CN117126668A - Rare earth composite nano material and preparation method and application thereof - Google Patents
Rare earth composite nano material and preparation method and application thereof Download PDFInfo
- Publication number
- CN117126668A CN117126668A CN202311098376.6A CN202311098376A CN117126668A CN 117126668 A CN117126668 A CN 117126668A CN 202311098376 A CN202311098376 A CN 202311098376A CN 117126668 A CN117126668 A CN 117126668A
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- 229910052761 rare earth metal Inorganic materials 0.000 title claims abstract description 118
- 150000002910 rare earth metals Chemical class 0.000 title claims abstract description 111
- 239000002086 nanomaterial Substances 0.000 title claims abstract description 62
- 239000002131 composite material Substances 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims description 30
- 239000002105 nanoparticle Substances 0.000 claims abstract description 52
- 229920000642 polymer Polymers 0.000 claims abstract description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 62
- 239000000243 solution Substances 0.000 claims description 53
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 42
- 229920001223 polyethylene glycol Polymers 0.000 claims description 38
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 19
- 229910052769 Ytterbium Inorganic materials 0.000 claims description 18
- 239000007864 aqueous solution Substances 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000002994 raw material Substances 0.000 claims description 14
- 229910052684 Cerium Inorganic materials 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 150000002500 ions Chemical class 0.000 claims description 12
- 230000003287 optical effect Effects 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 229910052691 Erbium Inorganic materials 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 238000002390 rotary evaporation Methods 0.000 claims description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 7
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- JLZUZNKTTIRERF-UHFFFAOYSA-N tetraphenylethylene Chemical group C1=CC=CC=C1C(C=1C=CC=CC=1)=C(C=1C=CC=CC=1)C1=CC=CC=C1 JLZUZNKTTIRERF-UHFFFAOYSA-N 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 6
- QGLWBTPVKHMVHM-KTKRTIGZSA-N (z)-octadec-9-en-1-amine Chemical compound CCCCCCCC\C=C/CCCCCCCCN QGLWBTPVKHMVHM-KTKRTIGZSA-N 0.000 claims description 5
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 5
- -1 polyoxyethylene Polymers 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 239000011159 matrix material Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 3
- 239000003480 eluent Substances 0.000 claims description 3
- 238000004062 sedimentation Methods 0.000 claims description 3
- 238000000108 ultra-filtration Methods 0.000 claims description 3
- 238000002604 ultrasonography Methods 0.000 claims description 3
- HBXWUCXDUUJDRB-UHFFFAOYSA-N 1-octadecoxyoctadecane Chemical compound CCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCC HBXWUCXDUUJDRB-UHFFFAOYSA-N 0.000 claims description 2
- 229910052779 Neodymium Inorganic materials 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 238000007664 blowing Methods 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 238000000265 homogenisation Methods 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims description 2
- 239000000032 diagnostic agent Substances 0.000 claims 1
- 229940039227 diagnostic agent Drugs 0.000 claims 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 abstract description 25
- 239000000463 material Substances 0.000 abstract description 25
- 239000011258 core-shell material Substances 0.000 abstract description 13
- 238000002428 photodynamic therapy Methods 0.000 abstract description 10
- 238000012984 biological imaging Methods 0.000 abstract description 4
- 239000000975 dye Substances 0.000 description 25
- 238000003745 diagnosis Methods 0.000 description 24
- 238000004020 luminiscence type Methods 0.000 description 16
- 230000000694 effects Effects 0.000 description 15
- 230000005284 excitation Effects 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 13
- 206010070834 Sensitisation Diseases 0.000 description 12
- 230000008313 sensitization Effects 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 7
- 238000003384 imaging method Methods 0.000 description 7
- 230000004048 modification Effects 0.000 description 7
- 238000012986 modification Methods 0.000 description 7
- 239000004094 surface-active agent Substances 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 5
- 230000002209 hydrophobic effect Effects 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- 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 4
- 230000010354 integration Effects 0.000 description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 4
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 3
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 239000005642 Oleic acid Substances 0.000 description 3
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 3
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 3
- CCCMONHAUSKTEQ-UHFFFAOYSA-N octadecene Natural products CCCCCCCCCCCCCCCCC=C CCCMONHAUSKTEQ-UHFFFAOYSA-N 0.000 description 3
- 239000003504 photosensitizing agent Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- MPNFMCAOBNNFJF-UHFFFAOYSA-N 2,3-diphenyl-1-benzofuran Chemical compound C1=CC=CC=C1C1=C(C=2C=CC=CC=2)C2=CC=CC=C2O1 MPNFMCAOBNNFJF-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000002159 nanocrystal Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 208000017983 photosensitivity disease Diseases 0.000 description 2
- 231100000434 photosensitization Toxicity 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 125000000542 sulfonic acid group Chemical group 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- OYINILBBZAQBEV-UWJYYQICSA-N (17s,18s)-18-(2-carboxyethyl)-20-(carboxymethyl)-12-ethenyl-7-ethyl-3,8,13,17-tetramethyl-17,18,22,23-tetrahydroporphyrin-2-carboxylic acid Chemical compound N1C2=C(C)C(C=C)=C1C=C(N1)C(C)=C(CC)C1=CC(C(C)=C1C(O)=O)=NC1=C(CC(O)=O)C([C@@H](CCC(O)=O)[C@@H]1C)=NC1=C2 OYINILBBZAQBEV-UWJYYQICSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000218378 Magnolia Species 0.000 description 1
- 229910017855 NH 4 F Inorganic materials 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000002189 fluorescence spectrum Methods 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 238000001126 phototherapy Methods 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical group CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- 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
- C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
- C08G81/02—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers at least one of the polymers being obtained by reactions involving only carbon-to-carbon unsaturated bonds
- C08G81/024—Block or graft polymers containing sequences of polymers of C08C or C08F and of polymers of C08G
- C08G81/025—Block or graft polymers containing sequences of polymers of C08C or C08F and of polymers of C08G containing polyether sequences
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0032—Methine dyes, e.g. cyanine dyes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
- A61K49/0089—Particulate, powder, adsorbate, bead, sphere
- A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
- A61K49/0093—Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/02—Use of particular materials as binders, particle coatings or suspension media therefor
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/02—Use of particular materials as binders, particle coatings or suspension media therefor
- C09K11/025—Use of particular materials as binders, particle coatings or suspension media therefor non-luminescent particle coatings or suspension media
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/08—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials
- C09K11/77—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing rare earth metals
- C09K11/7766—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing rare earth metals containing two or more rare earth metals
- C09K11/7772—Halogenides
- C09K11/7773—Halogenides with alkali or alkaline earth metal
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1074—Heterocyclic compounds characterised by ligands containing more than three nitrogen atoms as heteroatoms
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Materials Engineering (AREA)
- Epidemiology (AREA)
- Nanotechnology (AREA)
- Biomedical Technology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physics & Mathematics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- Crystallography & Structural Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Composite Materials (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Polymers & Plastics (AREA)
- Inorganic Chemistry (AREA)
- Optics & Photonics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The application relates to the technical field of organic-inorganic hybrid nano materials, and provides a rare earth composite nano material, which is prepared by modifying rare earth nano particles with core-shell structures of specific components by dye molecules, and then using amphiphilic polymers to prepare the water-soluble composite nano material based on the rare earth nano particles; the material can emit light in a near infrared IIb region of 1500 nm-1700 nm under 980nm laser irradiation for high-resolution biological imaging, and can also generate singlet oxygen efficiently under 808nm laser irradiation for photodynamic therapy.
Description
Technical Field
The application relates to the technical field of organic-inorganic hybrid nano material preparation, in particular to a rare earth composite nano material, a preparation method thereof and application thereof in preparing an optical diagnosis and treatment agent.
Background
With the development of the nanoprobe technology, the rare earth nanomaterial with the size of 1-100 nm is gradually developed into an emerging biological imaging and therapeutic agent, and is widely paid attention to, so that the rare earth nanomaterial can be used as a diagnosis and treatment agent for tumors due to the characteristics of large specific surface area, good light stability, excellent biological safety and the like, and various diagnosis and treatment agents based on the rare earth nanomaterial have been developed in the diagnosis and treatment integrated direction in the prior art, for example, a patent application with the publication number of CN115607669A provides a diagnosis and treatment integrated rare earth nanoparticle NaErF 4 @NaYF 4 @SiO 2 @mSiO 2 Ce6, which realizes imaging by down-converting and emitting 1550nm near infrared two-region light and photodynamic therapy by up-converting red light to excite photosensitizer Ce6 under excitation of a single wavelength 980nm laser source, and the diagnosis and treatment agent provided in the prior art as described above, although realizing diagnosis and treatment integration, has not solved the side effect of optical treatment generated in normal tissue area during diagnosis and treatment agent imaging.
The photodynamic therapy is a technology which utilizes photosensitizer to generate Reactive Oxygen Species (ROS) under the irradiation of light with specific wavelength and under the participation of molecular oxygen, and oxidizes and damages various biological macromolecules in tissues and cells to cause irreversible damage to abnormal cells and finally death of the cells, thereby achieving the aim of treatment. Due to limitations of photosensitizers, photodynamic therapy generally operates at wavelengths between 600 and 700nm, moreLong wavelengths can increase the penetration depth of light, whereas the singlet oxygen yield of the corresponding material decreases significantly with increasing wavelength. University of Zhejiang Deng Renren et al in the literature "Near-infrared photosensitization via direct triplet energy transfer from lanthanide inorganic nanocrystals" report NaGdF 4 Nd can directly transfer energy to the triplet state energy level of Ce6 after absorbing 808nm light so as to generate singlet oxygen, thus providing a thought for long-wavelength photodynamic therapy, but the active oxygen yield of the material is still low. Dye sensitization is one of the possible methods for improving the luminescent performance of rare earth materials, however, the effect is more effective in organic solvents and is more difficult to realize in aqueous solutions. See publications [ Wang Dan, xue Bin, wave-spreading flat, etc. ] enhanced dye-sensitized up-conversion luminescence [ J ] of neodymium-sensitized multilayer shell nanostructures]Dye sensitization is only used for improving the luminous performance of rare earth at present, and no report for improving the photodynamic performance of rare earth materials by using a dye sensitization technology is yet seen.
Disclosure of Invention
In order to overcome the defects in the prior art, the application provides a rare earth composite nanomaterial, which is prepared by modifying rare earth nanoparticles with core-shell structures of specific components by using amphiphilic polymers after the surfaces of dye molecules are modified, wherein the rare earth nanoparticles are water-soluble composite nanomaterial based on the rare earth nanoparticles; the material can generate near infrared IIb region luminescence of 1500 nm-1700 nm under 980nm laser irradiation for high-resolution biological imaging, and can also generate singlet oxygen with high efficiency under 808nm laser irradiation for photodynamic therapy.
In order to achieve the above purpose, the present application adopts the following technical scheme:
the application provides a rare earth composite nanomaterial, which comprises rare earth nanoparticles, chlorin e6 dye molecules, namely Ce6 and an amphiphilic polymer, wherein the Ce6 is modified on the surfaces of the rare earth nanoparticles, and the amphiphilic polymer is partially or completely coated on the surfaces of the rare earth nanoparticles modified by the dye;
the rare earth nano particles comprise an inner core, a first shell layer and a second shell layer, wherein the first shell layer and the second shell layer grow layer by layer on the surface of the inner core through an epitaxial growth method;
the kernel is made of NaYF 4 The matrix is doped with rare earth nano particles of 10 percent of Ce, 2 percent of Er and 20 percent of Yb, namely the chemical composition of the inner core is NaYF 4 10% Ce2% Er20% Yb, wherein the percentages of Ce, er and Yb refer to the mole percentage of the Ce, er and Yb in the total amount of all rare earth elements in a core, and the diameter of the core ranges from 10 nm to 20nm;
the first shell layer is of a chemical composition of NaYF 4 The thickness of the first shell layer is 1-3 nm;
the chemical composition of the second shell layer is NaYF 4 50% of Nd, wherein the Nd percentage refers to the mole percentage of the Nd percentage accounting for the total amount of all rare earth elements in a second shell layer, and the thickness of the second shell layer is 1-3 nm;
preferably, the amphiphilic polymer is selected from any one of PMA-PEG, F127, DSPE-PEG and polyoxyethylene (100) octadecyl ether.
Technical principle: the diagnosis and treatment integration is the development direction of the related field at present, in order to realize the diagnosis and treatment integration and reduce the side effect of the diagnosis and treatment integration nano diagnosis and treatment agent on the organism in the diagnosis stage as far as possible, the rare earth composite nanomaterial provided by the application is based on a core-shell structure of rare earth nano particles NaYF4:Ce, er, yb@NaYF4@NaYF4:Nd, dye molecules Ce6 are adopted to carry out surface modification on the rare earth nano particles, then amphiphilic polymer PMA-PEG is used for modification, and the rare earth composite nanomaterial can be used for preparing the multi-mode optical diagnosis and treatment agent for NIR-IIb fluorescence and optical diagnosis and treatment, and NaYF in the prior art 4 The nano structure of Yb and Er is a common up-conversion structure, and Yb in the inner core of rare earth material 3+ The ion can absorb light energy and transfer energy to Er under 980nm laser excitation 3+ Ions and achieve their NIR-IIb emission around 1530nm, i.e. NaYF 4 Yb and Er nanostructures capable of generating 1530nm down-conversion luminescence under 980nm excitation can be used as NIR-IIb fluorescence for precise imaging, but at the same time NaYF 4 The nano structure of Yb and Er can also generate up-conversion of 540nm and 660nm under 980nm excitationLight, and up-conversion luminescence of 660nm can generate photosensitive action on Ce6, so that singlet oxygen is generated; therefore, in order to avoid the therapeutic effect of the rare earth composite nano material as a nano diagnosis and treatment agent in imaging, 10 percent of Ce elements, namely NaYF4:Ce, er and Yb, are doped in the inner core of the rare earth composite nano material, and the doped Ce elements can obviously inhibit the original inner core NaYF 4 Up-conversion luminescence of Ce and Er, ce 3+ Ion is capable of passing through Er 3+ The cross relaxation of the ions improves the intensity of the NIR-IIb emitted luminescence near 1530nm, and remarkably improves the down-conversion luminescence of the whole kernel, so that the rare earth composite nano material provided by the application can be used as a nano diagnosis and treatment agent to improve the imaging performance, and meanwhile, avoid the photosensitization effect of 660nm luminescence on Ce6, so that the rare earth composite nano material provided by the application does not generate singlet oxygen under 980nm excitation; first shell NaYF 4 The layer can improve the NIR-IIb luminescence, inhibit the energy transfer between the outer Nd ion and the inner Yb and Er ion, improve the inner luminescence intensity, reduce the energy damage of Nd ion under 808nm excitation, and improve the photodynamic effect.
In conclusion, the rare earth composite nano material provided by the application can generate light in a near infrared IIb region of 1500 nm-1700 nm for high-resolution biological imaging under 980nm laser irradiation as a nano diagnosis and treatment agent, can also generate singlet oxygen for photodynamic therapy under 808nm laser irradiation, uses light with different wavelengths for imaging and treatment, can prevent harmful active oxygen free radicals from being generated in normal tissues during imaging, and is beneficial to reducing side effects of optical treatment.
In order to improve the photodynamic performance of the rare earth composite nanomaterial and improve the singlet oxygen yield of the rare earth composite nanomaterial under the 808nm light excitation effect as a nano diagnosis and treatment agent, as a preferred implementation mode of the rare earth composite nanomaterial, the rare earth composite nanomaterial further comprises a tetrastyrene modified cyanine dye IR783-TPE, wherein the IR783-TPE and Ce6 molecules are jointly modified on the surface of the rare earth nano ions; the tetrastyrene modified cyanine dye IR783-TPE is prepared by using IR783, namely 2- [2- [ 2-chloro-3- [2- [1, 3-dihydro-3, 3-dimethyl-1- (4-sulfolane)Acid butyl) -2H-indol-2-ylidene]Ethylene group]-1-cyclohexen-1-yl]Vinyl group]-3, 3-dimethyl-1- (4-sulfobutyl) -3H-indolium hydroxide inner salt sodium salt is used as a raw material to modify tetraphenyl ethylene to synthesize IR783-TPE; nd 3+ The absorption of the ion per se at 808nm is weaker, and after the dye IR783-TPE absorbs 808nm excitation light, energy can be transferred to Nd in rare earth nano particles through a non-radiative energy transfer process 3+ The ions, then energy is transferred to Ce6 to sensitize the Ce6 to generate singlet oxygen, so that efficient singlet generation is realized, and therefore, the light absorption capacity of the rare earth composite nanomaterial at 808nm can be greatly improved by adding a second dye IR783-TPE into the rare earth composite nanomaterial, thereby realizing effective dye sensitization and enhancing the photodynamic treatment effect of tumors.
As a preferred preparation method of the IR783-TPE, the preparation method comprises the following steps: with 4- (1, 2-tristyryl) phenol and K 2 CO 3 Stirring in anhydrous N, N-dimethylformamide DMF for 30min, and then adding IR783 dissolved in anhydrous DMF to the above solution by syringe; stirring the mixture of the two at 60 ℃ for 4 hours under nitrogen atmosphere; after the reaction is finished, the solvent is removed under reduced pressure, and column chromatography purification is carried out by taking methylene dichloride/methanol as eluent to obtain the cyanine dye IR783-TPE modified by tetraphenyl ethylene, wherein the 4- (1, 2-tristyryl) phenol and K 2 CO 3 And IR783 is 31:59:20, the configured molar ratio of the 4- (1, 2-tristyryl) phenol and the IR783 is 31:20; the mass volume ratio of the IR783 and the anhydrous DMF is 10 mg/1 mL. The reaction flow is shown in the following formula;
the rare earth nano particles with the core-shell structure are hydrophobic materials, water solubility is generally realized through surface modification in the prior art, so that biomedical application is realized, and the dispersibility of the common surfactants such as F127 and DSPE-PEG can be reduced when the dye sensitized rare earth is subjected to water solubility modification, and the optical performance of the common surfactants is influenced; in order to reduce the influence on the dispersity of the nano material during the water-solubility modification of the nano material, preferably, the amphiphilic polymer is PMA-PEG, and the preparation method of the PMA-PEG comprises the following steps: stirring tetrahydrofuran solution with the concentration of 0.03mg/mL poly (isobutylene-alt-maleic anhydride) and oleylamine at the temperature of 60 ℃ for 12 hours, dissolving in methylene dichloride after rotary evaporation, adding aminopolyethylene glycol monomethyl ether with the Mw of 5000, stirring for 15 minutes, adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and triethylamine, stirring for 24 hours, and dissolving in chloroform by rotary evaporation to obtain an amphiphilic polymer crude product PMA-PEG; the preparation volume ratio of the raw materials of the poly (isobutylene-alt-maleic anhydride) tetrahydrofuran solution, the oleylamine and the dichloromethane is 25:1:5, the preparation mass ratio of the raw materials of the poly (isobutylene-alt-maleic anhydride) and the amino polyethylene glycol monomethyl ether is 0.15:2, and the preparation mass ratio of the raw materials of the amino polyethylene glycol monomethyl ether and the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride is 2:230; the raw material preparation mass volume ratio of the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and the triethylamine is 0.23 mg/0.13 ml, and the raw material preparation volume ratio of the triethylamine and the chloroform is 0.13:3; the amphiphilic polymer provided by the application is a novel high molecular surfactant, and is different from other amphiphilic surfactants, a large number of carboxyl groups exist in the molecule besides hydrophobic olein groups and hydrophilic polyethylene glycol chains, the hydrophobic structure can be affinitized with oleic acid and tetraphenyl ethylene of IR783-TPE on the surfaces of rare earth nano particles through hydrophobic interaction, the hydrophobic structure is wrapped in surfactant micelles, the dissociation of a composite material is prevented, the carboxyl groups can generate coordination with rare earth ions, and the combination of the surfactant and the composite material is further improved, so that the rare earth composite material has a remarkable dye sensitization effect while good water solubility is maintained.
As a preferred preparation method of the rare earth composite nano material, the application comprises the following steps:
by NaYF 4 Preparing the matrix doped with 10% Ce, 2% Er and 20% Yb to obtain the inner core NaYF of the rare earth nanoparticle 4 10% of Ce2% of Er20% of Yb, and sequentially preparing a first shell layer NaYF on the surface of the inner core by an epitaxial growth method 4 And a second step ofShell NaYF 4 50% Nd, preparing rare earth nano particles, dispersing the rare earth nano particles in chloroform to prepare rare earth nano particle solution with the concentration of 20mg/mL;
preparing 0.5mg/mL of Ce6 tetrahydrofuran solution and 1mg/mL of IR783-TPE tetrahydrofuran solution, mixing the 20mg/mL of rare earth nanoparticle solution with the Ce6 and IR783-TPE tetrahydrofuran solution, stirring for 2 hours at 50 ℃ in a nitrogen atmosphere, adding ethanol for sedimentation, centrifuging, and dispersing in tetrahydrofuran to obtain about 4mg/mL of dye-modified rare earth nanoparticle solution; wherein, the raw material configuration volume ratio of the rare earth nanoparticle solution, the Ce6 solution and the IR783-TPE tetrahydrofuran solution is 1:3.2: (0.04-0.34);
removing chloroform by rotary evaporation of PMA-PEG chloroform solution, adding clear water, and heating at 80deg.C for 1 hr to obtain PMA-PEG aqueous solution; wherein the concentration of the PMA-PEG chloroform solution is 1000mg/mL, and the volume ratio of the PMA-PEG chloroform solution to the added clear water is 1:90; rapidly injecting 4mg/mL dye-modified rare earth nanoparticle solution into the PMA-PEG aqueous solution under the condition of ultrasound, wherein the configuration volume ratio of the dye-modified rare earth nanoparticle solution to the PMA-PEG aqueous solution is (0.5-2) to 9; after ultrasonic homogenization, nitrogen is used for blowing off tetrahydrofuran in the aqueous solution, and the rare earth composite nano material with optical diagnosis and treatment performance and near infrared two-region luminescence performance is obtained after ultrafiltration purification.
The beneficial effects of the application are as follows: the application constructs the rare earth nano particles with the core-shell structure by reasonably designing the rare earth element doping, and combines the rare earth nano particles with the organic dye to obtain the novel rare earth composite nano material, thereby realizing 980nm excited NIR-IIb fluorescence emission and 808nm excited photodynamic therapy, being a novel near infrared light excited optical integrated diagnosis and treatment agent, and being used for diagnostic imaging and treatment and not producing the problem of mutual interference.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of an IR783-TPE obtained in example I;
FIG. 2 is a graph showing the ultraviolet absorption spectrum of the material obtained in the first embodiment;
FIG. 3 is a near infrared two-region fluorescence emission spectrum of the material obtained in the first embodiment;
FIG. 4 is a transmission electron microscope image of the material obtained in example one;
FIG. 5 shows singlet oxygen generation after 808nm laser excitation for samples obtained in examples one to two and comparative example one.
Detailed Description
The present application will be described in detail below with reference to the drawings and the detailed description, in order to make the objects, technical solutions and advantages of the present application more apparent.
The following description of the relevant test procedure
Regarding the detection process of whether singlet oxygen is generated, specifically using diphenylbenzofuran DPBF as singlet oxygen probe, detecting the photodynamic effect of the material according to the absorbance change of the diphenylbenzofuran DPBF at 417nm, the specific test process is as follows: DPBF was mixed with an aqueous solution of a sample, and its absorption was measured by a Meissu Spectrometry model UV-1800 ultraviolet-visible spectrophotometer, and immediately after 808nm laser irradiation, its absorption spectrum was measured, and the generation of singlet oxygen was characterized by the decrease in absorbance of DPBF at 417 nm.
Preparation of rare earth nanoparticles
The core-shell structured rare earth nanoparticles used in the following examples had the chemical composition: naYF 4 :10％Ce2％Er20％Yb@NaYF 4 @NaYF 4 50% of Nd, and the preparation method specifically comprises the following steps: 0.68mmol Y (CH) 3 COO) 3 、0.2mmol Yb(CH 3 COO) 3 、0.1mmol Ce(CH 3 COO) 3 And 0.02mmol Er (CH) 3 COO) 3 Heated to 150 ℃ under nitrogen protection, dissolved in 7mL of oleic acid and 15mL of octadecene, cooled to room temperature after complete dissolution. To which a solution containing 4.0mmol NH was added 4 F and 2.5mmol sodium oleate in 10mL methanol at 50 degrees stirring for 30min. Heating to evaporate methanol, heating to 290 deg.C under nitrogen protection for 1.5 hr, cooling, precipitating with ethanol, centrifuging, washing with ethanol for 2 times, dispersing in 7mL chloroform to obtain NaYF 4 10% of Ce2% of Er20% of Yb rare earth nano particles. As above, 0.5mmol Y (CH 3 COO) 3 Dissolved in 7mL oleic acid15mL of octadecene, 3.5mL of the above-prepared nanonucleus and 2.0mmol of NH were added 4 F and 1.25mmol sodium oleate 10mL methanol solution, stirring at 50deg.C for 30min, heating to evaporate low boiling point solvent, heating to 290 deg.C under nitrogen protection, maintaining for 1.5h, settling with ethanol, centrifuging, washing, dispersing in 3.5mL chloroform to obtain core-shell rare earth nanoparticle
NaYF 4 :10％Ce2％Er20％Yb@NaYF 4 . 0.25mmol Y (CH) 3 COO) 3 And 0.25mmol Nd (CH) 3 COO) 3 Dissolving in 7mL oleic acid and 15mL octadecene, adding 3.5mL core-shell nano material prepared above and containing 2.0mmol NH 4 F and 1.25mmol of sodium oleate in 10mL of methanol solution, stirring for 30min at 50 ℃, heating to evaporate the low boiling point solvent, heating to 290 ℃ under the protection of nitrogen, maintaining for 1.5h, settling by ethanol, centrifugally washing, dispersing in 7mL of chloroform, and obtaining rare earth nano particles with a core-shell structure, wherein the concentration is about 20mg/mL; rare earth acetate was purchased from Alfa Aesar during synthesis and other reagents were purchased from Sigma-Aldrich.
Preparation of cyanine dyes modified with tetraphenyl ethylene
The preparation of the tetrastyrene-modified cyanine dye IR783-TPE used in the following examples specifically comprises the steps of: with 4- (1, 2-tristyryl) phenol (136 mg,0.31 mmol) and K 2 CO 3 (81 mg,0.59 mmol) in anhydrous N, N-Dimethylformamide (DMF) (10 mL) was stirred for 30min, then IR783 (100 mg,0.20mmol, available from Sigma-Aldrich) dissolved in anhydrous DMF was added to the solution via syringe. The mixture was stirred under nitrogen at 60℃for 4h. After the reaction is completed, the solvent is removed under reduced pressure, and column chromatography purification is carried out by taking methylene dichloride/methanol as eluent, so as to obtain the cyanine dye IR783-TPE modified by tetraphenyl ethylene. As shown in FIG. 1, IR783-TPE has been successfully synthesized.
Preparation of amphiphilic polymeric PMA-PEG
The preparation of the amphiphilic polymer PMA-PEG used in the following examples specifically comprises the steps of: 0.03mg/mL of poly (isobutylene-alt-maleic anhydride) (Mw 6000, available from Sigma-Aldrich) in tetrahydrofuran was prepared, 5mL of poly (isobutylene-alt-maleic anhydride) in tetrahydrofuran and 0.2mL of oleylamine were stirred at 60℃for 12 hours, dissolved in 10mL of methylene chloride after rotary evaporation, 2mg of aminopolyethylene glycol monomethyl ether (Mw 5000, cas. Number 80506-64-5, available from Michelia.) was added, stirred for 15 minutes, 230mg of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 0.13mL of triethylamine were added, and after stirring for 24 hours, dissolved in 3mL of chloroform to obtain the final product.
Example 1
The embodiment provides a specific preparation method of a rare earth composite nano material, which comprises the following steps:
0.5mg/mL of Ce6 tetrahydrofuran solution and 1mg/mL of IR783-TPE tetrahydrofuran solution are prepared, and 20mg/mL of rare earth nanoparticles with a core-shell structure, ce6 (purchased from a microphone reagent) and IR783-TPE are mixed according to a volume ratio of 1:3.2: mixing in a proportion of 0.153, heating and stirring for 2 hours at 50 ℃ under nitrogen atmosphere, adding ethanol for sedimentation, centrifuging, and dispersing in tetrahydrofuran to obtain dye-modified rare earth nanoparticle solution with a concentration of about 4 mg/mL;
taking 0.1mL of PMA-PEG chloroform solution with the concentration of 1000mg/mL, removing chloroform by rotary evaporation, adding 9mL of water, and heating at 80 ℃ for 1 hour to obtain PMA-PEG aqueous solution; under the condition of ultrasound, 1mL of the dye modified rare earth nanoparticle solution in the first step is quickly injected into the aqueous solution of 9mL of PMA-PEG obtained in the second step; after ultrasonic mixing, nitrogen is used to blow off tetrahydrofuran in the aqueous solution, and the rare earth composite nano material with optical diagnosis and treatment performance and near infrared two-region luminescence performance is obtained after ultrafiltration purification.
As shown in FIG. 2, the rare earth composite nanomaterial has four absorption peaks near 400nm, 500nm, 665nm and 785nm, the absorption of 400nm, 500nm and 665nm corresponds to Ce6, and the absorption of 785nm corresponds to IR783-TPE; as shown in fig. 3, the rare earth composite nanomaterial has fluorescence near 1530nm under 980nm laser excitation, corresponding to fluorescence emission of the rare earth composite nanomaterial; as shown in fig. 4, the particle size of the obtained rare earth composite nanomaterial is about 20nm; as shown in fig. 5, the material can efficiently generate singlet oxygen after 808nm laser irradiation; in addition, the material has 1060nm fluorescence under 808nm excitation, which corresponds to Nd ion luminescence, and does not generate 1530nm luminescence; the material showed no singlet oxygen formation upon 980nm excitation.
Example two
This example differs from example one only in that an equal volume of tetrahydrofuran solution was used instead of the tetrahydrofuran solution of IR783-TPE in example one, and the remaining conditions were unchanged, to prepare a rare earth composite nanomaterial as a nanoprobe.
The experimental results show that the material has singlet oxygen generation after 808nm laser irradiation, but is obviously lower than that of the first embodiment, and the dye sensitization plays an important role in improving the photodynamic therapy effect. In addition, fluorescence emission was also present at 1530nm, indicating that the luminescence of the core in the rare earth nanoparticle was not affected.
Comparative example one
The comparative example one differs from the example one only in that an equal volume of tetrahydrofuran solution was used instead of the tetrahydrofuran solution of Ce6 in the example one, and the remaining conditions were unchanged, to prepare a rare earth composite nanomaterial as a nanoprobe.
The experimental results show that the material has almost no singlet oxygen generation after the 808nm laser irradiation for 1 minute, which indicates that the system can hardly generate singlet oxygen in the absence of Ce6, as shown in fig. 5.
Comparative example two
The second comparative example differs from the first example only in that an equal concentration of NaYF was used 4 :Yb,Er,Ce@NaYF 4 Core-shell structure replaces NaYF in example one 4 :Yb,Er,Ce@NaYF 4 @NaYF 4 Nd core-shell structure, and the rest conditions are unchanged, and the rare earth composite nano material is prepared as a nano probe.
Experimental results show that the material has no singlet oxygen generation basically after being irradiated by 808nm laser for 1 minute, but has fluorescence emission at 1530nm, which shows that only NaYF is generated 4 The photosensitive agent Ce6 can be sensitized to generate singlet oxygen only when an Nd shell layer exists.
Comparative example three
The third comparative example differs from the first example only in that an equal concentration is usedDegree of NaYF 4 Nd replaces NaYF in example one 4 :Yb,Er,Ce@NaYF 4 @NaYF 4 Nd core-shell structure, and the rest conditions are unchanged, and the rare earth composite nano material is prepared as a nano probe.
Experimental results show that the material generates singlet oxygen after 808nm laser irradiation, but has no 1530nm fluorescence emission under 980nm excitation, which indicates that the fluorescence property in the first embodiment is derived from NaYF 4 Yb, er and Ce structure.
Example III
This example differs from example one only in that an equivalent amount of IR806 tetrahydrofuran solution is used instead of the tetrahydrofuran solution of IR783-TPE in example one, where IR806 is described in reference to published patent publication Enhanced-Enhanced up-conversion luminescence ofneodymium-Enhanced multi-shell nanostructures, doi:10.37188/CO.2020-0097 section "2.4 section for IR-806 molecule synthesis" and the rest conditions are unchanged, and the rare earth composite nano material is prepared as a nano probe.
Experimental results show that the dye has weaker binding force with the rare earth material due to no sulfonic acid group, no sensitization effect is observed in the aqueous solution, and the singlet oxygen generated by the material after 808nm laser irradiation is similar to that generated in the second embodiment, so that the advantages of IR783-TPE in the aspect of sensitization of rare earth are demonstrated.
Example IV
This example differs from example one only in that an equivalent amount of IR808 tetrahydrofuran solution was used instead of the tetrahydrofuran solution of IR783-TPE in example one, wherein IR808 was prepared as described in section "supplement material B7" in published Energy-Cascaded Upconversion in an Organic Dye-sensed Core/Shell Fluoride Nanocrystal, DOI 10.1021/acs. Nanolet.5b02830, with the remaining conditions unchanged, to prepare a rare earth composite nanomaterial as a nanoprobe.
The experimental result shows that the IR808 has sulfonic acid groups, but has poor solubility in nonpolar solvents such as tetrahydrofuran, chloroform and the like without tetraphenyl groups, is difficult to be combined with rare earth effectively, so that the sensitization effect is poor, and singlet oxygen generated by the material after 808nm laser irradiation is similar to that of the second embodiment, thereby illustrating the advantages of the IR783-TPE in the aspect of sensitization of rare earth.
Example five
The present example differs from example one only in that equal concentrations of F127 were used instead of PMA-PEG in example one, with the remaining conditions unchanged, to prepare rare earth composite nanomaterials as nanoprobes.
Experimental results show that the material has general stability in aqueous solution, and can generate precipitation after being placed for a short time.
Example six
The present example differs from example one only in that the PMA-PEG in example one was replaced with DSPE-PEG at equal concentrations, with the remaining conditions unchanged, to prepare rare earth composite nanomaterials as nanoprobes.
Experimental results show that the material has better dispersibility in aqueous solution, but no dye sensitization effect is observed in the aqueous solution, which indicates that only PMA-PEG developed by the application can ensure that the nanomaterial has good water solubility while keeping the dye sensitization effect in the aqueous solution.
In summary, the application provides a dye sensitized rare earth nanomaterial for optical diagnosis and treatment and a preparation method thereof, the method is simple to operate, and the obtained nanoparticle has good fluorescence emission in an NIR-IIb region under 980nm excitation, and can generate singlet oxygen after 808nm laser excitation, so that the nanoparticle can be used for optical diagnosis and treatment of tumors.
The above embodiments are only for illustrating the present application and not for limiting the technical solutions described in the present application, and it should be understood that the present application should be based on those skilled in the art, and although the present application has been described in detail with reference to the above embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made to the present application without departing from the spirit and scope of the present application and modifications thereof should be covered by the scope of the claims of the present application.
Claims (7)
1. The rare earth composite nanomaterial is characterized by comprising rare earth nanoparticles, dye molecules Ce6 and an amphiphilic polymer, wherein the Ce6 is modified on the surfaces of the rare earth nanoparticles, and the amphiphilic polymer is partially or completely coated on the surfaces of the dye-modified rare earth nanoparticles;
the rare earth nano particles comprise an inner core, a first shell layer and a second shell layer, wherein the first shell layer and the second shell layer grow layer by layer on the surface of the inner core through an epitaxial growth method;
the kernel is made of NaYF 4 The matrix is doped with rare earth nano particles of 10 percent of Ce, 2 percent of Er and 20 percent of Yb, namely the chemical composition of the inner core is NaYF 4 10% Ce2% Er20% Yb, wherein the percentages of Ce, er and Yb refer to the mole percentage of the Ce, er and Yb in the total amount of all rare earth elements in a core, and the diameter of the core ranges from 10 nm to 20nm;
the first shell layer is of a chemical composition of NaYF 4 The thickness of the first shell layer is 1-3 nm;
the chemical composition of the second shell layer is NaYF 4 50% of Nd, wherein the Nd percentage refers to the mole percentage of the Nd percentage accounting for the total amount of all rare earth elements in a second shell layer, and the thickness of the second shell layer is 1-3 nm.
2. The rare earth composite nanomaterial of claim 1, wherein: the rare earth composite nanomaterial also comprises a cyanine dye IR783-TPE decorated by tetraphenyl ethylene, wherein the IR783-TPE and Ce6 molecules are decorated on the surface of the rare earth nano ion together; the tetrastyrene modified cyanine dye IR783-TPE is synthesized by modifying tetrastyrene with IR783 as a raw material.
3. The rare earth composite nanomaterial of claim 2, characterized in that: the preparation method of the IR783-TPE comprises the following steps: with 4- (1, 2-tristyryl) phenol and K 2 CO 3 Stirring in anhydrous N, N-dimethylformamide DMF for 30min,IR783 dissolved in anhydrous DMF was then added to the above solution via syringe; stirring the mixture of the two at 60 ℃ for 4 hours under nitrogen atmosphere; after the reaction is finished, the solvent is removed under reduced pressure, and column chromatography purification is carried out by taking methylene dichloride/methanol as eluent to obtain the cyanine dye IR783-TPE modified by tetraphenyl ethylene, wherein the 4- (1, 2-tristyryl) phenol and K 2 CO 3 And IR783 is 31:59:20, the configured molar ratio of the 4- (1, 2-tristyryl) phenol and the IR783 is 31:20; the mass volume ratio of the IR783 and the anhydrous DMF is 10 mg/1 mL.
4. The rare earth composite nanomaterial of claim 1, wherein: the amphiphilic polymer is selected from any one of PMA-PEG, F127, DSPE-PEG and polyoxyethylene (100) octadecyl ether.
5. The rare earth composite nanomaterial of claim 4, wherein: the amphiphilic polymer is PMA-PEG, and the preparation method of the PMA-PEG comprises the following steps: stirring tetrahydrofuran solution with the concentration of 0.03mg/mL poly (isobutylene-alt-maleic anhydride) and oleylamine at the temperature of 60 ℃ for 12 hours, dissolving in methylene dichloride after rotary evaporation, adding aminopolyethylene glycol monomethyl ether with the Mw of 5000, stirring for 15 minutes, adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and triethylamine, stirring for 24 hours, and dissolving in chloroform by rotary evaporation to obtain an amphiphilic polymer crude product PMA-PEG; the preparation volume ratio of the raw materials of the poly (isobutylene-alt-maleic anhydride) tetrahydrofuran solution, the oleylamine and the dichloromethane is 25:1:5, the preparation mass ratio of the raw materials of the poly (isobutylene-alt-maleic anhydride) and the amino polyethylene glycol monomethyl ether is 0.15:2, and the preparation mass ratio of the raw materials of the amino polyethylene glycol monomethyl ether and the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride is 2:230; the raw material preparation mass volume ratio of the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and the triethylamine is 0.23 mg/0.13 ml, and the raw material preparation volume ratio of the triethylamine and the chloroform is 0.13:3.
6. The preparation method of the rare earth composite nano material is characterized by comprising the following steps of using NaYF 4 Preparing the matrix doped with 10% Ce, 2% Er and 20% Yb to obtain the inner core NaYF of the rare earth nanoparticle 4 10% of Ce2% of Er20% of Yb, and sequentially preparing a first shell layer NaYF on the surface of the inner core by an epitaxial growth method 4 And a second shell layer NaYF 4 50% Nd, preparing rare earth nano particles, dispersing the rare earth nano particles in chloroform to prepare rare earth nano particle solution with the concentration of 20mg/mL;
preparing 0.5mg/mL of Ce6 tetrahydrofuran solution and 1mg/mL of IR783-TPE tetrahydrofuran solution, mixing the 20mg/mL of rare earth nanoparticle solution with the Ce6 and IR783-TPE tetrahydrofuran solution, stirring for 2 hours at 50 ℃ in a nitrogen atmosphere, adding ethanol for sedimentation, centrifuging, and dispersing in tetrahydrofuran to obtain about 4mg/mL of dye-modified rare earth nanoparticle solution; wherein, the raw material configuration volume ratio of the rare earth nanoparticle solution, the Ce6 solution and the IR783-TPE tetrahydrofuran solution is 1:3.2: (0.04-0.34);
removing chloroform by rotary evaporation of PMA-PEG chloroform solution, adding clear water, and heating at 80deg.C for 1 hr to obtain PMA-PEG aqueous solution; wherein the concentration of the PMA-PEG chloroform solution is 1000mg/mL, and the volume ratio of the PMA-PEG chloroform solution to the added clear water is 1:90; rapidly injecting 4mg/mL dye-modified rare earth nanoparticle solution into the PMA-PEG aqueous solution under the condition of ultrasound, wherein the configuration volume ratio of the dye-modified rare earth nanoparticle solution to the PMA-PEG aqueous solution is (0.5-2) to 9; and after ultrasonic homogenization, blowing out tetrahydrofuran in the aqueous solution by using nitrogen, and performing ultrafiltration purification to obtain the rare earth composite nanomaterial.
7. Use of the rare earth composite nanomaterial of any one of claims 1 to 5 in the preparation of an optical diagnostic and therapeutic agent.
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| CN115607669A (en) * | 2022-09-27 | 2023-01-17 | 上海市第十人民医院 | Diagnosis and treatment integrated rare earth nanoparticle and preparation method thereof |
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| CN114231273A (en) * | 2021-12-24 | 2022-03-25 | 上海大学 | Near-infrared dye-sensitized rare earth luminescent multilayer core-shell structure material hybrid system material, and preparation method and application thereof |
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