CN104610497A - Core-shell structured bioadhesive polymer nanoparticle, and preparation method and application thereof - Google Patents
Core-shell structured bioadhesive polymer nanoparticle, and preparation method and application thereof Download PDFInfo
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- 239000002105 nanoparticle Substances 0.000 title claims abstract description 56
- 229920000642 polymer Polymers 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000000227 bioadhesive Substances 0.000 title abstract description 11
- 239000011258 core-shell material Substances 0.000 title abstract 2
- 239000000178 monomer Substances 0.000 claims abstract description 12
- 229910052709 silver Inorganic materials 0.000 claims abstract description 9
- 239000004332 silver Substances 0.000 claims abstract description 9
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims abstract 6
- 239000003814 drug Substances 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 14
- 210000001215 vagina Anatomy 0.000 claims description 12
- QWMJEUJXWVZSAG-UHFFFAOYSA-N (4-ethenylphenyl)boronic acid Chemical compound OB(O)C1=CC=C(C=C)C=C1 QWMJEUJXWVZSAG-UHFFFAOYSA-N 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 229940079593 drug Drugs 0.000 claims description 11
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- 238000006116 polymerization reaction Methods 0.000 claims description 6
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- 241000283973 Oryctolagus cuniculus Species 0.000 claims description 5
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 5
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- STVZJERGLQHEKB-UHFFFAOYSA-N ethylene glycol dimethacrylate Substances CC(=C)C(=O)OCCOC(=O)C(C)=C STVZJERGLQHEKB-UHFFFAOYSA-N 0.000 claims description 5
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
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- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000003999 initiator Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- ZIUHHBKFKCYYJD-UHFFFAOYSA-N n,n'-methylenebisacrylamide Chemical compound C=CC(=O)NCNC(=O)C=C ZIUHHBKFKCYYJD-UHFFFAOYSA-N 0.000 claims description 4
- 108090000623 proteins and genes Proteins 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
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- 125000005619 boric acid group Chemical group 0.000 claims description 3
- 102000004169 proteins and genes Human genes 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 238000001179 sorption measurement Methods 0.000 claims description 3
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims description 3
- 229940038773 trisodium citrate Drugs 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- LXEKPEMOWBOYRF-UHFFFAOYSA-N [2-[(1-azaniumyl-1-imino-2-methylpropan-2-yl)diazenyl]-2-methylpropanimidoyl]azanium;dichloride Chemical compound Cl.Cl.NC(=N)C(C)(C)N=NC(C)(C)C(N)=N LXEKPEMOWBOYRF-UHFFFAOYSA-N 0.000 claims description 2
- 238000005119 centrifugation Methods 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
- 230000004931 aggregating effect Effects 0.000 claims 1
- 230000014759 maintenance of location Effects 0.000 abstract description 4
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 abstract 1
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- 108010093825 Mucoproteins Proteins 0.000 abstract 1
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- 108010028349 saliva Orthana Proteins 0.000 description 13
- 239000002245 particle Substances 0.000 description 8
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 7
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- 210000004400 mucous membrane Anatomy 0.000 description 3
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- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
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- ABEXEQSGABRUHS-UHFFFAOYSA-N 16-methylheptadecyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C ABEXEQSGABRUHS-UHFFFAOYSA-N 0.000 description 1
- 206010059313 Anogenital warts Diseases 0.000 description 1
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- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
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- 208000036142 Viral infection Diseases 0.000 description 1
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- LPQOADBMXVRBNX-UHFFFAOYSA-N ac1ldcw0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 description 1
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- UWNADWZGEHDQAB-UHFFFAOYSA-N i-Pr2C2H4i-Pr2 Natural products CC(C)CCC(C)C UWNADWZGEHDQAB-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention belongs to the field of medicinal preparations, and relates to a core-shell structured bioadhesive polymer nanoparticle for vaginal administration, and a preparation method and an application thereof. The polymer nanoparticle adopts a silver nanoparticle as a core, and is prepared through copolymerizing an acrylamide cross-linking agent and a mono-olefin phenyl boric acid function monomer on the surface of the silver nanoparticle to form a shell. The polymer nanoparticle has good affinity to mucoproteins, has a long in-vivo retention time after mucosal administration, and has good practical values and application prospect in the vaginal administration field.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of nucleocapsid structure bioadhesive polymers nanoparticle and preparation method thereof and the application in vagina administration.
Background technology
Prior art discloses when the mucosal drug delivery at the positions such as vagina, Bioadhesive drug delivery system can realize persistence that preparation contacts with mucous membrane and compactness, the medicine of constantly release from drug delivery system or higher concentration can maintained in local, long-time onset, or the sustainable body that is constantly absorbed into circulates, and plays general action.Research display, for vagina administration, the bioadhesive nanoparticle foreign sense of particle diameter between 100 ~ 500nm, is easy to distribution, and mucus penetrativity is comparatively strong, is one of ideal form of medication.
Research display, Saliva Orthana is the most important adhesion object of Bioadhesive drug delivery system.Saliva Orthana is the glycoprotein that a class is extensively present in human body mucomembranous surface, and wherein secretor type Saliva Orthana constitutes the main component of mucus, and film mating type Saliva Orthana is then distributed in mucomembranous epithelial cell surface.In bioadhesive material disclosed in prior art, the synthesis such as carbopol class, chitosan class or natural macromolecular material rely on the strategies such as self long-chain and entwining of Saliva Orthana long-chain reach adhesion object, and sulfhydrylation is modified, Phytoagglutinin modified be then dependence sulfydryl and Saliva Orthana possible be cross-linked or lectin strengthens drug delivery system and mucinous interaction to mucinous natural avidity.
Prior art also discloses boric acid can with 1,2-dihydroxy compound or 1,3-dihydroxy compound reversibly covalent attachment in aqueous, form five yuan or six-membered cyclic ester, therefore boric acid base group can interact with the cis o-dihydroxy in sugared ring structure.Which constitute the unique advantage of boric acid functionalization material in the smart material for sugar designs.Utilize the analysis that the o-dihydroxy on monose (as glucose) and sugar chain and the reversible action between material surface boric acid base group can realize glycoprotein, separation and enrichment are (as JP3252555A, CN103304732, CN100506982, CN102962471), the bag of gene carries and sends (as CN101597349), glucose responding type drug delivery (CN102068700, CN102391504, CN102294212, CN102070756) with for the molecular imprinting (CN102516458) etc. of glycoprotein.
Up to now, the relevant report for the mucinous boric acid base group functionalization material/delivery system on slime layer and mucous membrane has, the contact lense (CN101312754) of tool Saliva Orthana avidity; A kind of year ciclosporin A eye nanoparticle (Shengyan Liu, Lyndon Jones, Frank X Gu, Macromol Biosci.2012Dec; 12 (12): 1622-6); But wherein said boric acid functionalization bioadhesive nanoparticle exist as follows: particle diameter (<50nm) less than normal, have difficulties effectively penetrating in mucus, be difficult to arrive mucous membrane, and relate to the synthesis of boric acid functionalized macromolecular in preparation, the defects such as technique is loaded down with trivial details.
Summary of the invention
The object of the invention is for the deficiencies in the prior art, provide a kind of and prepare easy, that particle diameter is applicable nucleocapsid structure polymer nano-particle.Especially a kind of nucleocapsid structure bioadhesive polymers nanoparticle and its preparation method and application.
For achieving the above object, the technical solution used in the present invention is:
Thering is provided a kind of is core with nano grain of silver, in the poly-4-vinylphenylboronic acid of galactic nucleus surface parcel, form the nucleocapsid structure polymer nano-particle with boric acid functional group, it is characterized in that: particle diameter is at about 100nm, the polydispersity coefficient of granularity is not more than 0.15, so-called " polydispersity coefficient " is the particle polymolecularity parameter that dynamic Laser scattering particle size analyzer provides, and polydispersity coefficient is less, illustrates that particle diameter distribution is more even.
In the present invention, first prepare nano grain of silver as galactic nucleus using sodium borohydride reduction, further with 4-vinylphenylboronic acid for function monomer, with N, N '-methylene-bisacrylamide and/or Ethylene glycol dimethacrylate are linking agent, shell is become, obtained a kind of polymer nano-particle with nucleocapsid structure at galactic nucleus surface aggregate.
The invention provides the method preparing nucleocapsid structure polymer nano-particle, its concrete steps are as follows:
1) galactic nucleus is formed: in the mixed aqueous solution of Silver Nitrate and Trisodium Citrate, add sodium borohydride, the obtained galactic nucleus of reaction under room temperature;
2) polymerization parcel: add sodium lauryl sulphate as stablizer in gained galactic nucleus, 4-vinylphenylboronic acid function monomer and N is added in galactic nucleus solution system, N '-linking agent such as methylene-bisacrylamide and/or Ethylene glycol dimethacrylate, initiator initiated polymerization, reacts 3-8 hour at 60-80 DEG C;
3) separation and purification: the polymer nano-particle pure water of the nucleocapsid structure obtained is dialysed more than 72 hours, centrifugation precipitates, and vacuum-drying or lyophilize are to constant weight.
In described step 1), silver nitrate concentration is 0.01 ~ 1mM, and sodium citrate concentration is 0.01 ~ 1mM, and the volume adding sodium borohydride solution (5 ~ 15mM) is 1/100 ~ 1/50 of Silver Nitrate-Trisodium Citrate mixed liquor volume;
Described step 2) in, sodium lauryl sulphate concentration for stable nano grain of silver is 0.1 ~ 1%, the mol ratio of 4-vinylphenylboronic acid function monomer and linking agent is 2.5 ~ 10:1, monomer and linking agent total mol concentration are 50 ~ 100mM, initiator is: 2,2 '-azo diisobutyl amidine dihydrochloride, add-on accounts for (function monomer+linking agent) 1 ~ 3% of total mole number.
The present invention is obtained that nucleocapsid structure polymer nano-particle carries protein and peptide drugs (such as Interferon, rabbit etc.), for vagina administration by the method bag of physical adsorption.Such as wrap the treatment that the nanoparticle vagina administration having carried Interferon, rabbit can be used for vagina disease of viral infection, as pointed condyloma, cervical erosion etc.
The present invention has the following advantages:
1) nucleocapsid structure polymer nanoparticle size of the present invention is at about 100nm, and narrow distribution, have good wetting ability, and raw material is commercial reagents, economical and convenient.
2) the poly-4-vinylphenylboronic acid case surface formed on galactic nucleus surface has a large amount of phenylo boric acid groups, have avidity to Saliva Orthana, bioadhesive is remarkable, can be trapped in local after vagina administration for a long time, play effect that is long-acting, slowly-releasing, be applicable to vagina administration.
3) anti-inflammatory, the sterilization effect that have of nanometer silver itself, as the core of vagina administration nanoparticle, is expected to together with contained medicine, plays collaborative anti-infectious effect.
4) nucleocapsid structure polymer nanoparticle of the present invention can the polypeptide drugs such as physical adsorption Interferon, rabbit, for polypeptide drugs mucosal drug delivery provides a kind of new carrier format.
Accompanying drawing explanation
Fig. 1 is form and the grain size distribution of nucleocapsid structure polymer nanoparticle, wherein,
Zuo Tu: TEM photo, right figure: DLS grain-size graph.
Fig. 2 be nucleocapsid structure polymer nanoparticle under different pH to mucinous adsorptive capacity (n=3, mean ± SD).
Fig. 3 is the local retention of nucleocapsid structure polymer nanoparticle after mouse vagina administration (n=5, mean ± SD) over time.
Fig. 4 is nucleocapsid structure polymer nanoparticle adsorptive power (n=3, mean ± SD) to IFN under different pH.
Embodiment
Specific embodiment is adopted to be described further technical scheme of the present invention below.
Embodiment 1
1, nucleocapsid structure polymer nano-particle is prepared
1) form galactic nucleus: in the mixed aqueous solution of 200mL Silver Nitrate (0.1mM) and Trisodium Citrate (0.1mM), dropwise add sodium borohydride aqueous solution (10mM) 2.5mL under agitation, under room temperature, reaction obtains galactic nucleus;
2) polymerization parcel: add sodium lauryl sulphate as stablizer in gained galactic nucleus, concentration is 0.5%(w/w).In 100mL galactic nucleus solution, add 4-vinylphenylboronic acid (1.00g), '-methylene-bisacrylamide linking agent (2mg) and Ethylene glycol dimethacrylate (40 μ L), pass into N2 and remove the O that may dissolve in the solution for N, N
2, add 1mL0.1M2,2'-azo diisobutyl amidine dihydrochloride initiated polymerization, react 5 hours at 70 DEG C;
3) separation and purification: 2), gained reaction solution pure water is dialysed and removed unreacted monomer and oligopolymer in 72 hours, the centrifugal 10min of 8000rpm, precipitation separation, and vacuum-drying, to constant weight, obtains nucleocapsid structure polymer nano-particle.
2, nucleocapsid structure polymer nano-particle is characterized
1) Morphological Characterization
Nanoparticle carries out transmission electron microscope (JEOL2100F Flied emission projection electron microscope) to be observed, and as shown in Fig. 1 (after phospho-wolframic acid negative staining), particle diameter is at about 100nm, and size is more even.
2) Saliva Orthana absorption property
By nanoparticle dispersion liquid, (every ml is containing 10mg nanoparticle, be called for short NP) or pure water (be called for short w) with Saliva Orthana solution (containing 10mM citric acid/sodium citrate or Tris-HCl buffering salt, pH is respectively 4,5,6 or 7, Saliva Orthana concentration 0.5mg/mL) with volume ratio 1:10 mixing, left at room temperature over night, with Saliva Orthana concentration in BCA kit measurement supernatant liquor after centrifugal, calculate drug loading as follows.What the C wherein in formula referred to is all mucinous concentration.
Result shows, and nanoparticle of the present invention has stronger adsorptivity (as shown in Figure 2) to Saliva Orthana, and this absorption property shows certain dependency to pH, and lower pH is conducive to absorption.
3) be detained at body intravaginal
In the 2nd step of preparation, 1mg/mL fluorescent probe (IR783) is added in reaction system, obtain fluorescently-labeled nanoparticle, fluorescently-labeled nanoparticle is dispersed in physiological saline according to the concentration of 10mg/mL, on ICR female mice, vagina administration is carried out with blunt needle tube, every mouse gives 10 μ L nanoparticle dispersion liquids, establish solution control group simultaneously, namely same vagina gives 10 μ LIR783 normal saline solutions (concentration 10 μ g/mL, its fluorescence intensity and nanoparticle dispersion liquid close), detect the change of administration local (abdomen and perineum) fluorescent signal at body fluoroscopic imaging systems with ISIS, measure the fluorescence intensity of administration local, after every animals administer, the fluorescence intensity of the gained of imaging is at once as 100%, result is normalized, administration 1 is represented as " local retention amount % ", 2, relative intensity of fluorescence after 3 days, nanoparticle group and each 5 animals of solution control group in the present embodiment, experimental result shows, and compared with solution control group, the local retention of nanoparticle group significantly improves (as shown in Figure 3).
The medicine carrying of embodiment 2 nucleocapsid structure polymer nano-particle
The present embodiment with recombinant human alpha-interferon for model drug, be dissolved in pH be respectively 4,5,6 10mM citric acid/sodium citrate and pH be in the Tris-HCl buffered soln of 7,8,9 respectively, make its concentration be 0.8mg/mL.Above-mentioned 6 kinds of interferon solutions are mixed with volume ratio 1:1, left at room temperature over night with nanoparticle dispersion liquid (every ml is containing 10mg nanoparticle), with Interferon, rabbit concentration in BCA kit measurement supernatant liquor after centrifugal, calculates drug loading as follows.
Result shows, and in the scope of pH4 ~ 9, lower pH have profit (as shown in Figure 4) to nanoparticle adsorptive hindrance, and in the scope of pH4 ~ 6, nanoparticle can adsorptive hindrance be plain effectively.
Claims (7)
1. a nucleocapsid structure polymer nano-particle, it is characterized in that: take nano grain of silver as core, the poly-4-vinylphenylboronic acid shell of galactic nucleus surface parcel, form the nucleocapsid structure polymer nano-particle with boric acid functional group, described nano particle diameter is at 100nm, and the polydispersity coefficient of granularity is not more than 0.15.
2. according to nucleocapsid structure polymer nano-particle according to claim 1, it is characterized in that: described nano grain of silver core is that 20 ~ 30nm, 4-vinylphenylboronic acid accounts for 28 ~ 91%(molar percentage in polymer shell).
3. the preparation method of a nucleocapsid structure polymer nano-particle according to claim 1, it is characterized in that, first prepare nano grain of silver as galactic nucleus using sodium borohydride reduction, further with 4-vinylphenylboronic acid for function monomer, with N, N '-methylene-bisacrylamide and/or Ethylene glycol dimethacrylate be linking agent, becomes shell at galactic nucleus surface aggregate, obtained a kind of polymer nano-particle with nucleocapsid structure, it comprises step:
1) galactic nucleus is formed: in the mixed aqueous solution of Silver Nitrate and Trisodium Citrate, add sodium borohydride, the obtained galactic nucleus of reaction under room temperature;
2) polymerization parcel: add sodium lauryl sulphate as stablizer in gained galactic nucleus, 4-vinylphenylboronic acid function monomer and N is added in galactic nucleus solution system, N '-linking agent such as methylene-bisacrylamide and/or Ethylene glycol dimethacrylate, initiator initiated polymerization, reacts 3-8 hour at 60-80 DEG C;
3) separation and purification: the polymer nano-particle pure water of the nucleocapsid structure obtained is dialysed more than 72 hours, centrifugation precipitates, and vacuum-drying or lyophilize are to constant weight.
4., according to the preparation method of nucleocapsid structure polymer nano-particle described in claim 3, it is characterized in that:
Form galactic nucleus period, silver nitrate concentration is 0.01 ~ 1mM, and sodium citrate concentration is 0.01 ~ 1mM, and the volume adding 5 ~ 15mM sodium borohydride solution is 1/100 ~ 1/50 of Silver Nitrate-Trisodium Citrate mixed liquor volume;
During aggregating into shell, sodium lauryl sulphate concentration for stable nano grain of silver is 0.1 ~ 1%, the mol ratio of 4-vinylphenylboronic acid function monomer and linking agent is 2.5 ~ 10:1, monomer and linking agent total mol concentration are 50 ~ 100mM, initiator is: 2,2'-azo diisobutyl amidine dihydrochloride, add-on accounts for 1 ~ 3% of the total mole number of function monomer and linking agent.
5. according to nucleocapsid structure polymer nano-particle according to claim 1, it is characterized in that: described nucleocapsid structure polymer nano-particle carries protein and peptide drugs by the method bag of physical adsorption.
6., by nucleocapsid structure polymer nano-particle according to claim 5, it is characterized in that: described protein and peptide drugs is Interferon, rabbit.
7. nucleocapsid structure polymer nano-particle according to claim 1 is for the preparation of the purposes in vagina administration preparation.
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| CN108543429A (en) * | 2018-05-08 | 2018-09-18 | 天津工业大学 | Anti-pollution antibacterial polyamide nano composite membrane and preparation method thereof |
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| CN108543429B (en) * | 2018-05-08 | 2019-08-30 | 天津工业大学 | Anti-pollution antibacterial polyamide nano composite membrane and preparation method thereof |
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