CN106176768A - A kind of preparation method and application of magnetic Nano antibacterial - Google Patents
A kind of preparation method and application of magnetic Nano antibacterial Download PDFInfo
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- CN106176768A CN106176768A CN201610573186.9A CN201610573186A CN106176768A CN 106176768 A CN106176768 A CN 106176768A CN 201610573186 A CN201610573186 A CN 201610573186A CN 106176768 A CN106176768 A CN 106176768A
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- magnetic nano
- mnps
- chenodeoxycholic acid
- cdca
- nano antibacterial
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- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims description 15
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 claims abstract description 39
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 claims abstract description 39
- 229960001091 chenodeoxycholic acid Drugs 0.000 claims abstract description 39
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000003814 drug Substances 0.000 claims abstract description 22
- 230000003115 biocidal effect Effects 0.000 claims abstract description 20
- 229940072172 tetracycline antibiotic Drugs 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- OGQYJDHTHFAPRN-UHFFFAOYSA-N 2-fluoro-6-(trifluoromethyl)benzonitrile Chemical compound FC1=CC=CC(C(F)(F)F)=C1C#N OGQYJDHTHFAPRN-UHFFFAOYSA-N 0.000 claims description 24
- 229960003185 chlortetracycline hydrochloride Drugs 0.000 claims description 24
- 230000032050 esterification Effects 0.000 claims description 20
- 238000005886 esterification reaction Methods 0.000 claims description 20
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 7
- 239000004380 Cholic acid Substances 0.000 claims description 7
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 7
- 229960002471 cholic acid Drugs 0.000 claims description 7
- 235000019416 cholic acid Nutrition 0.000 claims description 7
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- 238000013019 agitation Methods 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000012024 dehydrating agents Substances 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 239000007853 buffer solution Substances 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
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- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 2
- 238000002390 rotary evaporation Methods 0.000 claims description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 2
- SVDOODSCHVSYEK-IFLJXUKPSA-N (4s,4ar,5s,5ar,6s,12ar)-4-(dimethylamino)-1,5,6,10,11,12a-hexahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide;hydron;chloride Chemical compound Cl.C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O SVDOODSCHVSYEK-IFLJXUKPSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 210000000170 cell membrane Anatomy 0.000 abstract description 8
- 230000035699 permeability Effects 0.000 abstract description 8
- 239000002122 magnetic nanoparticle Substances 0.000 abstract description 6
- 238000002411 thermogravimetry Methods 0.000 abstract description 5
- 230000005540 biological transmission Effects 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000002844 chenodeoxycholic acid derivative Substances 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 238000002441 X-ray diffraction Methods 0.000 abstract description 2
- 239000002253 acid Substances 0.000 abstract description 2
- 238000002329 infrared spectrum Methods 0.000 abstract description 2
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 abstract 1
- CYDMQBQPVICBEU-UHFFFAOYSA-N chlorotetracycline Natural products C1=CC(Cl)=C2C(O)(C)C3CC4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-UHFFFAOYSA-N 0.000 description 23
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 241000588724 Escherichia coli Species 0.000 description 3
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 210000000941 bile Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 150000001801 chenodeoxycholic acids Chemical class 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
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- 238000005406 washing Methods 0.000 description 2
- DVWJFTGEISXVSH-CWVFEVJCSA-N (1R,3S,5S,7Z,11R,12S,13Z,15Z,17Z,19Z,21R,23S,24R,25S)-21-[(2R,3S,4S,5S,6R)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-12-ethyl-1,3,5,25-tetrahydroxy-11-methyl-9-oxo-10,27-dioxabicyclo[21.3.1]heptacosa-7,13,15,17,19-pentaene-24-carboxylic acid Chemical compound CC[C@H]1\C=C/C=C\C=C/C=C\[C@@H](C[C@@H]2O[C@@](O)(C[C@H](O)[C@H]2C(O)=O)C[C@@H](O)C[C@@H](O)C\C=C/C(=O)O[C@@H]1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](N)[C@@H]1O DVWJFTGEISXVSH-CWVFEVJCSA-N 0.000 description 1
- WYTZZXDRDKSJID-UHFFFAOYSA-N (3-aminopropyl)triethoxysilane Chemical compound CCO[Si](OCC)(OCC)CCCN WYTZZXDRDKSJID-UHFFFAOYSA-N 0.000 description 1
- 241000272814 Anser sp. Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000004099 Chlortetracycline Substances 0.000 description 1
- 229910017135 Fe—O Inorganic materials 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 239000004100 Oxytetracycline Substances 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 229960004475 chlortetracycline Drugs 0.000 description 1
- CYDMQBQPVICBEU-XRNKAMNCSA-N chlortetracycline Chemical compound C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-XRNKAMNCSA-N 0.000 description 1
- 235000019365 chlortetracycline Nutrition 0.000 description 1
- RPKLZQLYODPWTM-KBMWBBLPSA-N cholanoic acid Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC(O)=O)C)[C@@]1(C)CC2 RPKLZQLYODPWTM-KBMWBBLPSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000005034 decoration Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- LIKBJVNGSGBSGK-UHFFFAOYSA-N iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Fe+3].[Fe+3] LIKBJVNGSGBSGK-UHFFFAOYSA-N 0.000 description 1
- 239000000696 magnetic material Substances 0.000 description 1
- 230000005389 magnetism Effects 0.000 description 1
- 229960000625 oxytetracycline Drugs 0.000 description 1
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 description 1
- 235000019366 oxytetracycline Nutrition 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229910052596 spinel Inorganic materials 0.000 description 1
- 239000011029 spinel Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 229930183279 tetramycin Natural products 0.000 description 1
- 230000010415 tropism Effects 0.000 description 1
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- -1 within 1848 Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/65—Tetracyclines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
The invention provides a kind of novel magnetic Nano antibacterial, this magnetic Nano antibacterial is the Fe modified with chenodeoxycholic acid derivatives3O4Magnetic nano-particle load antibiotic prepares.Infrared spectrum (FTIR), transmission electron microscope (TEM), X x ray diffraction (XRD) and thermogravimetric analysis (TGA) method is used to characterize, it was demonstrated that Fe3O4Chenodeoxycholic acid it has been grafted on magnetic nano-particle.This antibacterial is by the good cell membrane permeability of chenodeoxycholic acid, Fe3O4The magnetic performance of magnetic nano-particle realizes the magnetic targeted transmission of medicine, and combination antibiotic can be as one antibacterial safely and efficiently.Tetracycline antibiotics is by Fe3O4After magnetic Nano complex inclusion, not only increase cell membrane permeability and the bactericidal activity of medicine, and decrease the consumption of antibiotic, curative effect of medication can be played to greatest extent.
Description
Technical field
The present invention relates to antibacterial, be specifically related to a kind of magnetic Nano antibacterial and its preparation method and application.
Background technology
Tetracycline antibiotics, belongs to hydrogenation aphthacene ring derivatives in chemical constitution, has that bactericidal range is relatively wide, price
The advantage such as cheap, is widely used in the disease treatment of humans and animals, makes an addition to for a long time in feedstuff simultaneously as germ killing drugs
With prevention disease and enhancing development.China is production of antibiotics and consumption big country, but the production and use to antibiotic lacks
The management of weary science, the abuse condition of antibiotic is the most serious.Therefore in China's environment, the residual concentration of antibiotic is higher, exists
Serious antibiotic pollution problem.For reducing antibiotic dosage, preventing abuse of antibiotics, we devise one safely and efficiently
Magnetic nano-disinfection agent.
Magnetic Nano material is the most emerging functional type material, Fe3O4Magnetic nano-particle because of its high-specific surface area,
Good biocompatibility, size tunable, easily preparation and under external magnetic field the characteristic such as quick response obtain the special concern of people, extensively
The general fields, the especially application in terms of magnetic targeted administration such as biological medicine, materials chemistry, separation science of being applied to causes and grinds
The persons of studying carefully continue and pay close attention to widely.
Cholic acid is made up of cyclopentanoperhydro-phenanthrene and an aliphatic side chains of a rigidity, is the general name of a big class cholanic acid in bile.Grind
Study carefully surface cholic acid and be combined cell membrane permeability and the drug effect that can improve medicine with medicine.Chenodeoxycholic acid
(Chenodeoxycholicacid is called for short CDCA) is the one of cholic acid, within 1848, extracts first from goose bile and obtains, has
Relieving asthma, reduce phlegm, antitussive and the effect of antiinflammatory.Be connected with two hydroxyls on the cyclopentanoperhydro-phenanthrene of CDCA acid molecule and carboxyl be prone to into
Row chemical modification, and there is preferable cell membrane permeability and higher turn-over capacity, with its derivant with magnetic nanometer by altogether
Carrier is done in valency condensation, gives medicinal inclusion compound cell membrane permeability and magnetic target tropism, it is possible to the efficient sterilizing realizing medicine is lived
Property, reduce antibiotic dosage.
Summary of the invention
It is an object of the invention to provide a kind of efficient magnetic Nano antibacterial and preparation method thereof.This magnetic Nano sterilizes
Agent, has preferable bactericidal activity, can reduce consumption, prevent abuse of antibiotics.
Magnetic Nano antibacterial provided by the present invention, is prepared by a method comprising the following steps and obtains:
(1) preparation of chenodeoxycholic acid it is esterified: be dissolved in formic acid solution by chenodeoxycholic acid, at 50-60 DEG C, machinery
After stirring reaction 5-6 hour, product rotary evaporation removes solvent, and gained solid is crossed post and purified；40-70 DEG C of vacuum drying 12 is little
Time, obtain the esterification chenodeoxycholic acid (CDCA) that formic acid is modified, seal and preserve；
(2) esterification chenodeoxycholic acid/Fe3O4Magnetic Nano complex (CDCA-APTES-Fe3O4MNPs) preparation: will
Esterification chenodeoxycholic acid is dissolved in anhydrous methylene chloride, adds dehydrating agent dicyclohexylcarbodiimide, catalyst 4-diformazan ammonia
Yl pyridines, mechanical agitation 10min, the mol ratio of described esterification chenodeoxycholic acid, dehydrating agent and catalyst is 1: 0.9-1.2:
0.8-1.2；Weigh the Fe having modified amino of esterification chenodeoxycholic acid quality 18-22% simultaneously3O4-MNPs is dissolved in anhydrous dichloro
In dichloromethane, ultrasonic make it dispersed after join in above-mentioned esterification chenodeoxycholic acid mixed solution, room temperature reaction is overnight；
Products therefrom filters, by dichloromethane, more successively with secondary water, saturated sodium bicarbonate, the washing of secondary water；40-70 DEG C true
Empty dry 12 hours, obtain complex CDCA-APTES-Fe3O4-MNPs；
(3) preparation of magnetic Nano antibacterial: by complex CDCA-APTES-Fe3O4It is 10 that-MNPs adds concentration- 2In the phosphate buffer solution of the pH 5-9 of mol/L, ultrasonic mixing, adding concentration is 10-3The tetracycline antibiotics of mol/L
The volume ratio 1: 0.5-3 of medicine, buffer solution and medicine, complex is 2-5: 1 with the mass ratio of medicine；The most ultrasonic
10min, vibrates 3-6 hour；Magnetic hysteresis separates, and is vacuum dried 12 hours, obtains CDCA-APTES-Fe at being deposited in 40-70 DEG C3O4-
MNPs and the clathrate of tetracycline antibiotics, i.e. magnetic Nano antibacterial.
In step (1), described mechanical agitation rotating speed 800r/min；Reaction temperature is at 55 DEG C, and the stirring response time is 5-6
Hour；The developing solvent crossing post purification is ethanol: dichloromethane=2: 98.
In step (2), described amidized Fe3O4The amount of-MNPs is the 20% of esterification cholic acid quality.
In step (1), (2), (3), vacuum drying temperature is preferably 60 DEG C.
In step (3), the preferred tetramycin hydrochloride of described tetracycline antibiotics (OTC) or chlortetracycline hydrochloride (CTC).
Compared with prior art beneficial effects of the present invention:
The present invention is at Fe3O4Be grafted chenodeoxycholic acid on magnetic nano-particle, and with tetracycline antibiotics inclusion, close
Become a kind of novel magnetic nano-disinfection agent.Magnetic Nano antibacterial cell membrane permeability is good, bactericidal activity is high for this, anti-reducing
Give birth to element consumption, prevent antibiotic pollution aspect from having significant application value.Owing to chenodeoxycholic acid is a kind of natural cholic acid, raw material is easy
, good biocompatibility, chemical constitution is prone to modify, and has preferable cell membrane permeability and higher turn-over capacity, with
Its derivant, as carrier, gives the cell membrane permeability that antibacterial is good, improves the bactericidal effect of antibacterial.The present invention is also
Have studied magnetic Nano antibacterial at extracellular releasability by changing the pH value of buffer, and by with simple antibiosis
Element bactericidal activity contrast, has carried out bactericidal activity evaluation to it.It is concluded that: this magnetic Nano antibacterial has higher
Bactericidal activity, can reduce consumption, prevent abuse of antibiotics.
Accompanying drawing explanation
Fig. 1 CDCA-APTES-Fe3O4The separation process of-MNPs.In figure: CDCA-APTES-Fe prepared by (a)3O4-
MNPs disperses in aqueous；(b)CDCA-APTES-Fe3O4-MNPs is separated by Magnet completely.
Fig. 2 APTES-Fe3O4-MNPs (a) and CDCA-APTES-Fe3O4The infrared spectrogram of-MNPs (b).
Fig. 3 APTES-Fe3O4-MNPs (a) and CDCA-APTES-Fe3O4The transmission electron microscope photo of-MNPs (b).
Fig. 4 CDCA-APTES-Fe3O4The x-ray diffraction pattern of-MNPs.
Fig. 5 CDCA-APTES-Fe3O4The hysteresis curve figure of-MNPs.
Fig. 6 APTES-Fe3O4-MNPs (a) and CDCA APTES-Fe3O4The thermogravimetric analysis figure of-MNPs (b).
Fig. 7 pH is to CDCA-APTES-Fe3O4-MNPs and the impact of CTC and OTC load effect, F:CDCA-APTES-
Fe3O4The fluorescence intensity of CTC and OTC, F in supernatant after-MNPs absorption0: the fluorescence intensity of CTC and OTC.
The In-vitro release curves of CTC magnetic Nano antibacterial under Fig. 8 condition of different pH.
The In-vitro release curves of OTC magnetic Nano antibacterial under Fig. 9 condition of different pH.
Figure 10 OTC magnetic Nano antibacterial bactericidal activity design sketch.
Figure 11 CTC magnetic Nano antibacterial bactericidal activity design sketch.
Detailed description of the invention
Embodiment 1: the preparation of magnetic Nano antibacterial
(1) preparation of chenodeoxycholic acid derivatives: weigh 1.0012g chenodeoxycholic acid, is dissolved in 10mL formic acid molten
In liquid；At 55 DEG C, magnetic agitation is after 5 hours, and product removes solvent by Rotary Evaporators, and gained solid is crossed post and purified (expansion
Agent: ethanol: dichloromethane=2: 98).60 DEG C are vacuum dried 12 hours, obtain the esterification chenodeoxycholic acid that formic acid is modified
(CDCA), preservation is sealed.
(2) esterification chenodeoxycholic acid/Fe3O4Magnetic Nano complex (CDCA-APTES-Fe3O4-MNPs) preparation: claim
Take esterification chenodeoxycholic acid 1g to be dissolved in 20mL anhydrous methylene chloride, add dehydrating agent dicyclohexylcarbodiimide 0.58g, urge
Agent DMAP 0.24g, stirs 10min.Weigh the amidized Fe of the modification of 0.2g simultaneously3O4-MNPs is dissolved in
In 20mL anhydrous methylene chloride solution, ultrasonic addition after it is dispersed is esterified in chenodeoxycholic acid mixed solution, and room temperature is anti-
Should be overnight.Products therefrom dichloromethane, more respectively with secondary water, saturated sodium bicarbonate, the washing of secondary water.60 DEG C of vacuum
It is dried 12 hours, obtains CDCA-APTES-Fe3O4-MNPs。
(3) preparation of magnetic Nano antibacterial: weigh 5mg CDCA-APTES-Fe3O4It is 10 that-MNPs adds 2mL concentration- 2In the phosphate buffer solution of the pH=6 of mol/L, ultrasonic mixing, adding 4mL concentration is 10-3The antibiotic OTC of mol/L,
Ultrasonic 10min under room temperature, vibrates 6 hours；Magnetic hysteresis separates, and is deposited at 60 DEG C vacuum drying 12 hours, obtains CDCA-APTES-
Fe3O4The clathrate of-MNPs and antibiotic OTC.
Weigh 5mg CDCA-APTES-Fe3O4It is 10 that-MNPs adds 2mL concentration-2The phosphoric acid buffer of the pH=9 of mol/L is molten
In liquid, ultrasonic mixing, adding 4mL concentration is 10-3The antibiotic CTC of mol/L, the most ultrasonic 10min, vibrate 3 hours；
Magnetic hysteresis separates, and is deposited at 60 DEG C vacuum drying 12 hours, obtains CDCA-APTES-Fe3O4The inclusion of-MNPs and antibiotic CTC
Thing.
Show from Fig. 2 infrared spectrogram: a spectral line 588cm-1The absworption peak at place is Fe3O4The tetrahedral spy of Fe-O in-MNPs
Levy absorption, 3420cm-1Place is Fe3O4The stretching vibration peak of-MNPs surface-OH, 1630cm-1For-NH and-NH2Stretching vibration
Peak.Show: APTES successfully modifies Fe3O4-MNPs surface.B spectral line is CDCA-APTES-Fe3O4The infrared line of-MNPs,
1077cm-1For the strong absworption peak of C-C (=O)-O in esterification cholic acid, this peak is strong and wide, is often the last the first in the infrared spectrum of ester
Peak.1716cm-1For C=O stretching vibration in ester, 1635cm-1For the stretching vibration peak of C=O, 1556cm in amide-1For N-H's
Bending vibration, 1412cm-1For the stretching vibration of C-N in amide, the appearance at features above peak confirms chenodeoxycholic acid derivatives
APTES-Fe is modified in success3O4On-MNPs.
The transmission electron microscope photo of Fig. 3 shows: in figure, a and b is respectively APTES-Fe3O4-MNPs and CDCA-APTES-
Fe3O4The TEM photo of-MNPs.APTES-Fe as can be seen from FIG.3O4-MNPs and CDCA-APTES-Fe3O4-MNPs shape approximates
Spherical or elliposoidal, favorable dispersibility, do not have obvious agglomeration.APTES-Fe3O4-MNPs and CDCA-APTES-Fe3O4-
The average particle size distribution of MNPs is at 14 ± 2nm, at Fe3O4In the range of-MNPs superparamagnetism Particle size requirements (particle diameter is less than 20nm),
The modification of esterification chenodeoxycholic acid is little on mean diameter impact.
Fig. 4 is CDCA-APTES-Fe3O4The X-ray diffracting spectrum (XRD) of-MNPs.In figure, 2 θ are positioned at 30.12,35.58,
43.35,53.62,57.13,62., 89 corresponding diffraction maximums correspond respectively to Fe3O4Face-centred cubic (220), (311),
(400), (422), (511) and (440) diffraction surfaces.The above results and bloodstone in JCPDS (No.85-1436) standard card
Collection of illustrative plates is consistent, shows the CDCA-Fe of synthesis3O4-MNPs has cubic spinel structure.Choose CDCA-APTES-Fe3O4-MNPs
The strongest diffraction maximum (311) for particle diameter estimate, Scherrer formula (1) calculate CDCA-APTES-Fe3O4-MNPs's is flat
All particle diameters are 15nm, close with the particle size data that TEM records.
D=0.89 λ/Bcos θ (1)
Wherein, D is the average diameter/nm of particle, and 0.89 is Scherrer constant, and λ is 0.154nm, is X-ray wavelength,
B is the halfwidth of diffraction maximum, and θ is the angle of diffraction/rad.
Fig. 5 is CDCA APTES-Fe3O4The hysteresis curve figure of-MNPs.Abscissa is applied field strengths, and vertical coordinate is single
Position quality magnetic material induced magnetism size in the presence of externally-applied magnetic field.From the figure, it can be seen that this curve is through initial point, when
When externally-applied magnetic field is 0, magnetic induction is 0, meets the concept of superparamagnetic, illustrates that this material is superparamagnetism.According to magnetic force
Square experiment obtains result and is: CDCA APTES-Fe3O4The saturation magnetisation value of-MNPs can reach 59emu/g.Chenodeoxycholic acid is modified
After, the most substantially weaken Fe3O4The magnetic of-MNPs.
Use thermogravimetric analysis (TGA) to be further characterized by chenodeoxycholic acid and modify Fe3O4-MNPs surface, and determine surface
The content of dressing agent.Fe3O4-MNPs and CDCA-APTES-Fe3O4The thermogravimetric curve of-MNPs is as shown in Figure 6.Fe3O4-MNPs exists
About 120 DEG C occur in that weightless first, and this is Fe3O4Solvent (water or the ethanol) volatilization of-MNPs surface adsorption causes.CDCA-
The weight-loss curve of APTES-Fe3O4-MNPs weightlessness (2.75%) between 155 DEG C-301.92 DEG C is attributed to 3-aminopropyl
Thermal decomposition weightless；There is significant weightlessness (3.4%) process between 301.92 DEG C-600 DEG C, this is owing to modification is arrived
The thermal decomposition of the organic structures such as the chenodeoxycholic acid in magnetic nano material causes.CDCA-APTES-Fe3O4-MNPs's is weightless bent
There is not the process of weightening finish in line, and CDCA-APTES-Fe is described3O4-MNPs is coated with Fe3O4It is not easy oxidized after-MNPs, surely
Qualitative had large increase.Showing by analyzing and calculating, esterification chenodeoxycholic acid successfully modifies Fe3O4-MNPs surface, repaiies
Decorations amount is 34.75mg/g.
Owing to antibiotic is more sensitive to pH, therefore have studied CDCA-APTES-Fe under different pH3O4The drug carrying ability of-MNPs.
The CDCA-APTES-Fe of configuration 0.2mg/mL3O4-MNPs solution, ultrasonic mixing, it is separately added into different pH (3-11) phosphoric acid buffer
Liquid and concentration are 1 × 10-5Antibiotic CTC or OTC of mol/L.Ultrasonic 10min, solution at room temperature vibrates 3-6 hour.Reaction
After, magnetic hysteresis separates, and takes supernatant and measures its fluorescence intensity.Process data, as it is shown in fig. 7, CTC is when pH≤9, CDCA-
APTES-Fe3O4The load capacity of CTC is increased by-MNPs along with the increase of pH, and when pH=9, load capacity substantially increases.pH
During for 9-11, load capacity is gradually reduced again.Therefore alkalescence condition (pH=9) is more beneficial for CDCA-APTES-Fe3O4-MNPs is to CTC
Load；OTC when pH≤6, CDCA-APTES-Fe3O4The load capacity of OTC is increased by-MNPs along with the increase of pH, and pH exists
During 7-11, load capacity is gradually reduced again, therefore selects pH=6 to load antibiotic OTC.
Embodiment 2: the extracorporeal releasing experiment of magnetic Nano antibacterial
Weigh the CTC clathrate of 2 parts of 2mg and the OTC clathrate of 2 parts of 2mg, be separately added into concentration 10-2Mol/LpH=7 and
The each 30mL of PB buffer solution of pH=9.In the water-bath of 37 DEG C, timing release, takes supernatant at regular intervals and surveys its fluorescence,
Calculate its accumulative release rate.As shown in Figure 8,9, during pH=7 and pH=9, the accumulative release rate of CTC respectively reaches 14% He
23%；The accumulative release rate of OTC is respectively 9% and 12%.Contrast release data are it can be seen that drug release has certain pH
Dependency.The release process of CTC and OTC is divided into two stages.CTC slope of release profiles in 60min is the biggest；This is described
Time rate of release very fast, this is likely due to adsorb the CTC at carrier surface and produces what diffusion caused due to concentration difference, becomes afterwards
Change relatively slow, within about 4 hours, reach platform.Illustrate that the CTC that carrier periphery is adsorbed has reached diffusion balance；OTC releases in 40min
Put slope of a curve very big, illustrate that now rate of release is very fast, change relatively slow afterwards, within about 2 hours, reach platform, illustrate to carry
The OTC of body periphery absorption has reached diffusion balance.Visible, this antibacterial rate of release is very fast, and practicality is stronger.
Embodiment 3: the experiment of magnetic Nano antibacterial bactericidal activity
Oxytetracycline OTC magnetic Nano antibacterial kills escherichia coli experiment, and every test tube takes 7.5mL Carnis Bovis seu Bubali cream albumen and freezes training
Supporting base, respectively adding 100 μ L concentration is 108The escherichia coli liquid of CFU/mL, be respectively configured concentration be 1mg/mL, 3 μ g/mL, 5 μ g/mL,
7 μ g/mL, 11 μ g/mL, OTC magnetic Nano antibacterial (experimental group) of 20 μ g/mL and magnetic Nano complex, naked medicine OTC are (right
According to group), cultivate 24h in 37 DEG C of constant-temperature tables.As shown in Figure 10, the superiors are magnetic Nano complex, and six test tubes are muddy entirely
Turbid, illustrate that escherichia coli amount reproduction, magnetic nanometer do not have sterilizing ability；Intermediate layer is naked medicine OTC, and front two test tubes are muddy
, antibacterial amount reproduction is described, test tube clarification afterwards is bright, and antibacterial can be effectively killed in explanation, and its minimal inhibitory concentration is at 5 μ g/
mL；Orlop is OTC magnetic Nano antibacterial, begins to clarify bright from second test tube, and its minimal inhibitory concentration is at 3 μ g/
mL.Understand magnetic Nano antibacterial bactericidal activity apparently higher than naked medicine.
Chlortetracycline CTC magnetic Nano antibacterial kills golden staphylococci experiment, and every test tube takes 6mL Carnis Bovis seu Bubali cream albumen and freezes training
Supporting base, respectively adding 100 μ L concentration is 108The golden staphylococci liquid of CFU/mL, be respectively configured concentration be 0.1 μ g/mL, 0.2 μ g/mL,
0.3 μ g/mL, 0.4 μ g/mL, 0.5 μ g/mL, CTC magnetic Nano antibacterial (experimental group) of 0.6 μ g/mL and magnetic Nano are compound
Body, naked medicine CTC (matched group), cultivate 24h in 37 DEG C of constant-temperature tables.As shown in figure 11, the superiors are magnetic Nano complex, six
Propping up test tube is muddy entirely, illustrates that golden staphylococci amount reproduction, magnetic nanometer do not have sterilizing ability；Intermediate layer is that CTC magnetic is received
Rice antibacterial, front two test tubes are muddy, and antibacterial amount reproduction is described, test tube clarification afterwards is bright, and explanation can effectively be killed
Antibacterial, its minimal inhibitory concentration is at 0.3 μ g/mL；Orlop is naked medicine CTC, just starts to clarify bright from the 4th test tube, and it is
Little Mlc is at 0.4 μ g/mL.Understand magnetic Nano antibacterial bactericidal activity higher than naked medicine.
In sum, magnetic nano-particle and tetracycline antibiotics are combined with synergism, can improve killing of antibiotic
Bacterium ability, it is seen that magnetic Nano antibacterial is Substitutes For Antibiotic safely and efficiently, can be as practical antibacterial.
Claims (7)
1. a magnetic Nano antibacterial, it is characterised in that be prepared by a method comprising the following steps and obtain:
(1) preparation of chenodeoxycholic acid it is esterified: be dissolved in formic acid solution by chenodeoxycholic acid, at 50-60 DEG C, mechanical agitation
After reacting 5-6 hour, product rotary evaporation removes solvent, and gained solid is crossed post and purified；40-70 DEG C is vacuum dried 12 hours,
The esterification chenodeoxycholic acid (CDCA) modified to formic acid, seals and preserves；
(2) esterification chenodeoxycholic acid/Fe3O4The preparation of magnetic Nano complex: esterification chenodeoxycholic acid is dissolved in anhydrous dichloro
In methane, add dehydrating agent dicyclohexylcarbodiimide, catalyst DMAP, mechanical agitation 10min, described esterification
The mol ratio of chenodeoxycholic acid, dehydrating agent and catalyst is 1: 0.9-1.2: 0.8-1.2；Weigh esterification chenodeoxycholic acid matter simultaneously
The amidized Fe of amount 18-22%3O4-MNPs is dissolved in anhydrous methylene chloride solution, ultrasonic make it dispersed after join
Stating in esterification chenodeoxycholic acid mixed solution, room temperature reaction is overnight；Products therefrom filters, and by dichloromethane, then uses successively
Secondary water, saturated sodium bicarbonate, secondary water wash；40-70 DEG C is vacuum dried 12 hours, obtains complex CDCA-APTES-
Fe3O4–MNPs；
(3) preparation of magnetic Nano antibacterial: by complex CDCA-APTES-Fe3O4It is 10 that-MNPs adds concentration-2Mol/L's
In the phosphate buffer solution of pH5-9, ultrasonic mixing, adding concentration is 10-3The tetracycline antibiotics medicine of mol/L, described
The volume ratio 1: 1-3 of buffer solution and medicine, complex is 2-5: 1 with the mass ratio of medicine；The most ultrasonic 10min, shakes
Swing 3-6 hour；Magnetic hysteresis separates, and is vacuum dried 12 hours, obtains CDCA-APTES-Fe at being deposited in 40-70 DEG C3O4-MNPs and four
The clathrate of ring element class antibiotic.
2. a kind of magnetic Nano antibacterial as claimed in claim 1, it is characterised in that in described step (1), mechanical agitation turns
Speed 800r/min.
3. a kind of magnetic Nano antibacterial as claimed in claim 1, it is characterised in that in described step (1) at 55 DEG C, machine
Tool stirring reaction 5-6 hour.
4. a kind of magnetic Nano antibacterial as claimed in claim 1, it is characterised in that cross what post purified in described step (1)
Developing solvent is ethanol: dichloromethane=2: 98.
5. a kind of magnetic Nano antibacterial as claimed in claim 1, it is characterised in that amidized in described step (2)
Fe3O4The amount of-MNPs is the 20% of esterification cholic acid quality.
6. a kind of magnetic Nano antibacterial as claimed in claim 1, it is characterised in that true in described step (1), (2), (3)
Empty baking temperature is 60 DEG C.
7. a kind of magnetic Nano antibacterial as claimed in claim 1, it is characterised in that described tetracycline antibiotics is salt
OXYTETRACYCLINE HCL or chlortetracycline hydrochloride.
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