CN107837403A - 用于影像引导脑肿瘤切除的双模态纳米探针 - Google Patents
用于影像引导脑肿瘤切除的双模态纳米探针 Download PDFInfo
- Publication number
- CN107837403A CN107837403A CN201610840237.XA CN201610840237A CN107837403A CN 107837403 A CN107837403 A CN 107837403A CN 201610840237 A CN201610840237 A CN 201610840237A CN 107837403 A CN107837403 A CN 107837403A
- Authority
- CN
- China
- Prior art keywords
- probe
- nano
- image
- magnetic resonance
- bimodal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000523 sample Substances 0.000 title claims abstract description 70
- 230000002902 bimodal effect Effects 0.000 title claims abstract description 41
- 208000003174 Brain Neoplasms Diseases 0.000 title claims abstract description 28
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 25
- 238000001069 Raman spectroscopy Methods 0.000 claims abstract description 25
- 238000002595 magnetic resonance imaging Methods 0.000 claims abstract description 24
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 24
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 23
- 235000013339 cereals Nutrition 0.000 claims abstract description 22
- 235000007164 Oryza sativa Nutrition 0.000 claims abstract description 21
- 235000009566 rice Nutrition 0.000 claims abstract description 21
- 108010064942 Angiopep-2 Proteins 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 230000004048 modification Effects 0.000 claims abstract description 14
- 238000012986 modification Methods 0.000 claims abstract description 14
- 230000008499 blood brain barrier function Effects 0.000 claims abstract description 13
- 210000001218 blood-brain barrier Anatomy 0.000 claims abstract description 13
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims abstract description 12
- 238000002271 resection Methods 0.000 claims abstract description 10
- ZPWOOKQUDFIEIX-UHFFFAOYSA-N cyclooctyne Chemical group C1CCCC#CCC1 ZPWOOKQUDFIEIX-UHFFFAOYSA-N 0.000 claims abstract description 9
- QRZUPJILJVGUFF-UHFFFAOYSA-N 2,8-dibenzylcyclooctan-1-one Chemical compound C1CCCCC(CC=2C=CC=CC=2)C(=O)C1CC1=CC=CC=C1 QRZUPJILJVGUFF-UHFFFAOYSA-N 0.000 claims abstract description 6
- 230000002776 aggregation Effects 0.000 claims abstract description 5
- 238000004220 aggregation Methods 0.000 claims abstract description 5
- 230000031998 transcytosis Effects 0.000 claims abstract description 4
- 241000209094 Oryza Species 0.000 claims description 20
- 230000002708 enhancing effect Effects 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 7
- 150000007857 hydrazones Chemical class 0.000 claims description 6
- 102000007330 LDL Lipoproteins Human genes 0.000 claims description 3
- 108010007622 LDL Lipoproteins Proteins 0.000 claims description 3
- -1 N-hydroxy-succinamide ester Chemical class 0.000 claims description 3
- 210000002889 endothelial cell Anatomy 0.000 claims description 2
- 125000003396 thiol group Chemical class [H]S* 0.000 claims 1
- 230000008685 targeting Effects 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 2
- 238000011160 research Methods 0.000 abstract description 2
- 240000007594 Oryza sativa Species 0.000 abstract 1
- 208000032612 Glial tumor Diseases 0.000 description 20
- 206010018338 Glioma Diseases 0.000 description 20
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 238000011580 nude mouse model Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 241000699660 Mus musculus Species 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 239000010931 gold Substances 0.000 description 6
- 229910052737 gold Inorganic materials 0.000 description 6
- 238000003384 imaging method Methods 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 5
- 238000000502 dialysis Methods 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 4
- 210000005013 brain tissue Anatomy 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000002105 nanoparticle Substances 0.000 description 4
- 239000000700 radioactive tracer Substances 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 230000035945 sensitivity Effects 0.000 description 4
- 238000004416 surface enhanced Raman spectroscopy Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 230000005672 electromagnetic field Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 229920002892 amber Polymers 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 230000006353 environmental stress Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- RVHGJNGNKGDCPX-KKUMJFAQSA-N Asn-Phe-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N RVHGJNGNKGDCPX-KKUMJFAQSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 229910003317 GdCl3 Inorganic materials 0.000 description 1
- BUAKRRKDHSSIKK-IHRRRGAJSA-N Glu-Glu-Tyr Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 BUAKRRKDHSSIKK-IHRRRGAJSA-N 0.000 description 1
- XEUCQOBUZPQUMQ-UHFFFAOYSA-N Glycolone Chemical compound COC1=C(CC=C(C)C)C(=O)NC2=C1C=CC=C2OC XEUCQOBUZPQUMQ-UHFFFAOYSA-N 0.000 description 1
- UWIULCYKVGIOPW-UHFFFAOYSA-N Glycolone Natural products CCOC1=C(CC=CC)C(=O)N(C)c2c(O)cccc12 UWIULCYKVGIOPW-UHFFFAOYSA-N 0.000 description 1
- ALSRJRIWBNENFY-DCAQKATOSA-N Lys-Arg-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O ALSRJRIWBNENFY-DCAQKATOSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- SJUCACGNNJFHLB-UHFFFAOYSA-N O=C1N[ClH](=O)NC2=C1NC(=O)N2 Chemical compound O=C1N[ClH](=O)NC2=C1NC(=O)N2 SJUCACGNNJFHLB-UHFFFAOYSA-N 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 238000001237 Raman spectrum Methods 0.000 description 1
- HQTKVSCNCDLXSX-BQBZGAKWSA-N Ser-Arg-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O HQTKVSCNCDLXSX-BQBZGAKWSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VEIKMWOMUYMMMK-FCLVOEFKSA-N Thr-Phe-Phe Chemical compound C([C@H](NC(=O)[C@@H](N)[C@H](O)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 VEIKMWOMUYMMMK-FCLVOEFKSA-N 0.000 description 1
- HIINQLBHPIQYHN-JTQLQIEISA-N Tyr-Gly-Gly Chemical compound OC(=O)CNC(=O)CNC(=O)[C@@H](N)CC1=CC=C(O)C=C1 HIINQLBHPIQYHN-JTQLQIEISA-N 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- XCEBOJWFQSQZKR-UHFFFAOYSA-N dbco-nhs Chemical compound C1C2=CC=CC=C2C#CC2=CC=CC=C2N1C(=O)CCC(=O)ON1C(=O)CCC1=O XCEBOJWFQSQZKR-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- FSXRLASFHBWESK-UHFFFAOYSA-N dipeptide phenylalanyl-tyrosine Natural products C=1C=C(O)C=CC=1CC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FSXRLASFHBWESK-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 238000002296 dynamic light scattering Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- MEANOSLIBWSCIT-UHFFFAOYSA-K gadolinium trichloride Chemical compound Cl[Gd](Cl)Cl MEANOSLIBWSCIT-UHFFFAOYSA-K 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 108010015792 glycyllysine Proteins 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 1
- 229960003132 halothane Drugs 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002077 nanosphere Substances 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229960003330 pentetic acid Drugs 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 210000004129 prosencephalon Anatomy 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 108010017949 tyrosyl-glycyl-glycine Proteins 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 238000013298 xenograft nude mouse model Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1866—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid
-
- 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
-
- 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
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
-
- 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
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0056—Peptides, proteins, polyamino acids
-
- 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
- A61K49/0065—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/103—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being acyclic, e.g. DTPA
- A61K49/105—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being acyclic, e.g. DTPA the metal complex being Gd-DTPA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1851—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
- A61K49/1857—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA
- A61K49/186—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA the organic macromolecular compound being polyethyleneglycol [PEG]
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nanotechnology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Radiology & Medical Imaging (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Magnetic Resonance Imaging Apparatus (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明属于分子影像探针领域,涉及双模态纳米探针及其制备方法和在影像引导的脑肿瘤切除方面的应用。该纳米探针以金纳米粒作为载体,在其表面修饰磁共振成像基团Gd3+‑DTPA、拉曼报告分子IR783B、环辛炔基团DBCO或叠氮基团N=N=N、聚乙二醇、跨血脑屏障靶向基团Angiopep2;靶向基团Angiopep‑2特异性引导纳米探针通过转胞吞作用跨越血脑屏障,在脑肿瘤酸性环境中形成聚集体,从而引起磁共振信号和拉曼散射信号同时增强;本探针利用表面增强共振拉曼散射和磁共振成像相结合的双模态影像技术,可以通过磁共振成像在术前对肿瘤定位,通过表面增强共振拉曼散射成像在术中引导肿瘤切除。本发明在提高脑肿瘤治疗效果,促进个性化治疗方法临床转化方面有着重要的科研和临床意义。
Description
技术领域
本发明属分子影像领域,涉及分子影像探针,具体涉及用于影像引导脑肿瘤切除的双模态纳米探针。该探针具有跨血脑屏障、微酸环境诱导双模态信号增强、稳定性好等特点。
背景技术
据文献报道,脑肿瘤具有发病率、复发率、死亡率高和治愈率低等特点。其中,脑胶质瘤占所有颅内肿瘤的69%,是脑肿瘤中最致命的一种,5年存活率不足5%,目前脑胶质瘤的治疗是世界公认的难题,手术切除是质瘤治疗中最主要的手段,但是,由于脑胶质瘤的弥漫性浸润生长的特点,很难精确定位,使得在手术中从周围的正常脑组织中精确切除它变得非常困难。因此,在手术中对脑肿瘤边界进行高信噪比示踪是指导肿瘤准确切除的关键。
核磁共振成像(MRI)由于其组织空间分辨率高、无电离辐射等优点成为手术前脑胶质瘤定位的最主要手段,但其灵敏度较低,且存在术中成像仪器复杂、操作繁琐耗时等问题,只能用于胶质瘤的诊断和术前初步定位。光学成像作为新兴影像技术具有灵敏度高,无电离辐射,成本低廉等优点。光学成像中的荧光成像能够灵敏度高,成像速度快,操作简便适于术中实时引导手术,但荧光信号往往受到生物体自发荧光的干扰且信号不稳定、易淬灭,因此限制了其临床的推广应用。近年来表面增强共振拉曼散射(SERRS)逐渐被应用于医学影像领域。表面增强共振拉曼散射可实现实时、原位探测且灵敏度高、准确率高,成为强有力的痕量检测技术,特别适用于手术过程中的实时引导,具有良好的临床应用前景。表面增强共振拉曼散射和磁共振成像相结合优势互补的双模式影像技术能够提供较单一影像技术更加灵敏和更高分辨率的示踪效果。
双模态影像技术用于临床的关键是高效成像探针的设计。传统的探针信号始终处于高水平状态,这造成正常组织中因探针非特异性分布而引起高背景信号和信噪比的降低。脑肿瘤组织中,癌细胞在缺氧条件下高水平糖代谢所造成的组织间液的弱酸性是肿瘤微环境最普遍的现象,另外,癌细胞溶酶体往往较正常细胞溶酶体呈现更强的酸性因此与传统探针相比,具有对肿瘤微酸环境应激能力的探针将较少受到肿瘤大小,受体表达水平等个体因素限制,探针信号从正常组织内的“沉默”状态到肿瘤组织内的“开启”,状态转变将大幅提高脑肿瘤/正常组织间的信噪比,为早期/小体积肿瘤的准确示踪提供帮助。
研究公开了若干新型高活性的纳米增强基底;金纳米粒因粒径小、化学稳定性好且具有较强的信号增强性能,常被作为增强基底用以制备纳米探针。然而,目前常采用的金纳米粒如金纳米球、金纳米棒和金纳米星等,其表面电磁场叠加较少且分布不均匀,导致仅有0.1%拉曼分子信号会增强至108倍,而总体信号增强效率较低。
基于上述问题,本申请的发明人拟提供一种用于影像引导脑肿瘤切除的双模态纳米探针。该探针具有跨血脑屏障、微酸环境诱导双模态信号增强、稳定性好等特点,有助于实现双模态影像引导的脑胶质瘤切除。
发明内容
本发明的目的是基于现有技术的缺陷,提供一对用于影像引导脑肿瘤切除的双模态纳米探针。
本发明还提供了发明所述纳米探针的合成方法、表征及其在影像引导脑肿瘤切除中的应用。
本发明提供了一对具有“脑肿瘤靶向跨血脑屏障”和“pH诱导双模态信号增强”的纳米探针Au-AZ和Au-AK。其中Au-AZ以金纳米粒作为载体,在其表面修饰磁共振成像基团Gd3+-DTPA、拉曼报告分子IR783B、叠氮基团N≡N、聚乙二醇、跨血脑屏障靶向基团Angiopep2;Au-AK以金纳米粒作为载体,在其表面修饰磁共振成像基团Gd3+-DTPA、拉曼报告分子IR783B、环辛炔基团DBCO、聚乙二醇、跨血脑屏障靶向基团Angiopep2。磁共振成像基团、拉曼报告分子、叠氮基团、环辛炔基团、靶向基团分别通过巯基修饰在金纳米粒表面;聚乙二醇通过酸敏感的腙键修饰到金纳米粒表面;在正常情况下中,叠氮基团和环辛炔基团被及纳米粒表面的聚乙二醇掩盖,两种探针呈游离状态;尾静脉注射后,双模态纳米探针Au-AZ和Au-AK上的靶向多肽Angiopep-2特异性识别脑血管内皮细胞上低密度脂蛋白相关受体蛋白,引导影像探针通过转胞吞作用穿越血脑屏障;进入脑胶质瘤微酸环境后,聚乙二醇与金纳米粒间酸敏感的腙键断裂,聚乙二醇层脱去,暴露出叠氮基团和环辛炔基团;所述的两种探针通过点击化学反应形成球形聚集体,在785nm激光的激发下,金纳米粒与金纳米粒间的电磁场叠加作用大幅增加,能极大提高拉曼分子的信号增强效率,从而提高拉曼信号强度,在术前通过磁共振成像对肿瘤定位,术中通过拉曼成像示踪脑胶质瘤组织,从而实现双模态影像引导的脑胶质瘤切除。
更具体的,本发明的用于影像引导下脑肿瘤切除的纳米探针是一对具有“脑肿瘤靶向跨血脑屏障”和“pH诱导双模态信号增强”的纳米探针Au-AZ和Au-AK。其特征在于,以金纳米粒作为载体,在其表面修饰磁共振成像基团Gd3+-DTPA、拉曼报告分子IR783B、环辛炔基团DBCO或叠氮基团N=N=N、聚乙二醇、跨血脑屏障靶向基团Angiopep2。
本发明中,金纳米粒作为纳米探针的载体,具有粒径小、化学稳定性好和信号增强性能号好的优点;金纳米粒紫外吸收在500-600nm范围,当采用785nm的激光器激发时,金纳米粒仅具有表面增强拉曼散射效应,拉曼信号较低;在肿瘤酸性环境下,金纳米粒聚集后,在相邻纳米粒与纳米粒的间隙中形成大量热点,电磁场叠加作用大幅增加,聚集体的紫外吸收红移至600-800nm范围,采用最大吸收为780nm的近红外荧光染料IR783B作为拉曼报告分子,在785nm的激光器激发下,产生表面增强共振拉曼散射效应,拉曼信号大幅提高;
本发明中,双模态纳米探针Au-AZ和Au-AK中,双模态成像指磁共振成像和表面增强共振拉曼散射成像;磁共振成像基团Gd3+-DTPA、拉曼报告分子IR783B、叠氮基团N≡N、环辛炔基团DBCO分别通过巯基修饰在金纳米粒表面;跨血脑屏障靶向基团Angiopep-2的氨基酸序列为TFFYGGSRGKRNNFKTEEY,聚乙二醇的分子量为2000。跨血脑屏障靶向基团Angiopep2通过聚乙二醇修饰在金纳米粒表面。聚乙二醇与Angiopep2相连一端为N-羟基琥珀酰亚胺酯,与金纳米粒相连一端为通过酸敏感的腙键修饰在聚乙二醇上的巯基;
本发明中,双模态纳米探针Au-AZ和Au-AK上的靶向多肽Angiopep-2特异性识别脑血管内皮细胞上的低密度脂蛋白相关受体蛋白,引导影像探针通过转胞吞作用穿越血脑屏障,在脑肿瘤酸性环境中,腙键断裂,聚乙二醇外壳脱去,Au-AZ上的叠氮基团和Au-AK的环辛炔发生点击化学反应,纳米探针聚集,磁共振信号和拉曼信号增强,在术前通过磁共振成像对肿瘤定位,术中通过表面增强共振拉曼散射成像引导肿瘤切除。
本发明的纳米探针的优点有:
能克服传统探针信号始终处于高水平状态、在正常组织中非特异性分布、背景信号高和信噪比低等缺点,利用表面增强共振拉曼散射和磁共振成像相结合优势互补的双模式影像技术,从而实现影像引导下的脑肿瘤切除;
该探针具有对肿瘤微酸环境应激能力,将较少受到肿瘤大小,受体表达水平等个体因素限制,探针信号从正常组织内的“沉默”状态到肿瘤组织内的“开启”,状态转变将大幅提高脑肿瘤/正常组织间的信噪比。
本发明在提高脑肿瘤治疗效果,促进个性化治疗方法临床转化方面有着重要的科研和临床意义。
附图说明
图1.双模态纳米探针Au-AZ和Au-AK的合成路线图。
图2.双模态纳米探针Au-AZ的红外光谱图。
图3.双模态纳米探针Au-AK的红外光谱图。
图4.双模态纳米探针的TEM图。
图5.双模态纳米探针的拉曼光谱图。
图6.双模态纳米探针的粒径和Zeta电位。
图7.荷瘤裸鼠术前T1-MRI成像及离体脑组织切片的HE染色图。
图8.术中影像引导的胶质瘤切除及离体脑组织切片的HE染色图。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。
实施例1合成双模态纳米探针Au-AZ和Au-AK
按图1所示的合成路线,聚乙二醇Mal-PEG-CHO(6.0mg,3μmol)和碳端赖氨酸修饰的Angiopep2(7.2mg,3μmol)溶于10mL DMF中,室温搅拌反应30min得到化合物1。3-巯基丙酸甲酯(50mg,0.42mmol)和水合肼(60mg,1.2mmol)溶于30mL乙醇,室温搅拌反应过夜,产物过硅胶柱纯化后得到化合物2;化合物1(13mg,3.0μmol)和化合物2(0.36mg,3.0μmol)溶于1.0M MES(pH 4.7)缓冲溶液中室温搅拌反应过夜,产物过经截流分子量1000的透析袋纯化后得到化合物3;
按上法,聚乙二醇PEG-CHO(60mg,0.03mmol)和化合物2(3.6mg,0.03mmol)反应得到化合物3a;二亚乙基三胺五乙酸二酸酐(100mg,0.28mmol)和2-巯基乙胺(21mg,0.28mmol)溶于1mL DMF中,室温搅拌反应4h得到化合物4;四氯金酸(5mg,0.015mmol)溶于50mL去离子水,煮沸,快速加入0.5柠檬酸钠水溶液(8mg,0.031mmol),回流反应5min,反应产物过经截流分子量10000的透析袋纯化后得到柠檬酸修饰的AuNS 5,粒径约为20nm。化合物4溶于3mL DMF中,逐滴加入10mL AuNS 5(1.3μM)中,室温搅拌反应过夜得到AuNS 6;GdCl3(26.3mg,0.16mmol)溶于300μL去离子水中(pH 7.4),加入10mL AuNS 6(1.0μM)的水溶液中,室温搅拌反应过夜,产物透析纯化后得到AuNS 7;巯基修饰的IR783B(15mg,15μmol)溶于0.2mL DMF中,逐滴加入10mL AuNS 7(1.3μM)中,室温搅拌反应过夜得到AuNS 8。末端叠氮基修饰的聚乙二醇N3-PEG-SH(14mg,0.07mmol)溶于300μL DMF,加入5mL AuNS 8(1.0μM)的水溶液,室温搅拌反应过夜,产物透析纯化后得到AuNS 9;AuNS 9(5.0nmol)、化合物3和3a混合物(1:99molar ratio,totally 0.03mmol)溶于5.0mL去离子水中,室温搅拌反应过夜,产物透析纯化后得到纳米探针Au-AZ;
同法,2-巯基乙胺(5.0mg,0.07mmol)和环辛炔化合物DBCO-NHS(35mg,0.07mmol)溶于200μL DMF反应得到化合物10,逐滴加入5mL AuNS 8(1.0μM)的水溶液中,室温搅拌反应过夜,产物透析纯化后得到AuNS 11。AuNS 11(5.0nmol)、化合物3和3a混合物(1:99molarratio,totally 0.03mmol)溶于5.0mL去离子水中,室温搅拌反应过夜,产物透析纯化后得到纳米探针Au-AK。
实施例2双模态纳米探针Au-AZ和Au-AK的表征
在双模态纳米探针Au-AZ和Au-AK合成过程中,取适量纯化后产物,溶于甲醇,滴加在溴化钾窗片上,吹干甲醇,采集红外光谱图如图2和图3所示,1720cm-1处为DTPA中C=O的伸缩振动峰;1044和1193cm-1处为IR783B中S=O的伸缩振动峰;2800-2960cm-1处为PEG中C-H的伸缩振动峰;1650and 1550cm-1为靶向多肽Angiopep2中酰胺键的红外吸收峰。Au-AZ的红外谱图中,2100cm-1为叠氮化合物中N=N=N的红外吸收峰;
取适量双模态纳米探针,溶于去离子水中,滴加在透射电镜专用铜网上,放在40度烘箱中烘干后,通过透射电镜采集TEM图。如图4所示,纳米探针粒径约为20nm,分散均匀,金核心外包裹有半透明的厚度约为3nm的聚乙二醇层;
取适量双模态纳米探针,溶于去离子水中,通过手持式拉曼扫描仪采集拉曼光谱图。如图5所示,509和541cm-1处双峰为拉曼报告分子IR783B中C-S的伸缩振动峰和C-C-C的弯曲振动峰;
双模态纳米探针的粒径和Zeta电位是在马尔文粒径分析仪上采用动态光散射法完成的。2.0mg/mL的牛血清白蛋白标准溶液用于设备校准。粒径和Zeta电位图谱见图6。所有测试样品用0.45μm的针孔式过滤器过滤。Au-AZ和Au-AK的平均粒径分别为26nm和23nm,平均Zeta电位为-16mV和-15mV。
实施例3双模态纳米探针在术前脑胶质瘤定位中的应用
按常法建立脑胶质瘤异种移植裸鼠模型;
将雄性裸鼠固定于脑立体定位仪上,将制备的U87细胞混悬液(10μL/鼠)注入裸鼠脑纹状体部位,2周后通过T2-MRI成像观察裸鼠脑内肿瘤生长状况,采用T1-MRI成像考察模型裸鼠的脑内胶质瘤大小并进行肿瘤初步定位,尾静脉注射纳米探针Au-AZ和Au-AK的混合液,MRI成像将在7.0T小动物Micro-MRI系统(Biospect,Bruker)上进行,采用头部线圈、异氟烷/氧气混合气体麻醉、温水循环系统保持裸鼠扫描期间体温,具体成像参数如下:FOV:25×25mm,激励次数:2,层数:4层,层厚:1mm,层空间分辨率:0.125mm,矩阵256×256。MRI成像结果如图7所示,注射纳米探针24h后,脑胶质瘤边界被清晰的描绘出来,此边界与离体脑切片的HE染色结果相吻合。
实施例4双模态纳米探针在术中引导脑胶质瘤切除中的应用
尾静脉注射纳米探针Au-AZ和Au-AK 24h后,采用10%水合氯醛对荷瘤裸鼠进行麻醉、灌流。分离脑组织,置于立体定位仪上,剥离出胶质瘤病灶部位;采用手持式拉曼成像仪采集SERRS信号,结合T1加权MRI图像分析定位胶质瘤区域,切除胶质瘤病灶;继续采集SERRS信号,尤其是肿瘤浸润区,根据信号有无判断进一步的手术切除区域,实时引导胶质瘤手术的完整切除;脑胶质瘤切除后的脑组织进行HE染色,结果如图8所示,胶质瘤组织被完整切除。
上述实施例结果表明本纳米探针可以选择性地浓集于胶质瘤组织,可实现在影像引导脑肿瘤切除。
SEQUENCE LISTING
<110> 复旦大学
<120> 用于影像引导脑肿瘤切除的双模态纳米探针
<130> 20160921
<160> 1
<170> PatentIn version 3.3
<210> 1
<211> 19
<212> PRT
<213> 靶向多肽Angiopep-2
<400> 1
Thr Phe Phe Tyr Gly Gly Ser Arg Gly Lys Arg Asn Asn Phe Lys Thr
1 5 10 15
Glu Glu Tyr
Claims (6)
1.用于影像引导脑肿瘤切除的双模态纳米探针,其特征在于,所述探针包括Au-AZ和Au-AK;其中Au-AZ由金纳米粒作为载体,在其表面修饰磁共振成像基团Gd3+-DTPA,拉曼报告分子IR783B,靶向多肽Angiopep2,叠氮基团N=N=N,聚乙二醇;Au-AK由金纳米粒作为载体,在其表面修饰磁共振成像基团Gd3+-DTPA,拉曼报告分子IR783B,靶向多肽Angiopep2,环辛炔基团DBCO,聚乙二醇。
2.按权利要求1所述的用于影像引导脑肿瘤切除的双模态纳米探针,其特征在于,所述的双模态为磁共振成像和表面增强共振拉曼散射成像。
3.按权利要求1所述的双模态纳米探针,其特征在于,所述的磁共振成像基团Gd3+-DTPA,拉曼报告分子IR783B,叠氮基团N=N=N,环辛炔基团DBCO分别通过巯基修饰在所述的金纳米粒表面。
4.按权利要求1所述的用于影像引导脑肿瘤切除的双模态纳米探针,其特征在于,所述的靶向多肽Angiopep-2的氨基酸序列为TFFYGGSRGKRNNFKTEEY;聚乙二醇的分子量为2000;金纳米粒的半径为20nm。
5.按权利要求1所述的用于影像引导脑肿瘤切除的双模态纳米探针,其特征在于,所述的靶向多肽Angiopep2通过聚乙二醇修饰在金纳米粒表面,聚乙二醇与Angiopep2相连一端为N-羟基琥珀酰亚胺酯,与金纳米粒相连一端为通过酸敏感的腙键修饰在聚乙二醇上的巯基。
6.按权利要求1所述的用于影像引导脑肿瘤切除的双模态纳米探针,其特征在于,所述的双模态纳米探针Au-AZ和Au-AK上的靶向多肽Angiopep-2特异性识别脑血管内皮细胞上的低密度脂蛋白相关受体蛋白,引导影像探针通过转胞吞作用穿越血脑屏障;在脑肿瘤酸性环境中,腙键断裂,聚乙二醇外壳脱去,Au-AZ上的叠氮基团和Au-AK的环辛炔发生点击化学反应,纳米探针聚集,磁共振信号和拉曼散射信号增强,在术前通过磁共振成像对肿瘤定位,术中通过表面增强共振拉曼散射成像引导肿瘤切除。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610840237.XA CN107837403B (zh) | 2016-09-21 | 2016-09-21 | 用于影像引导脑肿瘤切除的双模态纳米探针 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610840237.XA CN107837403B (zh) | 2016-09-21 | 2016-09-21 | 用于影像引导脑肿瘤切除的双模态纳米探针 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107837403A true CN107837403A (zh) | 2018-03-27 |
CN107837403B CN107837403B (zh) | 2020-10-20 |
Family
ID=61657565
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610840237.XA Active CN107837403B (zh) | 2016-09-21 | 2016-09-21 | 用于影像引导脑肿瘤切除的双模态纳米探针 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN107837403B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109975540A (zh) * | 2019-04-04 | 2019-07-05 | 扬州大学 | 一种核酸抗体修饰的免疫金探针及其制备方法和应用 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101679022A (zh) * | 2007-04-02 | 2010-03-24 | 爱默蕾大学 | 使用表面增强拉曼纳米粒子标记物的体内肿瘤靶向和光谱检测 |
CN102406949A (zh) * | 2010-09-21 | 2012-04-11 | 复旦大学 | 一种靶向示踪的多模式诊断纳米影像药物 |
CN103239737A (zh) * | 2013-04-27 | 2013-08-14 | 深圳先进技术研究院 | 荧光造影剂及其制备方法 |
CN103894557A (zh) * | 2014-03-19 | 2014-07-02 | 丽水市中心医院 | 磁共振成像下可视的功能化金纳米粒子的制备方法及应用 |
CN104258423A (zh) * | 2014-09-16 | 2015-01-07 | 首都医科大学 | 一种用于脑胶质瘤的钆掺杂碳酸锰双模式成像探针 |
-
2016
- 2016-09-21 CN CN201610840237.XA patent/CN107837403B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101679022A (zh) * | 2007-04-02 | 2010-03-24 | 爱默蕾大学 | 使用表面增强拉曼纳米粒子标记物的体内肿瘤靶向和光谱检测 |
CN102406949A (zh) * | 2010-09-21 | 2012-04-11 | 复旦大学 | 一种靶向示踪的多模式诊断纳米影像药物 |
CN103239737A (zh) * | 2013-04-27 | 2013-08-14 | 深圳先进技术研究院 | 荧光造影剂及其制备方法 |
CN103894557A (zh) * | 2014-03-19 | 2014-07-02 | 丽水市中心医院 | 磁共振成像下可视的功能化金纳米粒子的制备方法及应用 |
CN104258423A (zh) * | 2014-09-16 | 2015-01-07 | 首都医科大学 | 一种用于脑胶质瘤的钆掺杂碳酸锰双模式成像探针 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109975540A (zh) * | 2019-04-04 | 2019-07-05 | 扬州大学 | 一种核酸抗体修饰的免疫金探针及其制备方法和应用 |
CN109975540B (zh) * | 2019-04-04 | 2022-02-11 | 扬州大学 | 一种核酸抗体修饰的免疫金探针及其制备方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
CN107837403B (zh) | 2020-10-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Hu et al. | Dysprosium-modified tobacco mosaic virus nanoparticles for ultra-high-field magnetic resonance and near-infrared fluorescence imaging of prostate cancer | |
Li et al. | Fluorescence-guided probes of aptamer-targeted gold nanoparticles with computed tomography imaging accesses for in vivo tumor resection | |
CN104258425B (zh) | 一种rgd修饰的超小磁性氧化铁纳米颗粒的制备方法及其应用 | |
Huang et al. | Biomedical nanomaterials for imaging-guided cancer therapy | |
CN102406949B (zh) | 一种靶向示踪的多模式诊断纳米影像药物 | |
Qian et al. | Combination glioma therapy mediated by a dual‐targeted delivery system constructed using OMCN–PEG–Pep22/DOX | |
Lee et al. | In vivo delineation of glioblastoma by targeting tumor-associated macrophages with near-infrared fluorescent silica coated iron oxide nanoparticles in orthotopic xenografts for surgical guidance | |
US20100215581A1 (en) | Contrast agents for detecting prostate cancer | |
Chen et al. | Dynamic contrast-enhanced folate-receptor-targeted MR imaging using a Gd-loaded PEG-dendrimer–folate conjugate in a mouse xenograft tumor model | |
CN103083689B (zh) | 一种用于脑肿瘤诊断的跨血脑屏障靶向多模态纳米药物 | |
Xie et al. | Retro-enantio isomer of angiopep-2 assists nanoprobes across the blood-brain barrier for targeted magnetic resonance/fluorescence imaging of glioblastoma | |
Yue et al. | An EGFRvIII targeted dual-modal gold nanoprobe for imaging-guided brain tumor surgery | |
Cho et al. | Sensitive angiogenesis imaging of orthotopic bladder tumors in mice using a selective magnetic resonance imaging contrast agent containing VEGF121/rGel | |
Xi et al. | HER-2/neu targeted delivery of a nanoprobe enables dual photoacoustic and fluorescence tomography of ovarian cancer | |
CN107652358A (zh) | 一种uPAR靶向性多肽、探针和活体分子显像方法 | |
Wang et al. | Receptor-targeted quantum dots: fluorescent probes for brain tumor diagnosis | |
CN108219782A (zh) | 一种近红外荧光探针及基于该探针的多模态纳米造影剂及其制备和应用 | |
Qin et al. | Carbonized paramagnetic complexes of Mn (II) as contrast agents for precise magnetic resonance imaging of sub-millimeter-sized orthotopic tumors | |
He et al. | Recent advances of aggregation-induced emission materials for fluorescence image-guided surgery | |
CN109395101A (zh) | 靶向血脑屏障和脑胶质瘤的磁共振对比剂的制备方法 | |
CN106075469A (zh) | Gd3+诱导金纳米团簇自组装成金纳米颗粒的方法及应用 | |
Ptak et al. | The NCI Alliance for Nanotechnology in Cancer: achievement and path forward | |
Du et al. | Endoscopic molecular imaging of early gastric cancer using fluorescently labeled human H-ferritin nanoparticle | |
Yang et al. | Multifunctional upconversion nanoparticles for targeted dual-modal imaging in rat glioma xenograft | |
Ni et al. | Transferrin receptor 1 targeted optical imaging for identifying glioma margin in mouse models |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |