CN109400572B - 近红外第二窗口发射的荧光染料及其制备方法和应用 - Google Patents
近红外第二窗口发射的荧光染料及其制备方法和应用 Download PDFInfo
- Publication number
- CN109400572B CN109400572B CN201811304201.5A CN201811304201A CN109400572B CN 109400572 B CN109400572 B CN 109400572B CN 201811304201 A CN201811304201 A CN 201811304201A CN 109400572 B CN109400572 B CN 109400572B
- Authority
- CN
- China
- Prior art keywords
- fluorescent dye
- infrared
- compound
- window
- preparation
- 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.)
- Active
Links
- 239000007850 fluorescent dye Substances 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000000975 dye Substances 0.000 claims abstract description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- 229960001701 chloroform Drugs 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- -1 o-carboxyphenyl Chemical group 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000001632 sodium acetate Substances 0.000 claims description 7
- 235000017281 sodium acetate Nutrition 0.000 claims description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 239000012065 filter cake Substances 0.000 claims description 4
- 229910020366 ClO 4 Inorganic materials 0.000 claims description 3
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229920002866 paraformaldehyde Polymers 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims 2
- 239000004005 microsphere Substances 0.000 abstract description 12
- 238000003384 imaging method Methods 0.000 abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 9
- 238000010521 absorption reaction Methods 0.000 abstract description 7
- 230000008033 biological extinction Effects 0.000 abstract description 6
- GDIYMWAMJKRXRE-UHFFFAOYSA-N (2z)-2-[(2e)-2-[2-chloro-3-[(z)-2-(1,3,3-trimethylindol-1-ium-2-yl)ethenyl]cyclohex-2-en-1-ylidene]ethylidene]-1,3,3-trimethylindole Chemical compound CC1(C)C2=CC=CC=C2N(C)C1=CC=C1C(Cl)=C(C=CC=2C(C3=CC=CC=C3[N+]=2C)(C)C)CCC1 GDIYMWAMJKRXRE-UHFFFAOYSA-N 0.000 abstract description 2
- 239000012620 biological material Substances 0.000 abstract description 2
- 239000002798 polar solvent Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000693 micelle Substances 0.000 description 12
- 239000002202 Polyethylene glycol Substances 0.000 description 11
- 239000002872 contrast media Substances 0.000 description 11
- 229920001223 polyethylene glycol Polymers 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 150000003904 phospholipids Chemical class 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 238000000108 ultra-filtration Methods 0.000 description 6
- 238000002189 fluorescence spectrum Methods 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 238000000295 emission spectrum Methods 0.000 description 3
- 238000000799 fluorescence microscopy Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical group [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 3
- 229960004657 indocyanine green Drugs 0.000 description 3
- 229910010272 inorganic material Inorganic materials 0.000 description 3
- 239000011147 inorganic material Substances 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000009210 therapy by ultrasound Methods 0.000 description 3
- ANRHNWWPFJCPAZ-UHFFFAOYSA-M thionine Chemical compound [Cl-].C1=CC(N)=CC2=[S+]C3=CC(N)=CC=C3N=C21 ANRHNWWPFJCPAZ-UHFFFAOYSA-M 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000006862 quantum yield reaction Methods 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- PMJHHCWVYXUKFD-SNAWJCMRSA-N (E)-1,3-pentadiene Chemical compound C\C=C\C=C PMJHHCWVYXUKFD-SNAWJCMRSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000581650 Ivesia Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 239000002041 carbon nanotube Substances 0.000 description 1
- 229910021393 carbon nanotube Inorganic materials 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 125000003827 glycol group Chemical group 0.000 description 1
- JEFJSEIUEJBMSR-UHFFFAOYSA-N hydron;n-phenylaniline;chloride Chemical compound Cl.C=1C=CC=CC=1NC1=CC=CC=C1 JEFJSEIUEJBMSR-UHFFFAOYSA-N 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000002096 quantum dot Substances 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 229910052761 rare earth metal Inorganic materials 0.000 description 1
- 150000002910 rare earth metals Chemical class 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- SRLOHQKOADWDBV-NRONOFSHSA-M sodium;[(2r)-2,3-di(octadecanoyloxy)propyl] 2-(2-methoxyethoxycarbonylamino)ethyl phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCCNC(=O)OCCOC)OC(=O)CCCCCCCCCCCCCCCCC SRLOHQKOADWDBV-NRONOFSHSA-M 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001018 xanthene dye Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D311/82—Xanthenes
-
- 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
- A61K49/0063—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
- A61K49/0076—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 dispersion, suspension, e.g. particles in a liquid, colloid, emulsion
- A61K49/0082—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 dispersion, suspension, e.g. particles in a liquid, colloid, emulsion micelle, e.g. phospholipidic micelle and polymeric micelle
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B57/00—Other synthetic dyes of known constitution
-
- 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
-
- 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
- C09K2211/1003—Carbocyclic compounds
- C09K2211/1007—Non-condensed systems
-
- 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
- C09K2211/1088—Heterocyclic compounds characterised by ligands containing oxygen as the only heteroatom
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Dispersion Chemistry (AREA)
- Materials Engineering (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明属于生物材料技术领域,具体为一种近红外第二窗口发射的荧光染料及其制备方法和应用。本发明提供的近红外荧光染料,其摩尔消光系数大,吸收、发射波长长且可调范围宽,因此,可用于深组织多通道成像,荧光编码微球等应用。此外,该系列染料在极性溶剂中不易溶致变色,在水中具备相比现有常见的近红外第二窗口七甲川菁类荧光染料更好的稳定性,在较大的酸碱范围内具有很好的化学稳定性。
Description
技术领域
本发明属于生物材料技术领域,具体涉及一类近红外第二窗口发射的近红外荧光染料及其制备方法,以及该荧光染料在制备深组织单通道或多通道成像和荧光编码胶束或荧光编码微球用造影剂中的应用。
背景技术
目前常见的分子影像技术如断层扫描成像(CT),X-射线,超声成像(US)和磁共振成像(MRI)被用于对疾病等的医疗诊断,但这些方法具有较差的空间分辨率及其无法实现动态实时监测等缺点。荧光成像技术由于具有非侵入性、实时、所需样品量少、高分辨率等优点,在生命科学和医学等领域已经被广泛使用。在最近几年里,利用近红外第二窗口的发射光(1000 nm~1700 nm)进行荧光成像得到了越来越多的关注,相比于传统的荧光成像所用的波段(400 nm-900 nm),生物组织在近红外第二窗口自身的吸收和散射弱,这样就可以极大地提高成像质量和穿透深度。目前,常用的近红外第二窗口造影剂包括一些无机材料如碳纳米管,稀土掺杂纳米颗粒,量子点等,但是它们在生物体内的代谢缓慢且机理至今仍不明确,潜在的生物毒性较大,这大大限制了它们的生物应用价值。
与之相比,有机荧光染料具有相对分子量小,易于代谢等优点,近年来在近红外第二窗口的应用中备受关注。最典型的例子是FDA批准用于临床上血管造影的吲哚菁绿(ICG),近年来有研究者发现其在近红外第二窗口的荧光发射拖尾展现出了优异的成像效果。另外,斯坦福大学的戴宏杰课题组报道了一系列基于供体-受体-供体(D-A-D)结构的分子型荧光染料,其普遍特征是在808 nm激发下可发射出荧光峰值在1000-1200 nm的荧光,实现了对肿瘤、淋巴、脑部血管等的成像。但此类荧光染料的摩尔消光系数低且激发波长短,其荧光亮度较低。因而对ICG所代表的菁类荧光染料进行结构改造以获得更长波长更亮的近红外第二窗口发射是目前分子型荧光染料设计的焦点,这是由于该类荧光染料具有较大的摩尔消光系数,较高的荧光量子产率以及宽的波长可调范围等优点。遗憾的是,目前所有报道的波长达到近红外第二窗口的菁类荧光染料在水中均表现出摩尔消光系数大幅降低,波长变宽且蓝移,荧光显著淬灭,稳定性差等缺点,这严重限制了其在后续生物应用中的表现。相比之下,呫吨类染料如罗丹明其结构刚性好,稳定性比菁染料好,但目前还不能把这类染料波长红移到1000 nm以上。
发明内容
本发明的目的在于提供一类化学稳定高、光稳定性高、生物相容性好的近红外第二窗口发射的有机小分子荧光染料及其制备方法和应用。
本发明提供的近红外第二窗口发射的有机小分子荧光染料,其结构通式如下式(I)所示:
其中,R1和R2为H或N[(CH2)jCH3]2,OH或OCH3 ,R3和R4为H或邻羧基苯基或苯基或邻甲基苯基,j为0~6的整数;X选自ClO4、PF6、BF4、Cl、Br、I、CF3COO、CF3SO3、CH3COO或CH3SO3;Y选自氧(O)、硫(S);n为1到5整数;m和k为0或1。
本发明所提出的近红外荧光染料式的制备方法,其化学合成路线如下:
其中,R1和R2为H或N[(CH2)jCH3]2,OH或OCH3, R3和R4为H或邻羧基苯基或苯基或邻甲基苯基,j为0~6的整数;X选自ClO4、PF6、BF4、Cl、Br、I、CF3COO、CF3SO3、CH3COO或CH3SO3;Y选自氧(O)、硫(S);n为1到5整数;m和k为0或1;h为1或3;化合物3为甲醛或其等价物多聚甲醛或如图中通式。
制备的具体步骤为:
(1)中间体1的合成
将取代苯酰(化合物1)与环烷基酮(化合物2)溶于浓硫酸中,在80~100℃下反应1~3小时;冷却后加入碎冰淬灭反应,再加入质子酸,析出固体,干燥,即得到苯并吡喃翁盐(中间体1);其中化合物1和化合物2的投料摩尔比为1:(1.~ 3);质子酸可选自HClO4、HPF6、HBF4、HCl、HBr、HI、CF3COOH、CF3SO3H和CH3SO3H中的一种;
(2)近红外染料的合成
将中间体1、醛基等价物(化合物3)、醋酸钠混合于醋酸酐中,在氮气保护下,于20-130℃下反应1~8小时;反应结束后加入乙醚沉淀,过滤,用三氯甲烷溶解滤饼,并用柱色谱分离,最终得到近红外荧光染料;其中,中间体1、化合物3和醋酸钠的投料摩尔比为(1~1.5):0.5: (1~1.5)。
本发明制备得到荧光染料为长波长吸收、长波长发射光谱可调荧光染料(结构如通式I所示),可用于制备深组织单通道或多通道成像用的造影剂,制备的具体步骤如下:
将近红外荧光染料和甲氧基磷脂聚乙二醇(2000)溶于氯仿中,再搅拌0.5~1小时,旋除出去溶剂,真空干燥,加热至80℃后加入60-80℃的去离子水溶解,超声,冷却至室温后再通过30KD或10KD的超滤管超滤浓缩,得到最终造影剂;其中,近红外荧光染料和甲氧基磷脂聚乙二醇(2000)的质量百分比为(1:(500~50)),最终造影剂的浓度为0.005~0.5 mM。
该造影剂为胶束状,可用于对小鼠肝等深组织单通道或多通道成像。
本发明制备得到荧光染料为长波长吸收、长波长发射光谱可区分荧光染料(结构如通式I所示),可用于制备荧光编码胶束、荧光编码微球用的造影剂。制备荧光编码胶束造影剂的具体步骤如下:
将系列近红外荧光染料按不同比率和甲氧基磷脂聚乙二醇(2000)溶于氯仿中,再搅拌0.5~1小时,旋除出去溶剂,真空干燥,加热至80℃后加入60-80℃的去离子水溶解,超声,冷却至室温后再通过30KD或10KD的超滤管超滤浓缩,得到荧光编码胶束;其中,近红外荧光染料和甲氧基磷脂聚乙二醇(2000)的质量百分比为(1:(500~50)),最终造影剂的浓度为0.005~0.5 mM。
制备荧光编码微球造影剂的具体步骤如下:
将系列近红外荧光染料按不同比率与微球置于体积比为95:5的氯仿/异丙醇混合溶剂中,等溶剂自然挥发干,再用乙醇洗涤三遍即可得到最终的荧光编码微球;其中,近红外荧光染料和微球质量百分比为(1:(5000~50))。
本发明提供的近红外荧光染料,其摩尔消光系数大,吸收、发射波长长且可调范围宽,因此,可用于深组织单通道或多通道成像,荧光编码微球等应用。此外,该系列染料在极性溶剂中不易溶致变色,在水中具备相比现有常见的近红外第二窗口七甲川菁类荧光染料更优异的更好的稳定性,在较大的酸碱范围内具有很好的稳定性。
本发明的近红外荧光染料(通式I),在三氯甲烷溶液中,最大吸收峰位于883~1089nm,最大发射峰位于920~1140 nm。
本发明的近红外荧光染料(通式I),在三氯甲烷溶液中的摩尔消光系数为82000~190000 M-1cm-1。
本发明的近红外荧光染料(通式I),在三氯甲烷溶液中的荧光量子产率为0.09~0.66%。
本发明的近红外荧光染料(通式I)与甲氧基磷脂聚乙二醇2000形成的胶束,在磷酸盐缓冲溶液中,最大吸收峰位于920~1015 nm,最大发射峰位于880~1080 nm。
附图说明
图1为近红外荧光染料在三氯甲烷中的吸收谱图。
图2为近红外荧光染料在三氯甲烷中的荧光发射谱图。
图3为近红外荧光染料与磷脂聚乙二醇2000形成的胶束,在小鼠肝部多通道成像图。
图4为近红外荧光染料与磷脂聚乙二醇2000形成的荧光编码胶束荧光发射光谱图。
图5为近红外荧光染料与微球形成的荧光编码微球图。
图6为近红外荧光染料在三氯甲烷中的吸收和发射谱图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,本发明用以下具体实施例进行说明,但本发明绝非限于这些例子。以下所述仅为本发明较好的实施例,仅用于解释本发明,并不能因此而理解为对本发明专利范围的限制。应当指出的是,凡是本发明的精神和原则之内所做的任何修改、替代或改进均应包含在本发明的保护范围之内。
实施例1:
近红外荧光染料1a的制备,化合物结构式如下:
具体合成路线如下:
具体合成步骤如下:
化合物4(237 mg, 0.5 mmol),化合物5(177.5 mg, 0.5 mmol),多聚甲醛(15 mg,0.5mmol),醋酸钠(41 mg, 0.5 mmol)混合于10 mL醋酸酐中,在氮气保护下,于80℃下反应1小时。反应结束后趁热过滤,用二氯甲烷溶解滤饼,并用柱色谱(二氯甲烷/甲醇=100/1,v/v)分离得到最终荧光染料1a,产率50%。1H NMRδ8.02 (d, J = 6.28 Hz, 1H), 7.57 (t,J = 7.24 Hz, 1H), 7.51 (t, J = 7.56 Hz, 1H), 7.47 (s, 1H), 7.16 (d, J = 7.48Hz, 1H), 6.87 (d, J = 8.16 Hz, 1H), 6.60 (d, J = 8.92 Hz, 1H), 6.46 (s, 1H),6.41 (d, J = 8.92 Hz, 1H), 6.30 (d, J = 7.76 Hz, 2H), 6.25 (s, 1H), 3.36 (q,J = 6.92 Hz, 8H), 2.78-2.49 (m, 6H), 2.18-2.14 (m, 1H), 1.74-1.72 (m, 5H),1.17 (t, J = 6.92 Hz, 12H)。
实施例2:
近红外荧光染料2a的制备,化合物结构式如下:
具体合成路线如下:
具体合成步骤如下
中间体5(177.5 mg, 0.5 mmol),丙二醛二缩苯胺盐酸盐(64.7 mg, 0.25 mmol),醋酸钠(41 mg, 0.5 mmol)混合于10 mL醋酸酐中,在氮气保护下,于80℃下反应2小时。反应结束后用旋转蒸发仪旋干溶剂,再加入50 mL水并用二氯甲烷萃取,有机相浓缩后用柱色谱(二氯甲烷/甲醇=100/1, v/v)分离得到最终荧光染料2a,产率67%。1H NMRδ 7.81 (d, J = 12.20 Hz, 2H), 7.39 (s, 2H), 7.35 (d, J = 8.72 Hz, 2H), 6.81 (d, J = 8.12Hz, 2H), 6.78 (s, 2H), 6.43 (t, J = 12.20 Hz, 1H), 3.48-3.45 (m, 8H), 2.61(m, 4H), 2.51 (s, 4H), 1.74 (s, 4H), 1.17 (s, 12H)。
实施例3:
近红外荧光染料3a的制备,化合物结构式如下:
具体合成路线如下:
具体合成步骤如下
中间体5(177.5 mg, 0.5 mmol),戊二烯缩醛二苯胺盐酸盐(71 mg, 0.25 mmol),醋酸钠(41 mg, 0.5 mmol)混合于10 mL醋酸酐中,在氮气保护下,于80℃下反应2小时。反应结束后用旋转蒸发仪旋干溶剂,再加入50 mL水并用二氯甲烷萃取,有机相浓缩后用柱色谱(二氯甲烷/甲醇=100/1, v/v)分离得到最终荧光染料3a,产率61%。 1H NMR δ 7.68 (d,J = 9.36 Hz, 2H), 7.43 (s, 2H), 7.39 (d, J = 8.96 Hz, 2H), 7.31 (t, J = 12.72Hz, 1H), 6.84 (dd, J = 8.84 Hz, 1.88 Hz, 2H), 6.69 (d, J = 1.88 Hz, 2H), 6.64(d, J = 13.12 Hz, 2H), 3.50 (q, J = 7.04 Hz, 8H), 2.65-2.64 (m, 2H), 2.57-2.54 (m, 4H), 1.77 (t, J = 4.88 Hz, 4H), 1.18 (t, J = 7.04 Hz, 12H)。
实施例4:
近红外荧光染料与磷脂聚乙二醇形成胶束的制备方法,以荧光染料2a和DSPE-mPEG2000为例。具体步骤如下:
1 mg近红外荧光染料3a和100 mg DOPE-PEG2000溶于20 mL氯仿,搅拌1小时后,旋除溶剂,真空干燥,加热至80℃后加入20 mL 80℃的去离子水溶解,超声,冷却至室温后再通过30KD的超滤管超滤浓缩,得到最终造影剂,浓度为0.5 mM。
应用例:
近红外荧光染料I与磷脂聚乙二醇形成的胶束对小鼠肝部多色成像。具体步骤如下:
通过小鼠尾静脉同时注射50 μL染料1a浓度为200 μM的胶束溶液、50 μL染料2a浓度为200 μM的胶束溶液、50 μL染料3a浓度为200 μM的胶束溶液,分别用808 nm、965 nm、1064 nm外置激光器照射小鼠腹部,激光器功率密度为50 mW/cm2(参见图3)。
近红外荧光染料I与磷脂聚乙二醇形成的荧光编码胶束。具体步骤如下:
用808 nm激光激发荧光编码胶束溶液,分别采集在不同组织深度下850 nm长通、1000 nm长通、1100 nm长通的荧光发射光谱,三个通道的荧光强度比率既可以得到荧光编码信息。(参见图4)。
近红外荧光染料I与磷脂聚乙二醇形成的荧光编码微球。具体步骤如下:
用808 nm激光激发荧光编微球,分别采集在850 nm长通、1000 nm长通、1100 nm长通的荧光发射光谱,三个通道的荧光强度比率既可以得到荧光编码信息。(参见图5)。
Claims (1)
1.一种近红外第二窗口发射的荧光染料的制备方法,其特征在于,荧光染料结构通式如下:
合成路线如下:
其中,R1和R2为H或N[(CH2)jCH3]2,OH或OCH3,R3和R4为H或邻羧基苯基或苯基或邻甲基苯基,j为0~6的整数;X选自ClO4、PF6、BF4、Cl、Br、I、CF3COO、CF3SO3、CH3COO或CH3SO3;Y选自氧(O)、硫(S);n为1到5整数;m和k为0或1;h为1或3;化合物3为甲醛或其等价物多聚甲醛或如合成路线中通式;
制备的具体步骤如下:
(1)中间体1的合成
将化合物1与化合物2溶于浓硫酸中,在80~100℃下反应1~3小时;冷却后加入碎冰淬灭反应,再加入质子酸高氯酸,析出固体,干燥,即得到中间体1;其中化合物1和化合物2的投料摩尔比为1:(1~ 3);
(2)近红外染料的合成
将中间体1、化合物3、醋酸钠混合于醋酸酐中,在氮气保护下,于20-130℃下反应1~8小时;反应结束后加入乙醚沉淀,过滤,用三氯甲烷溶解滤饼,并用柱色谱分离,最终得到近红外荧光染料;其中,中间体1、化合物3和醋酸钠的投料摩尔比为(1~1.5):0.5: (1~1.5)。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811304201.5A CN109400572B (zh) | 2018-11-03 | 2018-11-03 | 近红外第二窗口发射的荧光染料及其制备方法和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811304201.5A CN109400572B (zh) | 2018-11-03 | 2018-11-03 | 近红外第二窗口发射的荧光染料及其制备方法和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109400572A CN109400572A (zh) | 2019-03-01 |
CN109400572B true CN109400572B (zh) | 2022-10-11 |
Family
ID=65471475
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201811304201.5A Active CN109400572B (zh) | 2018-11-03 | 2018-11-03 | 近红外第二窗口发射的荧光染料及其制备方法和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109400572B (zh) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110079117B (zh) * | 2019-04-22 | 2021-04-30 | 复旦大学 | 近红外第二窗口激发/发射的荧光染料及制备方法和应用 |
CN111849196B (zh) * | 2020-08-21 | 2022-03-22 | 湖南大学 | 一种近红外二区染料及其合成方法 |
CN113980036B (zh) * | 2021-09-30 | 2023-05-30 | 复旦大学 | 碱性和活性氧、活性氮双重响应的近红外荧光探针及其制备方法和应用 |
CN115745939A (zh) * | 2022-10-14 | 2023-03-07 | 广西大学 | 具有近红外二区波长的新型罗丹明类染料及其制备方法和应用 |
CN115925667B (zh) * | 2022-10-19 | 2024-02-02 | 复旦大学 | 一种比率型近红外荧光探针分子及其制备方法和应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007036561A2 (de) * | 2005-09-30 | 2007-04-05 | Siemens Aktiengesellschaft | Elektrochrome pasten mit neuen farbstoffen |
CN108219780A (zh) * | 2018-03-26 | 2018-06-29 | 南京邮电大学 | 一种近红外荧光探针及其制备方法和应用 |
CN108997771A (zh) * | 2018-06-12 | 2018-12-14 | 大连理工大学 | 一类在近红外区具有强吸收和光热效应的染料及其制备方法与应用 |
-
2018
- 2018-11-03 CN CN201811304201.5A patent/CN109400572B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007036561A2 (de) * | 2005-09-30 | 2007-04-05 | Siemens Aktiengesellschaft | Elektrochrome pasten mit neuen farbstoffen |
CN108219780A (zh) * | 2018-03-26 | 2018-06-29 | 南京邮电大学 | 一种近红外荧光探针及其制备方法和应用 |
CN108997771A (zh) * | 2018-06-12 | 2018-12-14 | 大连理工大学 | 一类在近红外区具有强吸收和光热效应的染料及其制备方法与应用 |
Non-Patent Citations (1)
Title |
---|
Reactions of β-chlorovinylaldehydes. IV. Syntheses of 2-formylmethylene-2H-1-benzopyrans and benzopyrylocyanine dyes from β-chlorovinylaldehydes;Weissenfels, Manfred et al.;《Journal fuer Praktische Chemie》;19781231;第320卷(第4期);第497-507页 * |
Also Published As
Publication number | Publication date |
---|---|
CN109400572A (zh) | 2019-03-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN109400572B (zh) | 近红外第二窗口发射的荧光染料及其制备方法和应用 | |
CN109336909B (zh) | 具有聚集诱导发光性质的近红外二区荧光化合物及制备方法、纳米粒胶束及其应用 | |
CN109180638A (zh) | 近红外第二窗口发射五甲川菁类荧光染料及其制备方法和应用 | |
CN108997771B (zh) | 一类在近红外区具有强吸收和光热效应的染料及其制备方法与应用 | |
Zhang et al. | Comparative study of two near-infrared coumarin–BODIPY dyes for bioimaging and photothermal therapy of cancer | |
Yan et al. | NIR organic dyes based on phenazine-cyanine for photoacoustic imaging-guided photothermal therapy | |
CN108440986A (zh) | 近红外第二窗口激发/发射的荧光染料及其制备方法和应用 | |
Hou et al. | Recent advances of pure organic room temperature phosphorescence materials for bioimaging applications | |
Zhang et al. | Organic room-temperature phosphorescence materials for bioimaging | |
Pi et al. | A curcumin-based TPA four-branched copper (II) complex probe for in vivo early tumor detection | |
CN113927027B (zh) | 一种类病毒空心氧化锰负载近红外二b区激发的稀土纳米晶及其制备方法和应用 | |
CN103865537A (zh) | 一种稀土上转换纳米荧光探针及其制备和应用 | |
CN109504363B (zh) | 一种近红外二区成像造影剂的制备方法和用途 | |
CN104830318B (zh) | 一种高聚集态荧光发射的荧光标记分子及其制备方法 | |
Huo et al. | Review of long wavelength luminescent carbon-based nanomaterials: preparation, biomedical application and future challenges | |
CN114591729B (zh) | 一种近红外IIb荧光探针、纳米粒子及其制备方法和应用 | |
CN114989174A (zh) | 一种有机小分子nir-ii荧光染料、纳米颗粒及其制备方法与应用 | |
CN114478587A (zh) | 一种近红外二区染料、纳米粒子及其制备方法和应用 | |
CN114271792A (zh) | 近红外第二窗口检测pH的双通道比率荧光传感器及其制备方法和应用 | |
Xu et al. | Synthesis and crystal structure of a novel copper (II) complex of curcumin-type and its application in in vitro and in vivo imaging | |
CN106970059B (zh) | 一种双光子荧光探针的制备及其应用 | |
CN108714223B (zh) | 一种兼具磁共振和荧光双重成像特性的造影剂及其制备方法 | |
Chen et al. | An Extended NIR‐II Superior Imaging Window from 1500 to 1900 nm for High‐Resolution In Vivo Multiplexed Imaging Based on Lanthanide Nanocrystals | |
CN113307803A (zh) | 一种具有优良性能的nir-ii aie分子及其应用 | |
CN102940893B (zh) | 具有上转换发光和磁共振成像双功能的造影剂及其制备方法 |
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 |