodiment of the present invention 1；
Fig. 5 is CS-g-PDEGMA nano particle diameter distribution map in the embodiment of the present invention 1；
Fig. 6 is CS-g-PDEGMA nano particle LCST figure in the embodiment of the present invention 1；
Fig. 7 is that the MTT of 3HA-CS-g-PDEGMA/PTX of embodiment of the present invention nano particle schemes；Wherein A is that control group is normal
Cell；B is cancer cell MDA-MB-231 group；
Fig. 8 is nano particle of embodiment of the present invention 4HA-CS-g-PDEGMA, HA-CS-g-PDEGMA/PTX to MBA-
The laser confocal microscope result of MD-231 and HUVEC cell.
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In addition, it should also be understood that, after reading the content taught by the present invention, those skilled in the art
Member can make various changes or modifications the present invention, and such equivalent forms equally fall within the application the appended claims and limited
Range.
Embodiment 1
(1) CS-g-PDEGMA nano particle the preparation method comprises the following steps: take 5g chitosan, certain density acetum is added,
Magnetic force for 24 hours, is then added the absolute ethyl alcohol and stirring of 250mL to clarifying, adds 0.5mL acetic anhydride, be stirred at room temperature one at room temperature
10%NaOH is added to get the chitosan (N-CS) of acetylation is arrived in the section time；N-CS 0.292g is taken to be dissolved in 30mL DMF, by chain
Transfer agent DDACT (0.37g) is slowly added thereto, and it is small to be stirred at room temperature 40 in the presence of DCC (0.205g) and DMAP (0.015g)
When, dialysis is dried to obtain N-CS-RAFT；Take 0.0468g N-CS-RAFT to be dissolved in 5mL DMF, be added 0.0016g AIBN and
The DEGMA of 0.50g, stirs in 40 DEG C of oil baths, precipitates, and filtering is dried to obtain N-CS-g-PDEGMA nano particle.It will finally obtain
The N-CS-g-PDEGMA nano particle obtained is dissolved in 10% acetum, and N- acetyl group is removed in hydrolysis for 24 hours for stirring, is freeze-dried
Obtain CS-g-PDEGMA nano particle.
(2) 20mg HA is taken to be dissolved in dry formamide, 50 DEG C of heating water baths make it completely dissolved, and add after being cooled to room temperature
Enter magnetic agitation under 20mg EDC and 10mg NHS ice bath；It takes 20mg CS-g-PDEGMA to be dissolved in DMF, is slowly added to after dissolution
Into HA mixed solution, after being stirred to react 5h under 40 DEG C of nitrogen atmosphere protections, reaction is stirred at room temperature for 24 hours, obtains HA- after dialysis is dry
CS-g-PDEGMA。
(3) it takes 20mg HA-CS-g-PDEGMA to be dissolved in 10mL ultrapure water, 4mg PTX is taken to be dissolved in 10mL ethyl alcohol,
The PTX of dissolution is slowly dropped into the HA-CS-g-PDEGMA solution being completely dissolved quickly stirred, reacts use afterwards for 24 hours at room temperature
3500DaMw bag filter dialyses 72h at room temperature to remove small molecule.It is cold after solution after dialysis is centrifuged 30 minutes (6000rpm)
It is lyophilized dry to get to HA-CS-g-PDEGMA/PTX nano particle.
The Zeta potential of CS, CS-RAFT, CS-g-DEGMA, HA-CS-g-PDEGMA, HA-CS-g-PDEGMA/PTX, such as
Shown in table 1.
Table 1:
| Compound | CS | CS-RAFT | CS-g-PDEGMA | HA-CS-g-PDEGMA/PTX |
| Zeta potential (mv) | 32±2.0 | 20.7±1.5 | -18.5±1.5 | -15.5±1.5 |
Table 1 shows that the potential of nano particle is gradually reduced, and relatively stable.Transmission electron microscope and DLS show the several of synthesis
The partial size of nano particle is both less than 180nm, relatively stable, can be good at the EPR effect for playing neoplasm targeted therapy, is suitble to body
Internal jugular vein injection；And HA-CS-g-PDEGMA/PTX carries medicine particle carrying drug ratio with higher (12.1%) and encapsulation rate
(73%) Fig. 2 and Fig. 3 shows the successful preparation of CS-g-PDEGMA.
Fig. 4 and Fig. 5 show: HA-CS-g-PDEGMA drug-loading nanoparticles have unified spherical morphology, favorable dispersibility,
There is fuzzy coronal edge outside the hydrophobic core of solid, is the hydrophobic centers that PDEGMA is formed.And HA-CS-g- shown in TEM
The partial size of PDEGMA nano particle is slightly less than the value that DLS is measured, and is made because TEM detection sample can be dehydrated during the preparation process
Partial size reduces.
Fig. 6 is the different light absorption values of CS-g-PDEGMA variation with temperature, it can be seen that graft copolymer CS-g-
Apparent temperature sensitive phase transformation has occurred at 27~37 DEG C by PDEGMA, and LCST is about 32 DEG C, this demonstrate that the polymer of preparation has
Good temperature sensitivity energy, has temperature-responsive.
Embodiment 2
Drug-loading nanoparticles 5mg after taking freeze-drying takes it respectively after completely dissolution in 1ml PBS buffer solution
50 μ L are placed in two microdialysis pipes, are suspended in centrifuge tube, and the phosphoric acid of pH 7.4 and pH 5.0 are added in centrifuge tube
Salt buffer 20mL is respectively placed in 37 DEG C of water bath chaders, and frequency of oscillation is 100 times/min, timing sampling 1mL；Or
It takes 50 μ L to be placed in two microdialysis pipes respectively, is suspended in centrifuge tube, the phosphate of pH 7.4 is added in centrifuge tube
Buffer is placed it in respectively in 25 DEG C or 37 DEG C of water bath chaders, and frequency of oscillation is 100 times/min, and timing sampling 1mL takes
It is supplemented fresh phosphate buffer 1mL afterwards.The sample of taking-up is centrifuged in supercentrifuge, revolving speed 10000r/min, and 30
Minute.HPLC method measures the content of taxol in supernatant.Drug release situation is calculated after arranging data.
Different pH (pH5.0 and pH7.4) and different temperatures (25 DEG C and 37 DEG C), research vitro variation is respectively set
Influence to taxol release.As shown in Figure 1, drug release is slow when pH7.4 under the conditions of 25 DEG C under condition of different temperatures
Slowly, maximum release rate is 38.4%, and in pH5.0, drug releasing rate is slightly accelerated, and maximum release rate is 47.6%；In temperature
Under the conditions of 37 DEG C, when PH is 7.4, maximum release rate is 58.8%, and is accelerated rapidly in pH5.0 rate of release, is tired out in 48 hours
Product release up to 70.1%.The temperature of the ratio normal tissue of tumor environment is about 0.5 DEG C high, and pH is also lower than normal tissue, institute
Prove that CS-g-PDEGMA nano medicament carrying system can respond tumor microenvironment well by above drug release data.
Embodiment 3
It is planted in 96 orifice plates into HUVEC and MDA-MB-231 cell, the number of cells in every hole is about 10000, every hole
The full culture medium of DMEM for supplying 200 μ L, in 37 DEG C and 5%CO2It is cultivated for 24 hours in constant incubator.Remove old culture medium later,
After being cleaned with PBS buffer solution every hole be added 20 μ L contain various concentration dissolved with PTX, HA-CS-g-PDEGMA and HA-CS-g-
The PBS solution of PDEGMA/PTX, and 180 μ L fresh cultures are supplied, continue to be put into addition 20 after constant incubator culture for 24 hours
The MTT solution of the 5mg/ml of μ L is incubated for 4h in the incubator, removes culture solution in hole, and add 200 μ L DMSO, sets on shaking table
It is protected from light low-speed oscillation 15-20min, uses the ultraviolet absorption value in each hole at enzyme-linked immunosorbent assay instrument detection 490nm.Each group drug
Cell MTT experiment result is not as shown in fig. 7, it may be seen that no matter HA-CS-g-PDEGMA carries the nano particle of medicine to normal
Cell or cancer cell are all almost without toxicity, it was demonstrated that the safety of this material is very high；Simple taxol to two kinds of cells all
There is biggish toxicity；HA-CS-g-PDEGMA/PTX is far longer than to normal cell the killing ability of cancer cell, and is testing
Within the scope of drug concentration, the bigger effect of drug concentration is more obvious.
Embodiment 4
It is put into 18mm coverslip in 24 porocyte culture plates, is planted respectively into HUVEC and MBA-MD-231 cell, every hole is thin
Born of the same parents' density is about~1.0 × 104It is a, and the culture solution of every hole 2mL is supplied, in 5%CO2, under conditions of 37 DEG C in incubator
Culture is for 24 hours.Old culture medium is outwelled, the HA-CS-g-PDEGMA/PTX drug-loading nanoparticles containing the FITC PTX being marked are added
200 μ L of PBS solution, and supply the fresh culture of 1.5mL, be incubated for 3h.The culture solution containing material is sucked, and is rinsed with PBS,
The fixed 15min of glutaraldehyde of 1ml 2.5% is added.Glutaraldehyde is sucked, and is rinsed with PBS, 1ml DAPI is added and dyes 15min.
DAPI is sucked, and is rinsed with PBS, coverslip is taken out, fluorescence sealer is dripped, is placed on glass slide, carries out laser copolymerization
Focusing microscope detection.
Cell fluorescence after CS-g-PDEGMA/PTX drug-loading nanoparticles hyaluronic acid decorated and being not decorated are incubated for is aobvious
Micro mirror image result is shown as shown in figure 8, two kinds of nano particles are in the nucleus of control group HUVEC cell, is showed no obvious
Fluorescence, but occur fluorescence around nucleus.On the other hand, the CS-g-PDEGMA/PTX that hyaluronic acid is not decorated carries medicine
Nano particle shows faint green fluorescence intensity in the nucleus of MDA-MB-231 breast cancer cell, and hyaluronic acid is repaired
The CS-g-PDEGMA/PTX drug-loading nanoparticles of decorations show strong glimmering in the nucleus of MDA-MB-231 breast cancer cell
Luminous intensity.Illustrate the modification of hyaluronic acid so that drug-loading nanoparticles more easily enter breast cancer cell.
The preparation method of HA-CS-g-PDEGMA/PTX drug-loading nanoparticles:
It takes 20mg HA-CS-g-PDEGMA to be dissolved in 10mL ultrapure water, 4mg PTX is taken to be dissolved in 10mL ethyl alcohol, it will
The PTX of dissolution is slowly dropped into the atwirl HA-CS-g-PDEGMA solution being completely dissolved, after reacting 24~48h at room temperature
Dialyse 72h at room temperature with 3500DaMw bag filter to remove small molecule.By the solution after dialysis be centrifuged 30 minutes (6000rpm) with
It is freeze-dried after removing non-encapsulated PTX to get HA-CS-g-PDEGMA/PTX nano particle is arrived.
Claims (10)
1. a kind of chitosan graft polymer medicine-carrying nanoparticles, which is characterized in that the nano particle is hyaluronic acid decorated
Chitosan graft poly- two (ethylene glycol) methyl ether methyl methacrylate PDEGMA.
2. nano particle according to claim 1, which is characterized in that the load medicine of the nano particle is taxol PTX.
3. a kind of preparation method of the chitosan graft polymer medicine-carrying nanoparticles as described in claim 1-2 is any, step
Include:
(1) chitosan graft polymer CS-g-PDEGMA solution is added in hyaluronic acid HA solution, is stirred, dialysis, freezing is done
It is dry, obtain hyaluronic acid decorated chitosan graft polymer nano granules HA-CS-g-PDEGMA；Wherein HA and CS-g-
The mass ratio of PDEGMA is 1:2~10；
(2) drug solution is added dropwise in the HA-CS-g-PDEGMA aqueous solution quickly stirred, is stirred to react for 24 hours, dialysis purification
After be freeze-dried to get；Wherein the mass ratio of HA-CS-g-PDEGMA nano particle and drug is 1:0.05~1:0.1.
4. preparation method according to claim 3, which is characterized in that chitosan graft polymer CS-g- in the step (1)
The concentration of PDEGMA solution is 0.5mg/ml~1mg/ml, and solution solvent is dimethylformamide DMF.
5. preparation method according to claim 3, which is characterized in that hyaluronic acid HA solution in the step (1) specifically:
HA is dissolved in solvent, 40 DEG C of heating water baths make it completely dissolved, and are added under EDC the and NHS ice bath that mass ratio is 2:1 after cooling
Magnetic agitation 4h, wherein HA and EDC, NHS mass ratio are 2:2:1.
6. preparation method according to claim 5, which is characterized in that the solvent is dry formamide.
7. preparation method according to claim 3, which is characterized in that stirring in the step (1) specifically: magnetic agitation,
First 4-5h is stirred under 40 DEG C of nitrogen atmospheres, then with continue at room temperature stirring for 24 hours.
8. preparation method according to claim 3, which is characterized in that the solvent of drug solution is anhydrous in the step (2)
Ethyl alcohol.
9. preparation method according to claim 3, which is characterized in that HA-CS-g-PDEGMA aqueous solution in the step (2)
In: the ratio of HA-CS-g-PDEGMA nano particle and water is 0.5mg:1mL~20mg:1mL.
10. a kind of application of chitosan graft polymer medicine-carrying nanoparticles.
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| CN113943382A (en) * | 2020-07-16 | 2022-01-18 | 孛朗孚(杭州)生物科技有限公司 | Acrylate modified hyaluronic acid (sodium) and synthesis method and application thereof |
| CN114558176A (en) * | 2022-03-23 | 2022-05-31 | 中国科学院兰州化学物理研究所 | Chitosan-chondroitin sulfate nanoparticle and drug-loaded joint lubricant |
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| CN110859782A (en) * | 2019-12-30 | 2020-03-06 | 杜立波 | Multifunctional transdermal absorption enhancer and preparation method and application thereof |
| CN110897930A (en) * | 2019-12-30 | 2020-03-24 | 霖汐(北京)生物科技有限公司 | Anti-aging skin care product and preparation method thereof |
| CN113943382A (en) * | 2020-07-16 | 2022-01-18 | 孛朗孚(杭州)生物科技有限公司 | Acrylate modified hyaluronic acid (sodium) and synthesis method and application thereof |
| CN113943382B (en) * | 2020-07-16 | 2023-03-10 | 孛朗孚(杭州)生物科技有限公司 | Acrylate modified hyaluronic acid (sodium) and synthesis method and application thereof |
| CN114558176A (en) * | 2022-03-23 | 2022-05-31 | 中国科学院兰州化学物理研究所 | Chitosan-chondroitin sulfate nanoparticle and drug-loaded joint lubricant |
| CN114558176B (en) * | 2022-03-23 | 2023-01-31 | 中国科学院兰州化学物理研究所 | Chitosan-chondroitin sulfate nanoparticle and drug-loaded joint lubricant |
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