CN107384863B - 荧光和spect/ct双影像功能微球示踪的神经干细胞及应用 - Google Patents
荧光和spect/ct双影像功能微球示踪的神经干细胞及应用 Download PDFInfo
- Publication number
- CN107384863B CN107384863B CN201710456006.3A CN201710456006A CN107384863B CN 107384863 B CN107384863 B CN 107384863B CN 201710456006 A CN201710456006 A CN 201710456006A CN 107384863 B CN107384863 B CN 107384863B
- Authority
- CN
- China
- Prior art keywords
- spect
- fluorescent
- neural stem
- microsphere
- image functional
- 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.)
- Expired - Fee Related
Links
- 210000001178 neural stem cell Anatomy 0.000 title claims abstract description 66
- 238000002603 single-photon emission computed tomography Methods 0.000 title claims abstract description 53
- 238000002591 computed tomography Methods 0.000 title description 5
- 239000004005 microsphere Substances 0.000 claims abstract description 114
- 150000002504 iridium compounds Chemical class 0.000 claims abstract description 24
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 15
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 15
- 229920000642 polymer Polymers 0.000 claims abstract description 14
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 210000002569 neuron Anatomy 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 229920006237 degradable polymer Polymers 0.000 claims abstract description 5
- 230000006378 damage Effects 0.000 claims abstract description 4
- 208000027418 Wounds and injury Diseases 0.000 claims abstract description 3
- 239000003814 drug Substances 0.000 claims abstract description 3
- 208000014674 injury Diseases 0.000 claims abstract description 3
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 239000002202 Polyethylene glycol Substances 0.000 claims description 16
- 229920001223 polyethylene glycol Polymers 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 13
- 108010011110 polyarginine Proteins 0.000 claims description 10
- 239000002245 particle Substances 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 7
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 5
- 229920002125 Sokalan® Polymers 0.000 claims description 5
- 229920001577 copolymer Polymers 0.000 claims description 5
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 claims description 5
- 239000004584 polyacrylic acid Substances 0.000 claims description 5
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 5
- 239000006285 cell suspension Substances 0.000 claims description 4
- 238000012258 culturing Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 108010039918 Polylysine Proteins 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 238000004113 cell culture Methods 0.000 claims description 3
- 238000004945 emulsification Methods 0.000 claims description 3
- 239000001963 growth medium Substances 0.000 claims description 3
- -1 poly (lactic acid-polyethylene Chemical group 0.000 claims description 3
- 229920000724 poly(L-arginine) polymer Polymers 0.000 claims description 3
- 229920000656 polylysine Polymers 0.000 claims description 3
- 238000004114 suspension culture Methods 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 230000009977 dual effect Effects 0.000 claims 4
- 210000004027 cell Anatomy 0.000 abstract description 29
- 238000000034 method Methods 0.000 abstract description 9
- 230000008439 repair process Effects 0.000 abstract description 9
- 241000282414 Homo sapiens Species 0.000 abstract description 5
- 238000005516 engineering process Methods 0.000 abstract description 4
- 230000000007 visual effect Effects 0.000 abstract description 2
- 239000000700 radioactive tracer Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 29
- 239000012071 phase Substances 0.000 description 14
- 210000000130 stem cell Anatomy 0.000 description 10
- 238000009826 distribution Methods 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 239000000839 emulsion Substances 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 230000005284 excitation Effects 0.000 description 5
- 238000003384 imaging method Methods 0.000 description 5
- 230000008901 benefit Effects 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000002372 labelling Methods 0.000 description 4
- 230000005012 migration Effects 0.000 description 4
- 238000013508 migration Methods 0.000 description 4
- 230000004693 neuron damage Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 206010011878 Deafness Diseases 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 230000010370 hearing loss Effects 0.000 description 3
- 231100000888 hearing loss Toxicity 0.000 description 3
- 208000016354 hearing loss disease Diseases 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000001588 bifunctional effect Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 210000003477 cochlea Anatomy 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 238000000703 high-speed centrifugation Methods 0.000 description 2
- 210000001320 hippocampus Anatomy 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 210000002901 mesenchymal stem cell Anatomy 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000003068 molecular probe Substances 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000006862 quantum yield reaction Methods 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000011476 stem cell transplantation Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 229920006022 Poly(L-lactide-co-glycolide)-b-poly(ethylene glycol) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 208000027115 auditory system disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000002041 carbon nanotube Substances 0.000 description 1
- 229910021393 carbon nanotube Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000006727 cell loss Effects 0.000 description 1
- 238000000701 chemical imaging Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000005786 degenerative changes Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 238000002189 fluorescence spectrum Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- MILUBEOXRNEUHS-UHFFFAOYSA-N iridium(3+) Chemical compound [Ir+3] MILUBEOXRNEUHS-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- 238000002715 modification method Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 210000000944 nerve tissue Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 238000012634 optical imaging Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 239000002096 quantum dot Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 238000000482 two photon fluorescence microscopy Methods 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0618—Cells of the nervous system
- C12N5/0623—Stem cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/30—Nerves; Brain; Eyes; Corneal cells; Cerebrospinal fluid; Neuronal stem cells; Neuronal precursor cells; Glial cells; Oligodendrocytes; Schwann cells; Astroglia; Astrocytes; Choroid plexus; Spinal cord tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
-
- 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
- A61K49/005—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
- A61K49/0069—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
- A61K49/0476—Particles, beads, capsules, spheres
- A61K49/048—Microparticles, microbeads, microcapsules, microspheres, i.e. having a size or diameter higher or equal to 1 micrometer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
- A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
- A61K51/1244—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles
- A61K51/1251—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles micro- or nanospheres, micro- or nanobeads, micro- or nanocapsules
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Medicinal Chemistry (AREA)
- Cell Biology (AREA)
- Pharmacology & Pharmacy (AREA)
- Developmental Biology & Embryology (AREA)
- Wood Science & Technology (AREA)
- Organic Chemistry (AREA)
- Neurology (AREA)
- Optics & Photonics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Nanotechnology (AREA)
- Physics & Mathematics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Neurosurgery (AREA)
- Biochemistry (AREA)
- General Engineering & Computer Science (AREA)
- Ophthalmology & Optometry (AREA)
- Immunology (AREA)
- Virology (AREA)
- Microbiology (AREA)
- Dispersion Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明涉及一种荧光和SPECT/CT双影像功能微球示踪的神经干细胞，神经干细胞内吞有荧光和SPECT/CT双影像功能微球，荧光和SPECT/CT双影像功能微球包括以下质量分数的各组分：聚合物70‑99.9％，环金属铱化合物0.05‑20％，I125剂0.05‑10％；聚合物为可降解聚合物。本发明还公开了上述荧光和SPECT/CT双影像功能微球示踪的神经干细胞在制备螺旋神经元损伤或神经退行性疾病的示踪剂和/或治疗剂中的应用。本发明所制荧光和SPECT/CT双影像功能微球示踪的神经干细胞，为示踪植入活体及人体内的组织工程种子细胞提供了一种无创动态、直观简便的方法，提供了一种针对神经退行性疾病的观察和修复技术。
Description
技术领域
本发明涉及分子探针技术领域，尤其涉及一种荧光和SPECT/CT双影像功能微球示踪的神经干细胞及应用。
背景技术
目前，神经退行性疾病(Neurodegenerative disease)是一类慢性进行性疾病。不同类型神经退行性疾病的病变部位和病因虽然各不相同，但大脑内的特定部位的神经元细胞的退化病变是这种疾病的共同特征。阿尔兹海默症，帕金森氏症等神经退行性疾病严重影响人类的工作生活。大脑内的神经元细胞一般是不会再生的，并且神经退行性疾病会随着时间的推移而恶化，最终导致功能障碍。神经退行性疾病的发病机理尚未得到证实，但大量研究指明神经元细胞损伤和缺失是导致其发病的关键因素。因此治疗神经退行性疾病的关键在于增加新生神经元细胞的数目。
鼠神经干细胞由17.5-18.5天胎鼠海马组织分离培养，来源丰富，取材方便。体外培养、体内植入均有多向分化潜能、增殖分化能力强、免疫原性低等特性，是神经组织工程中修复神经元缺损的理想种子细胞。
神经干细胞(neural stem cells,NSCs)因其在体外经诱导能表达成神经元和神经胶质细胞表型，且具有良好的体外扩增能力，已经成为组织工程修复受损的神经元及神经退行性疾病的优势细胞。在动物中运用神经干细胞修复神经退行性疾病已经取得了显著的成效。然而对在体在位移植的细胞研究缺乏一些有效的识别和追踪检测手段，目前对于外源性NSCs在神经退行性疾病的修复中的作用、对体内新形成的神经元细胞的来源仍存在争议。
目前常用的细胞鉴定方法均需要在移植后一定时间内处死动物，在离体的情况下对组织进行免疫组化切片来分析鉴定移植细胞的情况，无法动态实时检测移植细胞在活体内的迁移、分布、增殖等生命过程，而且也不适于人体干细胞移植研究。因此，需要探索出一种有效的能够活体追踪移植干细胞的方法，从而可以明确移植干细胞的功能作用。
目前，具有优良光学特性并且运用于光学成像的纳米材料包括金纳米颗粒、量子点、多孔二氧化硅纳米颗粒、纳米碳管、聚乳酸荧光微球等，其中荧光微球示踪的优越性在于：稳定形态结构，粒径分布集中(50-300nm)；稳定而高效的发光效率；具有优良的生物降解性和生物相容性；大大降低了某些小分子荧光素体内代谢率。因此，荧光微球示踪在分子影像技术领域得到广泛关注和高度重视。
此外，环金属铱(III)化合物本身具有发光量子效率高、激发波长和发射波长间Stokes位移大、抗光漂白能力强及可发射近红外波长(580-700nm)的光谱等优势，在生物标记和成像方面得到广泛应用。至今未发现基于铱化合物的具有光学特性的分子探针示踪NSCs并且进行成像观察的报道。
发明内容
为解决上述技术问题，本发明的目的是提供一种荧光和SPECT/CT双影像功能微球示踪的神经干细胞及应用，本发明所制荧光和CT双影像功能微球标记的干细胞，为示踪植入活体及人体内的组织工程种子细胞提供了一种无创动态、直观简便的方法，提供了一种针对神经退行性疾病的观察和修复技术。
本发明公开了一种荧光和SPECT/CT双影像功能微球示踪的神经干细胞，神经干细胞内吞有荧光和SPECT/CT双影像功能微球，荧光和SPECT/CT双影像功能微球包括以下质量分数的各组分：聚合物70-99.9％，环金属铱化合物0.05-20％，I125剂0.05-10％；聚合物为可降解聚合物。
荧光和SPECT/CT双影像功能微球的粒径为50-300nm。SPECT为单光子发射计算机断层成像术的英文缩写。
进一步地，可降解聚合物为聚乙丙交酯、聚乳酸-聚乙二醇共聚物或聚乙丙交酯-聚乙二醇共聚物。优选地，聚乙丙交酯的分子量为5-100kg/mol，聚乳酸-聚乙二醇共聚物或聚乙丙交酯-聚乙二醇共聚物的分子量为10-100kg/mol，其中聚乙二醇的分子量为2-5kg/mol。
进一步地，微球表面还连接有修饰化合物，修饰化合物为聚精氨酸或聚赖氨酸。微球表面连接修饰化合物后，能增加进入干细胞的微球量，提高干细胞的荧光强度。
进一步地，环金属铱化合物的荧光发射光谱波长为550-750nm，量子产率为0.005-0.5，双光子散射界面为50-20000，环金属铱化合物能够使微球具有单光子和双光子荧光成像功能，且具有荧光稳定性好、耐光漂白，双光子散射界面大等优点。
进一步地，I125剂为I125Na，适用于SPECT/CT影像示踪，适用于深层组织的影像观察，提高干细胞的追踪可分辨性。。
进一步地，荧光和SPECT/CT双影像功能微球的制备方法包括以下步骤：
将聚合物和环金属铱化合物溶解于有机溶剂，作为油相，将I125剂溶于水，作为内水相，将聚丙烯酸和聚乙烯醇溶于水，作为外水相；通过复乳法制备荧光和SPECT/CT双影像功能微球。
进一步地，有机溶剂为氯仿。复乳法操作步骤如下：首先将油相、内水相制成初乳，将初乳加入外水相制得水/油/水的复乳，待油相的有机溶剂挥发除尽，即得到荧光和SPECT/CT双影像功能微球。
进一步地，还包括以下步骤：通过氨酯化反应，将微球与修饰化合物的氨基偶联。
进一步地，荧光和SPECT/CT双影像功能微球示踪的神经干细胞的制备方法包括以下步骤：
(1)将荧光和SPECT/CT双影像功能微球与细胞培养液混合均匀，得到微球溶液，并在4℃下孵育12h-72h；
(2)将神经干细胞悬浮培养，使神经干细胞增殖成球，得到神经干细胞悬浮液；
(3)将步骤(1)孵育后的微球加入到神经干细胞悬浮液中，在37℃下培养1-3天，离心富集悬浮的神经干细胞，得到荧光和SPECT/CT双影像功能微球示踪的神经干细胞。
进一步地，在步骤(1)中，微球溶液的浓度为0.02-0.4mg/mL。
进一步地，在步骤(3)中，离心速度为1000rpm左右。
进一步地，在步骤(3)中，还包括用纯培养基洗涤，除去未进入神经干细胞的微球的步骤。
进一步地，神经干细胞由小鼠的海马提取得到，使用上述方法，荧光和SPECT/CT双影像功能微球示踪的神经干细胞被神经干细胞吞噬，且测试结果表明，神经干细胞的微球标记率可达90％以上。
本发明还公开了上述荧光和SPECT/CT双影像功能微球示踪的神经干细胞在制备螺旋神经元损伤或神经退行性疾病治疗剂中的应用，微球标记的干细胞在使用过程中，不仅能示踪干细胞的迁移过程，还能提供对神经损伤和退行疾病的治疗作用。
应用时，使用单光子、双光子共聚焦显微镜下观察标记后细胞荧光亮度，并使用CT扫描I125放射性信号强度，以此作为细胞做动物活体实验的标准。
借由上述方案，本发明至少具有以下优点：
本发明中环金属铱化合物通过制成微球的方式大大降低荧光素铱本身的细胞毒性，提高组织相容性。与铱化合物直接进行细胞标记相比，铱化合物被聚合物负载后，微球细胞毒性低、粒径分布均匀(160-220nm)、易被吞噬，良好的生物降解性和生物相容性，同时，环金属铱化合物本身具有优良的荧光特性，如量子产率高、Stokes位移大、抗光漂白，双光子散射界面大，对生物组织损伤小等特性。
放射性核素标记可实现细胞的深层精准追踪，通过将I125负载于聚合物微球，延长了I125(同样包括铱化合物)的代谢时间，降低放射性I125快速代谢对人体的毒性，增加了神经干细胞的可观察时间。
利用荧光和SPECT/CT双功能示踪微球标记和示踪NSCs，可以在双光子显微镜和SPECT/CT设备下无创、动态、可重复性观察，组织穿透力深但组织损伤小，减少自身背景荧光，图像获得较高信噪比，真正实现活体辨别NSCs植入受体后的动态生存和迁移情况，更好地重复性观察NSCs在螺旋神经元损伤所导致的听力损失小鼠耳蜗区域增殖分化能力和修复状况，在运用分子影像学技术动态示踪动物体内NSCs修复局部螺旋神经元损伤具有广泛的发展前景。
本发明为铱化合物在示踪NSCs方面提供了一种直观简便、动态无创的方案，进一步深入观察和证实螺旋神经元损伤引起的听力缺失，以及评估NSCs在螺旋神经元损伤引起的听力缺失中的应用，在听觉功能修复领域具有广泛的运用前景。
本发明所制荧光和SPECT/CT双影像功能微球示踪的神经干细胞，为示踪植入活体及人体内的组织工程种子细胞提供了一种无创动态、直观简便的方法，提供了一种针对神经退行性疾病的观察和修复技术。
上述说明仅是本发明技术方案的概述，为了能够更清楚了解本发明的技术手段，并可依照说明书的内容予以实施，以下以本发明的较佳实施例并配合附图详细说明如后。
附图说明
图1为本发明荧光和SPECT/CT双影像功能微球的制备过程示意图；
图2为使用含本发明微球的培养液培育神经干细胞后，于单光子激光共聚焦显微镜下拍摄的荧光图片；
图3为表面修饰了聚精氨酸的微球与未修饰聚精氨酸的微球的标记细胞的情况对比图；
图4图示了本发明微球标记的神经干细胞在小鼠皮下的小动物活体成像追踪图。
具体实施方式
下面结合附图和实施例，对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明，但不用来限制本发明的范围。
本发明使用的神经干细胞(NSCs)来源于小鼠的海马。
实施例1
荧光和SPECT/CT双影像功能微球的制备方法，包括以下步骤：
(1)称量2mg(Bis(2-methyldibenzo[f,h]quinoxaline)(acetylacetonate)iridium(III))(Ir(MDQ)2acac)和25mg聚乙丙交酯-聚乙二醇－共聚物(PLGA-PEG)混合，用1mL氯仿溶解，得到油相，准备120μL I125Na作内水相。
(2)将步骤(1)得到的油相和内水相超声混合5次(2s,100W,BILON92-II)，得到初乳剂。
(3)向步骤(2)的产物加入4mL PVA(聚乙烯醇，poly vinyl alcohol)水溶液(5wt％)，超声混合5次(2s，100W)形成复乳剂。
(4)将步骤(3)的产物稀释到PAA(聚丙烯酸，poly acrylic acid)水溶液中(5wt％，40mL)，室温下过夜搅拌、避光挥发。
(5)用50mL高速离心管收集步骤(4)含微球溶液，先用无水乙醇清洗一次，高速离心(14500rpm，20min)，弃上清，超声均匀，再加入超纯水清洗，高速离心(12000rpm，10min)，重复2-3次，最终所得微球沉淀溶于1mL纯水。
(6)均匀抽取10μL步骤(5)溶液，烘干后称量，计算得到步骤(5)微球溶液浓度，为3-4mg/mL。
图1为上述微球的制备过程示意图，从图中可看出，微球的外层为聚合物壳，内层I125剂，微球的聚合物壳的表面为环金属铱化合物。本实施例中，上述各组分的含量为聚合物93％，环金属铱化合物4％，I125剂3％。
实施例2
(1)NSCs正常传代培养，在非粘附性培养瓶中悬浮培养；
(2)将实施例1所得微球溶液与细胞培养基混合，配成微球培养液(0.04-0.8mg/mL)置于培养箱(37℃，5％CO2)中孵育24h。
(3)24h后，神经干细胞正常增殖生长，加入相同体积步骤(2)制备的含铱化合物的微球培养液(0.04-0.8mg/mL)，使细胞与微球混合后微球的终浓度为0.02-0.4mg/mL，将微球与细胞混合置于培养箱(37℃，5％CO2)，继续培养1-3天，优选3天。
(4)1-3天后，1000rpm离心5min，去除培养液，PBS清洗2遍后，将细胞接种到预先孵育12h laminin(层粘连蛋白)的24孔皿玻片中继续孵育12h，然后去除培养基，加入4％多聚甲醛处理30min，再用PBS清洗两遍，将皿底爬片制成玻片标本。
(5)利用Nuance多光谱成像系统，绿光激发，采集图片。
(6)单光子激光共聚焦显微镜下观察玻片标本，激发光波长405nm，放射波长接收范围560nm-660nm(此激发和发射光基于长Stoke位移效应)，采集图片。
(7)双光子激光共聚焦显微镜下观察玻片标本，激发波长820nm，观察摄片。
(8)取适量微球溶液注入玻璃细管中(直径2mm，长度10cm，液高2-3cm)，进行SPECT/CT扫描，和I125剂对比信号强度。
(9)若步骤(7)(8)得到的荧光强度和信号强度达到示踪标准，将荧光和SPECT/CT双功能微球铱化合物微球标记的NSCs(5×105-5×106)注入小鼠耳蜗柯蒂氏器区域，双光子共聚焦显微镜连续动态观察，比较荧光/信号强弱和分布，结合SPECT/CT扫描评估局部干细胞的分布状况；进一步观察1-4周干细胞的分布状况，4周后评价小鼠的听觉恢复情况。对小鼠进行ABR检测，在4K,8K,16K,24K,32K均有显著性的听域下移，说明干细胞移植对于修复受损伤部位具有一定的作用。通过结合荧光、SPECT信号，可以动态观察和追踪干细胞在受损区域的变化，进而阐明NSC对听觉疾病的修复过程。
图2为10倍镜405nm激发光下观察到的孵育上述微球72h的NSCs，从图中可看出与上述微球共孵育72h的神经干细胞球被标记上了荧光，荧光亮度极强，可用于后续的荧光示踪。
综合微球标记的NSC的细胞毒性和荧光、SPECT强度数据，微球的浓度选择0.02-0.4mg/mL为佳，即可保证NSC的细胞存活率，又可以有明显的追踪信号。
实施例3
(1)称量0.2mg Ir化合物，分别与25mg聚乙丙交酯、聚乳酸-聚乙二醇共聚物、聚乙丙交酯-聚乙二醇共聚物混合，再分别用1mL氯仿溶解，得到油相，准备10μL I125Na作内水相；
(2)将步骤(1)得到的油相和内水相超声混合5次(2s,100W,BILON92-II)，得到初乳剂；
(3)向步骤(2)的产物加入4mL PVA水溶液(5wt％)，超声混合5次(2s，100W)形成复乳剂；
(4)将步骤(3)的产物稀释到PAA水溶液中(5wt％，40mL)，室温下过夜搅拌、避光挥发；
(5)用50mL高速离心管收集步骤(4)含微球溶液，先用无水乙醇清洗一次，高速离心(14500rpm，20min)，弃上清，超声均匀，再加入纯水清洗，高速离心(12000rpm，10min)，重复2-3次，最终所得微球沉淀溶于1mL纯水；
(6)均匀抽取10μL步骤(5)溶液，烘干后称量，计算得到步骤(5)微球溶液浓度，采用聚乙丙交酯所制得微球为1-2mg/mL，采用聚乳酸-聚乙二醇共聚物所制得微球为3-4mg/mL，采用聚乙丙交酯-聚乙二醇共聚物所制得微球为2-3mg/mL；本实施例中，上述各微球中各组分的含量为聚合物99.9％％，I125剂0.05％，环金属铱化合物0.05％。
(7)抽取100μL所制备的微球溶液，用纯水稀释成2mL，在纳米粒度及zeta电位分析仪(Zetasizer Nano ZS90)测得微球粒径，聚乙丙交酯所制得微球粒径分布范围200-300nm，聚乳酸-聚乙二醇共聚物所制得微球粒径分布范围50-200nm，聚乙丙交酯-聚乙二醇共聚物所制得微球粒径分布范围150-300nm。
类似地，增加环金属铱化合物和I125剂的量，如制备时选用10mg铱化合物和100μL10mg/mL的I125剂，25mg聚乙丙交酯-聚乙二醇共聚物，制得微球中，聚合物的质量分数为70％，铱化合物的质量分数为20％，I125剂的质量分数为10％。
此外，微球表面还可以连接一些修饰化合物，修饰化合物为聚精氨酸、聚赖氨酸或聚乙二胺。修饰化合物能够提高微球的干细胞内吞量。以下以聚精氨酸为例，具体修饰方法如下：
向实施例1或3制备的微球溶液中加入聚精氨酸，通过氨酯化反应，修饰化合物表面的氨基与微球表面的羧基反应后连接到微球表面。将最终所得的微球与间充质干细胞用上述方法进行培养，得到荧光和MRI双影像功能微球示踪的间充质干细胞。
图3为表面修饰了聚精氨酸的微球(3A)与未修饰聚精氨酸的微球(3B)的标记细胞的情况对比图，从图中可看出修饰聚精氨酸的微球(3A)的标记细胞的荧光强度是未修饰聚精氨酸的微球(3B)的标记细胞的荧光强度的2-3倍，说明表面修饰了聚精氨酸能够促进微球进入细胞，从而增强细胞标记强度。
实施例4
(1)NSCs正常传代培养；
(2)将实施例3中采用聚乳酸-聚乙二醇共聚物所制得微球，用培养液稀释成浓度分别为0.02、0.1、0.2、0.3、0.4mg/mL的微球溶液，4℃冰箱避光过夜孵育；
(3)次晨，将含微球培养液分别替换掉培养相同细胞数目的细胞培养皿中的培养液；
(4)三天后，单光子共聚焦显微镜下观察细胞荧光亮度，结果显示0.4mg/mL微球培养液所培养的NSCs，细胞状态最佳，荧光亮度最强，SPECT的电子信号也最强。
实施例5
(1)将荧光和SPECT/CT双功能铱化合物微球标记好的NSCs取5×105-10×106个细胞，用100μL PBS重悬，1mL注射器抽取后注入准备好的4周龄雄性裸鼠皮下；
(2)小动物荧光成像系统、SPECT/CT定期扫描，观察注射部位荧光迁移及淬灭及放射性成像情况。
图4为上述实验进行0-28天的追踪结果，从图中可看出，微球标记好的NSCSs5×105-10×106个细胞皮下注射4周龄雄性裸鼠后注射当天荧光强度最强，在随后的四周内荧光强度逐渐减弱，直到第28天荧光标记消失，说明本发明提供的荧光和SPECT/CT双功能铱化合物微球标记可持续四周，有利于长时间持续观察注射细胞在体内的持续迁移变化。
以上所述仅是本发明的优选实施方式，并不用于限制本发明，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变型，这些改进和变型也应视为本发明的保护范围。
Claims (6)
1. 一种荧光和SPECT/CT双影像功能微球示踪的神经干细胞，其特征在于：所述神经干细胞内吞有所述荧光和SPECT/CT双影像功能微球，所述荧光和SPECT/CT双影像功能微球包括以下质量分数的各组分：聚合物99.9%，环金属铱化合物0.05%，I125剂0.05%；所述聚合物为可降解聚合物；所述荧光和SPECT/CT双影像功能微球的粒径为160-220 nm；所述可降解聚合物为聚乙丙交酯、聚乳酸-聚乙二醇共聚物或聚乙丙交酯-聚乙二醇共聚物；微球表面还连接有修饰化合物，所述修饰化合物为聚精氨酸或聚赖氨酸；
荧光和SPECT/CT双影像功能微球示踪的神经干细胞的制备方法包括以下步骤：
（1）将荧光和SPECT/CT双影像功能微球与细胞培养液混合均匀，得到微球溶液，并在4℃下孵育12 h-72 h；微球溶液的浓度为0.02-0.4mg/mL；
（2）将所述神经干细胞悬浮培养，使所述神经干细胞增殖成球，得到神经干细胞悬浮液；
（3）将步骤（1）孵育后的微球加入到所述神经干细胞悬浮液中，在37℃下培养1-3天，离心富集悬浮的神经干细胞，得到所述荧光和SPECT/CT双影像功能微球示踪的神经干细胞。
2.根据权利要求1所述的荧光和SPECT/CT双影像功能微球示踪的神经干细胞，其特征在于：所述I125剂为I125Na。
3.根据权利要求1或2所述的荧光和SPECT/CT双影像功能微球示踪的神经干细胞，其特征在于，所述荧光和SPECT/CT双影像功能微球的制备方法包括以下步骤：
将所述聚合物和环金属铱化合物溶解于有机溶剂，作为油相，将所述I125剂溶于水，作为内水相，将聚丙烯酸和聚乙烯醇溶于水，作为外水相；通过复乳法制备所述荧光和SPECT/CT双影像功能微球。
4.根据权利要求3所述的荧光和SPECT/CT双影像功能微球示踪的神经干细胞，其特征在于，还包括以下步骤：通过氨酯化反应，将微球与修饰化合物的氨基偶联。
5.根据权利要求1所述的荧光和SPECT/CT双影像功能微球示踪的神经干细胞，其特征在于：在步骤（3）中，还包括用纯培养基洗涤，除去未进入神经干细胞的微球的步骤。
6.根据权利要求1或2所述的荧光和SPECT/CT双影像功能微球示踪的神经干细胞在制备螺旋神经元损伤或神经退行性疾病的追踪剂和治疗剂中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710456006.3A CN107384863B (zh) | 2017-06-16 | 2017-06-16 | 荧光和spect/ct双影像功能微球示踪的神经干细胞及应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710456006.3A CN107384863B (zh) | 2017-06-16 | 2017-06-16 | 荧光和spect/ct双影像功能微球示踪的神经干细胞及应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107384863A CN107384863A (zh) | 2017-11-24 |
| CN107384863B true CN107384863B (zh) | 2020-10-13 |
Family
ID=60333024
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710456006.3A Expired - Fee Related CN107384863B (zh) | 2017-06-16 | 2017-06-16 | 荧光和spect/ct双影像功能微球示踪的神经干细胞及应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107384863B (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110064059B (zh) * | 2019-05-17 | 2021-09-28 | 中国医学科学院放射医学研究所 | 一种荧光/光声/spect多模式成像纳米探针的制备方法及其在癌症诊断中的应用 |
| CN113222887A (zh) * | 2021-03-03 | 2021-08-06 | 复旦大学附属华山医院 | 基于深度学习的纳米铁标记神经干细胞示踪的方法 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120065614A1 (en) * | 2010-09-10 | 2012-03-15 | University Of North Texas | Polyionic transitional metal phosphorescent complex/polymer hybrid systems for bioimaging and sensing applications |
| CN104910211A (zh) * | 2015-05-07 | 2015-09-16 | 中山大学 | 一种环金属铱(iii)配合物及其制备方法和在活细胞线粒体染色中的应用 |
| CN105778916B (zh) * | 2016-03-14 | 2019-02-26 | 哈尔滨工程大学 | 具有细胞示踪功能的液体荧光微球的制备及应用方法 |
| CN106822924B (zh) * | 2017-02-23 | 2020-06-16 | 中山大学 | 一种能进行mr-荧光双模态成像的可降解纳米胶束及其制备方法和应用 |
-
2017
- 2017-06-16 CN CN201710456006.3A patent/CN107384863B/zh not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN107384863A (zh) | 2017-11-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Ong et al. | Recent advances in polymeric nanoparticles for enhanced fluorescence and photoacoustic imaging | |
| Scialabba et al. | Highly homogeneous biotinylated carbon nanodots: red-emitting nanoheaters as theranostic agents toward precision cancer medicine | |
| Ai et al. | Near infrared-emitting persistent luminescent nanoparticles for hepatocellular carcinoma imaging and luminescence-guided surgery | |
| Wang et al. | Biocompatible and photostable AIE dots with red emission for in vivo two-photon bioimaging | |
| Xia et al. | Aggregation-induced emission-active near-infrared fluorescent organic nanoparticles for noninvasive long-term monitoring of tumor growth | |
| US11291736B2 (en) | pH-responsive ultrasensitive fluorescent nanoprobe, preparation and using method thereof | |
| Ahmed et al. | Fluorescent multiblock π-conjugated polymer nanoparticles for in vivo tumor targeting | |
| Chen et al. | Tumor vasculature targeting: a generally applicable approach for functionalized nanomaterials | |
| Pu et al. | Phosphorylcholine‐Coated Semiconducting Polymer Nanoparticles as Rapid and Efficient Labeling Agents for In Vivo Cell Tracking | |
| Li et al. | In vivo cancer targeting and imaging-guided surgery with near infrared-emitting quantum dot bioconjugates | |
| Zhang et al. | Supramolecular hybrids of AIEgen with carbon dots for noninvasive long-term bioimaging | |
| CN106415246A (zh) | 作为组织可定位的生物传感器的近红外荧光单壁碳纳米管 | |
| Kang et al. | NIR fluorescence imaging and treatment for cancer immunotherapy | |
| Yuan et al. | Tumor‐Responsive Fluorescent Light‐up Probe Based on a Gold Nanoparticle/Conjugated Polyelectrolyte Hybrid | |
| Yin et al. | Folic acid-conjugated organically modified silica nanoparticles for enhanced targeted delivery in cancer cells and tumor in vivo | |
| Dai et al. | Dextran-based fluorescent nanoprobes for sentinel lymph node mapping | |
| Sekiyama et al. | Delayed increase in near-infrared fluorescence in cultured murine cancer cells labeled with oxygen-doped single-walled carbon nanotubes | |
| Xiong et al. | Highly luminescent and photostable near-infrared fluorescent polymer dots for long-term tumor cell tracking in vivo | |
| Men et al. | Biomimetic semiconducting polymer dots for highly specific NIR-II fluorescence imaging of glioma | |
| CN107384863B (zh) | 荧光和spect/ct双影像功能微球示踪的神经干细胞及应用 | |
| Wang et al. | Lipid coated upconverting nanoparticles as NIR remote controlled transducer for simultaneous photodynamic therapy and cell imaging | |
| Zhang et al. | Near-infrared BODIPY-paclitaxel conjugates assembling organic nanoparticles for chemotherapy and bioimaging | |
| Cui et al. | Self-carried AIE nanoparticles for in vitro non-invasive long-term imaging | |
| Lu et al. | Dual-modal photoacoustic and magnetic resonance tracking of tendon stem cells with PLGA/iron oxide microparticles in vitro | |
| Saskia et al. | Targeted labeling of an early-stage tumor spheroid in a chorioallantoic membrane model with upconversion nanoparticles |
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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20201013 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |