CN116726194A - Porphyrin-antibiotic supermolecule nanoparticle, preparation method and application thereof - Google Patents
Porphyrin-antibiotic supermolecule nanoparticle, preparation method and application thereof Download PDFInfo
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- CN116726194A CN116726194A CN202310630706.5A CN202310630706A CN116726194A CN 116726194 A CN116726194 A CN 116726194A CN 202310630706 A CN202310630706 A CN 202310630706A CN 116726194 A CN116726194 A CN 116726194A
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- Prior art keywords
- porphyrin
- antibiotic
- supermolecule
- solution
- cyclodextrin
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- 239000002105 nanoparticle Substances 0.000 title claims abstract description 63
- 238000002360 preparation method Methods 0.000 title abstract description 9
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims abstract description 64
- 150000004032 porphyrins Chemical class 0.000 claims abstract description 44
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 33
- 229960003405 ciprofloxacin Drugs 0.000 claims abstract description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 230000003115 biocidal effect Effects 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 13
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 208000035143 Bacterial infection Diseases 0.000 claims abstract description 6
- 208000022362 bacterial infectious disease Diseases 0.000 claims abstract description 6
- 206010034133 Pathogen resistance Diseases 0.000 claims abstract 2
- 238000007385 chemical modification Methods 0.000 claims abstract 2
- 239000000243 solution Substances 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- -1 azido cyclodextrin Chemical compound 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- JIJUSCLGGWAISB-UHFFFAOYSA-N C12=CC=C(N1)C=C1C=CC(=N1)C=C1C=CC(N1)=CC=1C=CC(N1)=C2.C2(=CC=CC=C2)[Zn] Chemical compound C12=CC=C(N1)C=C1C=CC(=N1)C=C1C=CC(N1)=CC=1C=CC(N1)=C2.C2(=CC=CC=C2)[Zn] JIJUSCLGGWAISB-UHFFFAOYSA-N 0.000 claims description 9
- QCWPXJXDPFRUGF-UHFFFAOYSA-N N1C=2C=C(N=3)C=CC=3C=C(N3)C=CC3=CC(=N3)C=CC3=CC1=CC=2C1=CC=CC=C1 Chemical compound N1C=2C=C(N=3)C=CC=3C=C(N3)C=CC3=CC(=N3)C=CC3=CC1=CC=2C1=CC=CC=C1 QCWPXJXDPFRUGF-UHFFFAOYSA-N 0.000 claims description 9
- YIYFFLYGSHJWFF-UHFFFAOYSA-N [Zn].N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 Chemical compound [Zn].N1C(C=C2N=C(C=C3NC(=C4)C=C3)C=C2)=CC=C1C=C1C=CC4=N1 YIYFFLYGSHJWFF-UHFFFAOYSA-N 0.000 claims description 9
- 239000008367 deionised water Substances 0.000 claims description 9
- 229910021641 deionized water Inorganic materials 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 238000004108 freeze drying Methods 0.000 claims description 6
- 238000002390 rotary evaporation Methods 0.000 claims description 6
- QBQQANPKYCNDDH-UHFFFAOYSA-N OC=1C2=C(C3=C(C(=C(N3O)C=C3C=CC(C=C4C=CC(=CC(C1)=N2)N4)=N3)C3=CC=CC=C3)O)O Chemical compound OC=1C2=C(C3=C(C(=C(N3O)C=C3C=CC(C=C4C=CC(=CC(C1)=N2)N4)=N3)C3=CC=CC=C3)O)O QBQQANPKYCNDDH-UHFFFAOYSA-N 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 4
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 4
- 229960005055 sodium ascorbate Drugs 0.000 claims description 4
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 4
- 238000005303 weighing Methods 0.000 claims description 4
- YZYKBQUWMPUVEN-UHFFFAOYSA-N zafuleptine Chemical compound OC(=O)CCCCCC(C(C)C)NCC1=CC=C(F)C=C1 YZYKBQUWMPUVEN-UHFFFAOYSA-N 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical group BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 claims description 2
- 239000004599 antimicrobial Substances 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- KYGZCKSPAKDVKC-UHFFFAOYSA-N Oxolinic acid Chemical group C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC2=C1OCO2 KYGZCKSPAKDVKC-UHFFFAOYSA-N 0.000 claims 1
- 239000003306 quinoline derived antiinfective agent Substances 0.000 claims 1
- 238000010025 steaming Methods 0.000 claims 1
- 239000003242 anti bacterial agent Substances 0.000 abstract description 22
- 229940088710 antibiotic agent Drugs 0.000 abstract description 22
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 15
- 241000894006 Bacteria Species 0.000 abstract description 13
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 abstract description 13
- 239000000463 material Substances 0.000 abstract description 8
- 238000002428 photodynamic therapy Methods 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 abstract description 7
- 206010059866 Drug resistance Diseases 0.000 abstract description 4
- 230000003993 interaction Effects 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 2
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 15
- 238000010521 absorption reaction Methods 0.000 description 12
- 239000003504 photosensitizing agent Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 238000005286 illumination Methods 0.000 description 7
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 5
- 241000191967 Staphylococcus aureus Species 0.000 description 5
- 229960003085 meticillin Drugs 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000000862 absorption spectrum Methods 0.000 description 4
- 238000000502 dialysis Methods 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- ZKSVYBRJSMBDMV-UHFFFAOYSA-N 1,3-diphenyl-2-benzofuran Chemical compound C1=CC=CC=C1C1=C2C=CC=CC2=C(C=2C=CC=CC=2)O1 ZKSVYBRJSMBDMV-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000002189 fluorescence spectrum Methods 0.000 description 3
- 229920002521 macromolecule Polymers 0.000 description 3
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000013522 chelant Substances 0.000 description 2
- 238000012650 click reaction Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002296 dynamic light scattering Methods 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 238000002802 antimicrobial activity assay Methods 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000002678 macrocyclic compounds Chemical class 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
- C08G83/008—Supramolecular polymers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention belongs to the field of organic synthesis and biomedical materials, and particularly relates to porphyrin-antibiotic supermolecule nano particles, a preparation method and application thereof. The related supramolecular nanoparticle is prepared by connecting cyclodextrin on porphyrin by chemical modification, the water solubility of the porphyrin is obviously improved by using the cyclodextrin, and simultaneously, the quinolone antibiotics ciprofloxacin is combined with the cyclodextrin through supramolecular interaction, so that the porphyrin-antibiotic supramolecular nanoparticle is formed. By combining antibiotic therapy with photodynamic therapy, the amount of antibiotic used is reduced, thereby reducing the occurrence of bacterial resistance. Meanwhile, for some bacteria which have developed drug resistance to antibiotics, singlet oxygen generated in the photodynamic process can be effectively killed. Therefore, the method has excellent antibacterial effect and low biotoxicity, and can play an excellent role in the treatment of future bacterial infection.
Description
Technical Field
The invention belongs to the field of organic synthesis and biomedical materials, and particularly relates to porphyrin-antibiotic supermolecule nano particles, a preparation method and application thereof.
Background
Currently, the normal operation of human society is severely affected by the hazards of a range of diseases caused by bacterial infection. The occurrence of antibiotics can greatly relieve the harm of bacterial infection, common antibiotics such as amoxicillin, ciprofloxacin and the like can effectively inhibit the growth of pathogenic bacteria, and the diseases caused by bacterial infection after a plurality of operations are reduced. However, the overuse of antibiotics has made bacteria resistant, and even some strains gradually evolve into "super bacteria", severely threatening human and animal health. As bacteria continue to develop resistance to various antibiotics, current research into new antibiotics appears to fall into the stagnation phase, and it is difficult to find new small-molecule antibiotics that can be used clinically. Therefore, it is necessary to study new therapeutic approaches to combat bacterial infections and to prevent them from developing resistance.
Photodynamic therapy is a new therapeutic approach with great potential, the main components of which are photosensitizers, light of specific wavelengths and oxygen. The photosensitizer is activated by illumination with a specific wavelength, so that the photosensitizer transfers self energy to surrounding oxygen molecules, thereby generating singlet oxygen with high cytotoxicity, and the singlet oxygen has a certain killing effect on tumor cells and bacteria. Photodynamic therapy has attracted strong attention due to its low biotoxicity, rapid onset of action, reproducibility, and other advantages. In the photodynamic therapy process, the photosensitizer plays a vital role, and a stable and efficient photosensitizer can effectively improve the photodynamic therapy effect.
Porphyrins are aromatic heterocyclic compounds which are ubiquitous in the life system and play an important role in many vital activities. The conjugated macromolecule formed by interconnecting alpha-carbon atoms of four pyrrole subunits through a methylene bridge (= CH-) has a special rigid structure, and a plurality of active modification sites are arranged on the macrocycle of the conjugated macromolecule, so that the conjugated macromolecule can be applied in multiple aspects through diversified modification. Meanwhile, a plurality of kinds of metal ions can be chelated in the cavity of the porphyrin center to form a metalloporphyrin chelate, so that the porphyrin chelate has wide application prospect. As a photosensitizer, porphyrin has strong absorption at about 425 and nm and a characteristic absorption peak at about 650 and nm, and is widely applied to different fields because of the wavelength range of visible light, and porphyrin molecules have better stability, so that the photosensitizer is an excellent photosensitizer.
Cyclodextrin is a natural chemical product, has excellent biocompatibility and excellent water solubility, and its preparation process is well established, so that it is widely used in the field of biology. In addition, cyclodextrin is a main compound commonly used in supermolecule assembly, and can be combined with porphyrin to improve the water solubility of porphyrin, and meanwhile, the rigid structure of cyclodextrin can also provide certain steric hindrance for porphyrin, so that quenching caused by aggregation among porphyrin molecules is avoided, and the effect of porphyrin photodynamic therapy can be enhanced to a certain extent. The quinolone antibiotics have broad-spectrum antibacterial effect, and meanwhile, the molecular size of the quinolone antibiotics is matched with the cavity of the cyclodextrin, and the quinolone antibiotics can be combined with the cyclodextrin through the host-guest effect, so that the quinolone antibiotics are further combined with photosensitizer porphyrin to form supermolecule nano particles, and the quinolone antibiotics are applied to photodynamic synergistic antibiotic.
Disclosure of Invention
In view of the above, the invention provides a porphyrin-antibiotic supermolecule nanoparticle, a preparation method and application thereof. Cyclodextrin is modified on porphyrin through chemical reaction, and then the antibiotic is combined through host-guest interaction between the cyclodextrin and the antibiotic to form the supermolecule nano particle. The supermolecule nano-particles have good biocompatibility and water solubility, obvious antibacterial effect and are not easy to cause bacteria to generate drug resistance. Can be used for solving the problems that antibiotics in the current antibacterial field can cause bacteria to generate drug resistance, and the traditional photosensitizer is poor in water solubility and easy to gather so as to reduce photodynamic therapy effect.
In order to achieve the technical purpose, the invention is realized by adopting the following technical scheme:
the first aspect of the invention provides a porphyrin-antibiotic supermolecule nanoparticle, which has the structure as follows:
wherein, the porphyrin is tetrahydroxyphenyl porphyrin of cyclodextrin modified by click reaction, and the structure is as follows:
wherein, R is quinolone antibiotics, preferably, the antibiotics are ciprofloxacin, and the structure is as follows:
the second aspect of the invention provides a method for preparing porphyrin-antibiotic supermolecule nano-particles, comprising the following steps:
s1: the preparation method comprises the steps of taking DMF as a solvent, tetrahydroxyphenyl porphyrin and 3-bromopropyne as reaction raw materials, and potassium carbonate as a catalyst, and reacting to obtain the tetraalkynyloxy phenyl porphyrin. The reaction formula is as follows:
s2: and (2) taking a mixed system of methanol and dichloromethane as a solvent, and reacting the tetraalkynyloxy phenyl porphyrin obtained in the step (S1) with zinc acetate dihydrate to obtain the tetraalkynyloxy phenyl zinc porphyrin. The reaction formula is as follows:
s3: and (2) taking DMF as a solvent, and carrying out click reaction on the azido cyclodextrin and the tetraacetyloxy phenyl zinc porphyrin obtained in the step (S2) in the presence of sodium ascorbate to obtain the tetracyclodextrin zinc porphyrin. The reaction formula is as follows:
s4: and (3) taking DMF as a solvent, and removing zinc which is complexed in the middle of the tetra-cyclodextrin zinc porphyrin obtained in the step (S3) by using concentrated hydrochloric acid and triethylamine to obtain the tetra-cyclodextrin porphyrin. The reaction formula is as follows:
s5: and (3) assembling the tetracyclodextrin porphyrin and the ciprofloxacin antibiotic obtained in the step (S4) through a host-guest interaction to obtain the final porphyrin-antibiotic supermolecule nanoparticle.
Preferably, step S1 specifically includes: weighing a certain amount of tetrahydroxyphenyl porphyrin in DMF, adding excessive 3-bromopropylene and potassium carbonate, carrying out reflux reaction at 70 ℃ for 24-h, carrying out suction filtration, carrying out rotary evaporation, and purifying by column chromatography to obtain the tetraalkynyloxy phenyl porphyrin.
Preferably, step S2 specifically includes: weighing a certain amount of the tetraalkynyloxy phenyl porphyrin obtained in the step S1 and zinc acetate dihydrate in a mixed solution of methanol and dichloromethane, reacting for 2 hours at room temperature, then performing rotary evaporation to remove the solvent, and washing the product for three times to obtain the tetraalkynyloxy phenyl zinc porphyrin.
Preferably, step S3 specifically includes: and (2) dissolving the azido cyclodextrin, the tetraalkynyloxy phenyl zinc porphyrin obtained in the step (S2) and sodium ascorbate in DMF, rapidly adding anhydrous copper sulfate aqueous solution, reacting at 50 ℃ under the protection of nitrogen for 48h, dialyzing for 5 days after the completion of the reaction, and then freeze-drying to obtain the tetracyclodextrin zinc porphyrin.
Preferably, step S4 specifically includes: dissolving tetracyclodextrin zinc porphyrin in a certain amount of DMF, adding concentrated hydrochloric acid, stirring for 2h, adding a proper amount of triethylamine, changing the solution into porphyrin red, dialyzing the solution, and freeze-drying to obtain tetracyclodextrin porphyrin.
Preferably, step S5 specifically includes: preparing a product obtained in the step S4 and the antibiotics into DMF solution with a certain concentration, mixing a certain amount of DMF solution, slowly dripping deionized water into the DMF solution, and dialyzing for 2 days to obtain the final porphyrin-antibiotic supermolecule nano-particles.
In a third aspect, the invention provides an application of porphyrin-antibiotic supramolecular nanoparticles in antibacterial aspect.
The porphyrin-antibiotic supermolecule nano-particles provided by the invention have good biocompatibility and stability, high singlet oxygen generation capacity and good antibacterial effect, and can be applied to antibacterial.
The application includes the following tests:
s1: preparing ciprofloxacin, tetra-cyclodextrin porphyrin and supermolecule nano-particles into an aqueous solution, testing ultraviolet absorption spectrum and fluorescence emission spectrum of a sample by an ultraviolet-visible spectrophotometer and a fluorescence spectrophotometer, and testing particle size distribution of the supermolecule nano-particle sample by dynamic light scattering;
s2: blending a singlet oxygen tester DPBF solution and the supermolecule nano-particles, illuminating, testing ultraviolet absorption of the solution at 425nm, and characterizing the singlet oxygen generation capacity of the supermolecule nano-particles by using the reduction rate of the ultraviolet absorption;
s3: the antibacterial effect of the supermolecule nano-particles is tested by using escherichia coli and methicillin-resistant staphylococcus aureus as experimental strains and using a plate counting method.
The invention has the beneficial effects that:
1. experiments prove that the supermolecule nano particles provided by the invention have excellent water solubility, show purple solution and have no obvious precipitation;
2. experiments prove that the porphyrin-antibiotic supermolecule nano-particles provided by the invention can effectively inhibit the growth of bacteria, and have no toxic or side effect on normal cells;
3. the porphyrin and the antibiotics adopted in the invention are relatively easy to synthesize and obtain, and the method is simple and easy to operate and is suitable for large-scale implementation;
4. in the invention, the tetracyclodextrin porphyrin is prepared by click chemistry; the formation of the supramolecular nanoparticles is realized through non-covalent bond connection such as hydrogen bond acting force between cyclodextrin and antibiotics; according to the invention, the antibacterial treatment is performed by the photodynamic treatment of the synergistic porphyrin and the antibacterial activity of the antibiotics, so that the antibacterial effect is remarkably enhanced, meanwhile, the generation of bacterial drug resistance is reduced, and the application prospect is wide;
drawings
FIG. 1 is an azido cyclodextrin 1 H NMR spectrum.
FIG. 2 shows a tetraalkynyloxy phenyl porphyrin 1 H NMR spectrum.
FIG. 3 shows a tetracyclodextrin porphyrin 1 H NMR spectrum.
FIG. 4 is a graph of ultraviolet absorption spectra of ciprofloxacin, tetracyclodextrin porphyrin, and supramolecular nanoparticles.
FIG. 5 is a graph of fluorescence spectra of ciprofloxacin, tetracyclodextrin porphyrin, and supramolecular nanoparticles.
FIG. 6 is a graph showing the particle size distribution of supramolecular nanoparticles.
FIG. 7 is a graph showing the DPBF ultraviolet absorption degradation curve after treatment with tetracyclodextrin porphyrin and supramolecular nanoparticles.
FIG. 8 is a graph of the results of an antimicrobial assay of supramolecular nanoparticles (methicillin-resistant Staphylococcus aureus).
FIG. 9 is a graph of the results of an antibacterial test of supramolecular nanoparticles (E.coli).
Detailed Description
The following description of the preferred embodiments of the invention, which will be described in sufficient detail to enable those skilled in the art to practice the invention, is provided with a further understanding of the invention, and is made clear to a person skilled in the art by reference to the accompanying drawings. The idea of the invention is described by a specific operation procedure for better understanding of the essence of the invention, but this is not a limitation of the invention, and a person skilled in the art may make optimization and improvement according to the basic idea of the invention without departing from the basic idea of the invention, all within the scope of the invention.
Example 1
The present embodiment 1 provides a method for preparing azido cyclodextrin, which has the following structure:
the preparation method of the azido cyclodextrin comprises the following steps:
s1: synthesis of p-toluenesulfonyl cyclodextrin
Beta-cyclodextrin (30 g,26.43 mmol) was dissolved in deionized water (200 mL), and sodium hydroxide solution (1.0M, 10 mL) was added to the solution. Then, p-toluenesulfonyl chloride (5.04 g,26.43 mmol) was dissolved in acetonitrile (15 mL), and slowly dropped into the above reaction solution under an ice bath to react at room temperature for 4 hours. After the reaction, the mixture was filtered by suction, and the pH of the filtrate was adjusted to be acidic with a 10% hydrochloric acid solution. Standing, filtering, collecting precipitate, recrystallizing twice in 70 ℃ deionized water to obtain the product p-toluenesulfonyl cyclodextrin as white solid, and obtaining the yield: 21 Percent of the total weight of the composition. The reaction formula is as follows:
s2: synthesis of azido cyclodextrin
The p-toluenesulfonyl cyclodextrin (1.03 g,0.8 mmol) obtained in S1 was dissolved in DMF (10 mL), and sodium azide (0.26 g,4 mmol) was added. Reflux reaction was carried out under nitrogen atmosphere at 70℃for 24 hours. After the reaction was completed, the mixture was cooled and filtered, and the filtrate was collected. The solution was precipitated 3 times in acetone, the solids were collected and the solvent was removed by drying in a vacuum oven to give the azidocyclodextrin in the yield: 78 Percent of the total weight of the composition. The reaction formula is as follows (nuclear magnetism see fig. 1):
example 2
The present example 2 provides a method for preparing tetracyclodextrin porphyrin, which has the following structure:
the preparation method of the tetracyclodextrin porphyrin comprises the following steps:
s1: synthesis of tetraynyloxy phenyl porphyrin
Tetrahydroxyphenylporphyrin (0.2 g,0.295 mmol) was dissolved in 30 mL of DMF, and excess 3-bromopropyne (1.4 g,11.77 mmol) and potassium carbonate (1.66 g,11.77 mmol) were added and reacted at 70℃under reflux 24 h. After the reaction is finished, suction filtration is carried out to collect filtrate, then solvent is removed by rotary evaporation, then purification is carried out by column chromatography, solvent is removed by rotary evaporation, and the tetraalkynyloxy phenyl porphyrin is obtained after drying, and the yield is: 86 Percent of the total weight of the composition. The reaction formula is as follows (nuclear magnetism see fig. 2):
s2: synthesis of tetraynyloxy phenyl zinc porphine
The tetraynyloxyphenyl porphyrin (0.1 g,0.127 mmol) obtained in S1 and zinc acetate dihydrate (0.26 g,1.3 mmol) were weighed out and dissolved in a mixture of methanol and dichloromethane (v/v=1/3) and reacted at room temperature for 2 h. After the reaction is finished, removing the solvent by rotary evaporation, and washing the product for multiple times to obtain the tetraalkynyloxy phenyl zinc porphyrin with the yield: 94 Percent of the total weight of the composition. The reaction formula is as follows:
s3: synthesis of tetracyclodextrin zinc porphyrin
The azido cyclodextrin (1.04 g,0.896 mmol) prepared in example 1 and the tetraacetyloxy phenyl zinc porphyrin (0.1 g,0.112 mmol) obtained in S2 were dissolved in DMF (30 mL), and sodium ascorbate (0.44 g,2.24 mmol) was added. After passing through nitrogen for 30 min, 1mL of an aqueous solution of copper sulfate pentahydrate (56 mg,0.28 mmol) was rapidly added by syringe and reacted under nitrogen for 48 hours. After the reaction is finished, the solution is filled into a dialysis bag (MWCO: 3500 Da) and is dialyzed by deionized water for 3 days, and the tetra-cyclodextrin zinc porphyrin is obtained after freeze-drying, the product is green solid, and the yield is: 34 Percent of the total weight of the composition. The reaction formula is as follows:
s4: synthesis of tetracyclodextrin porphyrin
The tetracyclodextrin zinc porphyrin obtained in the step S3 is dissolved in DMF, 2 mL concentrated hydrochloric acid is slowly dripped into the DMF, and the solution is stirred for 2 hours at room temperature. After the reaction is finished, a proper amount of triethylamine is dripped into the reaction liquid to recover the reddish brown color of the solution, the solution is filled into a dialysis bag (MWCO: 3500 Da), and then deionized water is used for dialysis for 3 days, and the tetra-cyclodextrin porphyrin is obtained after freeze-drying, and the product is purple solid and has the yield: 98%. The reaction formula is as follows (nuclear magnetic resonance diagram is shown in fig. 3):
example 3
This example 3 provides a method for preparing porphyrin-antibiotic supramolecular nanoparticles, which comprises the following steps:
the product of the tetracyclodextrin porphyrin and the ciprofloxacin antibiotic in the embodiment 2 are prepared into DMF solution with a certain concentration, a certain amount of DMF solution is taken and mixed, deionized water is slowly added dropwise into the DMF solution for assembly, stirring is carried out for 2 hours after the assembly is finished, and then the final porphyrin-antibiotic supermolecule nanoparticle solution can be obtained after dialysis for 2 days.
Example 4
This example 4 provides a characterization of the properties of the porphyrin-antibiotic supramolecular nanoparticles of example 3
S1: ultraviolet absorption testing of ciprofloxacin, tetracyclodextrin porphyrin, and supramolecular nanoparticles;
experimental materials: an aqueous ciprofloxacin solution, an aqueous tetracyclodextrin porphyrin solution, and the porphyrin-antibiotic supramolecular nanoparticle solution prepared in example 3;
the experimental method comprises the following steps: preparing ciprofloxacin and tetracyclodextrin porphyrin into deionized water solution, scanning the base line with deionized water, and scanning ciprofloxacin aqueous solution (CIP) and tetracyclodextrin porphyrin aqueous solution (TPP-CD) 4 ) And supramolecular nanoparticle solutions (TPP-CD) 4 CIP) with a wavelength in the range of 300nm to 700nm;
experimental results: the ultraviolet absorption spectrum is shown in figure 4, the absorption peak of ciprofloxacin is 325nm, the absorption peak of tetra-cyclodextrin porphyrin is 425nm, and the two absorption peaks of the super-molecular nano-particles are respectively 325nm and 425nm, which are consistent with the absorption peaks of ciprofloxacin and tetra-cyclodextrin porphyrin, thus indicating the successful assembly of porphyrin and antibiotics;
s2: fluorescence testing of ciprofloxacin, tetracyclodextrin porphyrin and supramolecular nanoparticles;
experimental materials: an aqueous ciprofloxacin solution, an aqueous tetracyclodextrin porphyrin solution, and the porphyrin-antibiotic supramolecular nanoparticle solution prepared in example 3;
the experimental method comprises the following steps: according to ultraviolet absorption spectrum, selecting proper excitation wavelength, detecting ciprofloxacin aqueous solution (CIP), tetra-cyclodextrin porphyrin aqueous solution (TPP-CD) 4 ) And supramolecular nanoparticle solutions (TPP-CD) 4 CIP), the set parameters are as follows: the excitation wavelength is 425nm, the receiving wavelength is 550nm-750nm, and the slit widths are all set to 20nm;
experimental results: the fluorescence spectrum is shown in figure 5, the fluorescence emission peak of the tetracyclodextrin porphyrin is 655nm, the fluorescence emission peak of the supramolecular nanoparticle after combining the antibiotic ciprofloxacin by the action of a host and a guest is 655nm, and the fluorescence intensity is enhanced;
s3: detecting the particle size of the supramolecular nanoparticles;
experimental materials: porphyrin-antibiotic supramolecular nanoparticle solution prepared in example 3;
the experimental method comprises the following steps: determining the particle size distribution of the supramolecular nanoparticle solution using dynamic light scattering;
experimental results: the particle size distribution of the supramolecular nanoparticles is shown in fig. 6, with a hydrodynamic diameter of 209nm and a polydispersity index of 0.16. The size of the supermolecule nano particles is less than 300nm, and the supermolecule nano particles are uniformly distributed.
This example 5 provides a singlet oxygen production capability test for the porphyrin-antibiotic supramolecular nanoparticles of example 3
Experimental materials: porphyrin-antibiotic supramolecular nanoparticle solution prepared in example 3;
the experimental method comprises the following steps: the tetracyclodextrin porphyrin (TPP-CD) prepared in example 2 was taken 4 ) Porphyrin-antibiotic supramolecular nanoparticles (TPP-CD) prepared in example 3 4 CIP) and singlet oxygen detection reagent DPBF were formulated into solutions, each group was irradiated with a light source having a wavelength of 650 nm, the ultraviolet absorption of the solution at 425nm was detected every 20 seconds, and the test was repeated3 times;
experimental results: the singlet oxygen generating capacity results of the ultraviolet absorption reaction are shown in table 1 and fig. 7:
table 1: singlet oxygen production Capacity results
| 0s | 20s | 40s | 60s | 80s | 100s | |
| TPP-CD 4 | 1 | 0.97 | 0.91 | 0.85 | 0.82 | 0.79 |
| TPP-CD 4 /CIP | 1 | 0.95 | 0.89 | 0.84 | 0.80 | 0.77 |
From Table 1 and FIG. 4, it can be seen that TPP-CD 4 And TPP-CD 4 The singlet oxygen generating capacity of/CIP is not greatly different, the better singlet oxygen generating capacity is achieved, and the added antibiotic guest molecules do not obviously cause the reduction of the singlet oxygen yield.
This example 6 provides an antimicrobial evaluation of the porphyrin-antibiotic supramolecular nanoparticles of example 3
Experimental materials: porphyrin-antibiotic supramolecular nanoparticle solution prepared in example 3;
the experimental method comprises the following steps: the test uses colibacillus and methicillin-resistant staphylococcus aureus as test strains to test Ciprofloxacin (CIP) and tetracyclodextrin porphyrin (TPP-CD) 4 ) And porphyrin-antibiotic supramolecular nanoparticles (TPP-CD) 4 CIP). 100 mu L concentration is added into a 96-well plate to be 2 multiplied by 10 6 CFU/mL bacterial liquid and 100 mu L supermolecule material solution diluted by culture medium. Each well is irradiated by laser with the wavelength of 650 and nm for 15 min, is cultivated at 37 ℃ for 24h, different groups of numbers are diluted by the same multiple by using sterile PBS, 20 mu L is smeared on a solid culture medium plate which is prepared in advance, after being cultivated for 18 hours, a viable bacteria colony counting method is carried out to determine the concentration of bacteria and calculate the bacteriostasis rate;
the calculation formula of the bacteriostasis rate is as follows: x= (a-B)/a×100%
Wherein: x-antibacterial rate; a-average colony count of control samples; b average colony count of test sample
Experimental results: the results of the antibacterial test are shown in Table 2 and FIGS. 8 and 9
Table 2: results of the antibacterial test
| Methicillin-resistant staphylococcus aureus | Coli bacterium | |
| CIP-illumination | 86.53% | 79.88% |
| CIP+light | 87.89% | 81.28% |
| TPP-CD 4 Illumination of | 6.49% | 3.87% |
| TPP-CD 4 +illumination | 93.24% | 75.36% |
| TPP-CD 4 CIP-illumination | 8.69% | 8.73% |
| TPP-CD 4 CIP+ illumination | 99.86% | 96.85% |
As can be seen from the results in Table 2 and FIG. 5, the porphyrin-antibiotic supramolecular nanoparticle prepared in example 3 of the present invention can effectively kill Escherichia coli and methicillin-resistant Staphylococcus aureus, and has high antibacterial activity. This can also demonstrate that under the synergistic effect of porphyrin and antibiotic, a more excellent effect against general bacteria and drug-resistant bacteria is produced. In addition, under the condition of no illumination, bacterial toxicity and release of antibiotics can not be generated, which indicates that the supermolecule nano-particles have better biocompatibility and stability.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that other examples, which would be obtained by a person of ordinary skill in the art without making any inventive effort, are also considered to be within the scope of the present invention.
Claims (5)
1. A porphyrin-antibiotic supermolecule nanoparticle, characterized in that the supermolecule nanoparticle which is constructed by using chemical modification and supermolecule action and comprises porphyrin, cyclodextrin and antibiotic has the following structure:
2. the porphyrin antibiotic supermolecule nanoparticle of claim 1, wherein R is quinolone antibiotic in chemical structure; preferably, the antibiotic is ciprofloxacin, which has the structure:
3. the method for preparing porphyrin-antibiotic supermolecule nano-particles according to claim 1, comprising the steps of:
s1, weighing a certain amount of tetrahydroxyphenyl porphyrin in DMF, adding excessive 3-bromopropylene and potassium carbonate, carrying out reflux reaction at 70 ℃ for 24 hours, carrying out suction filtration, carrying out rotary evaporation, and purifying by column chromatography to obtain the tetraalkynyloxy phenyl porphyrin;
s2, weighing a certain amount of tetraalkynyloxy phenyl porphyrin and zinc acetate dihydrate, dissolving in a mixed solution of methanol and dichloromethane, reacting for 2 hours at room temperature, then steaming to remove the solvent, and washing the product to obtain the tetraalkynyloxy phenyl zinc porphyrin;
s3, dissolving azido cyclodextrin, tetraalkynyloxy phenyl zinc porphyrin and sodium ascorbate in DMF, rapidly adding anhydrous copper sulfate aqueous solution, reacting for 48 hours at 50 ℃ under the protection of nitrogen, dialyzing for 5 days after the completion of the reaction, and freeze-drying to obtain tetracyclodextrin zinc porphyrin;
s4, dissolving tetracyclodextrin zinc porphyrin in a certain amount of DMF, adding concentrated hydrochloric acid, stirring for 2 hours, adding a proper amount of triethylamine to change the solution into porphyrin red, dialyzing the solution, and then freeze-drying to obtain tetracyclodextrin porphyrin;
s5, preparing a DMF solution with a certain concentration by the product obtained in the S4 and the ciprofloxacin, mixing a certain amount of the DMF solution, slowly dripping deionized water into the DMF solution, and dialyzing for 2 days to obtain the final porphyrin-antibiotic supermolecule nano-particles.
4. The method for preparing porphyrin-antibiotic supermolecule nano-particles according to claim 2, wherein: the size of the supermolecule nano particles is less than 300nm.
5. Use of the porphyrin-antibiotic supramolecular nanoparticle of claim 5 as an antimicrobial agent for the treatment of superficial bacterial infections, effective to reduce antibiotic consumption and thus bacterial resistance.
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