CN113773667A - 有机小分子近红外二区荧光染料及其制备方法和应用 - Google Patents
有机小分子近红外二区荧光染料及其制备方法和应用 Download PDFInfo
- Publication number
- CN113773667A CN113773667A CN202111105760.5A CN202111105760A CN113773667A CN 113773667 A CN113773667 A CN 113773667A CN 202111105760 A CN202111105760 A CN 202111105760A CN 113773667 A CN113773667 A CN 113773667A
- Authority
- CN
- China
- Prior art keywords
- infrared
- fluorescent dye
- region
- organic
- solution
- 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
- 239000007850 fluorescent dye Substances 0.000 title claims abstract description 45
- 150000003384 small molecules Chemical class 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000002105 nanoparticle Substances 0.000 claims abstract description 46
- 239000007864 aqueous solution Substances 0.000 claims abstract description 26
- 238000000799 fluorescence microscopy Methods 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000003384 imaging method Methods 0.000 claims abstract description 11
- 239000000975 dye Substances 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- FYNROBRQIVCIQF-UHFFFAOYSA-N pyrrolo[3,2-b]pyrrole-5,6-dione Chemical group C1=CN=C2C(=O)C(=O)N=C21 FYNROBRQIVCIQF-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000000975 co-precipitation Methods 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- 229910052698 phosphorus Inorganic materials 0.000 claims description 6
- 239000011574 phosphorus Substances 0.000 claims description 6
- -1 2-octyldodecyl Chemical group 0.000 claims description 5
- WIHHVKUARKTSBU-UHFFFAOYSA-N 4-bromobenzene-1,2-diamine Chemical compound NC1=CC=C(Br)C=C1N WIHHVKUARKTSBU-UHFFFAOYSA-N 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 239000012670 alkaline solution Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical group [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 3
- 239000012528 membrane Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 229920001992 poloxamer 407 Polymers 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- 229940124597 therapeutic agent Drugs 0.000 claims description 3
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 3
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical group CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 230000031700 light absorption Effects 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 238000011282 treatment Methods 0.000 abstract description 13
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 9
- 238000013461 design Methods 0.000 abstract description 3
- 238000001126 phototherapy Methods 0.000 abstract description 3
- 230000008685 targeting Effects 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 206010028980 Neoplasm Diseases 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 9
- 238000007626 photothermal therapy Methods 0.000 description 8
- ZKSVYBRJSMBDMV-UHFFFAOYSA-N 1,3-diphenyl-2-benzofuran Chemical compound C1=CC=CC=C1C1=C2C=CC=CC2=C(C=2C=CC=CC=2)O1 ZKSVYBRJSMBDMV-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000002086 nanomaterial Substances 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 4
- 238000002428 photodynamic therapy Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 239000002872 contrast media Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000002189 fluorescence spectrum Methods 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 241000995070 Nirvana Species 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000012632 fluorescent imaging Methods 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002091 nanocage Substances 0.000 description 1
- 239000002135 nanosheet Substances 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000003504 photosensitizing agent Substances 0.000 description 1
- 208000007578 phototoxic dermatitis Diseases 0.000 description 1
- 231100000018 phototoxicity Toxicity 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
Images
Classifications
-
- 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
- C09B57/004—Diketopyrrolopyrrole dyes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
-
- 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
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-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
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/1702—Systems in which incident light is modified in accordance with the properties of the material investigated with opto-acoustic detection, e.g. for gases or analysing solids
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
- G01N21/643—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" non-biological material
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/645—Specially adapted constructive features of fluorimeters
- G01N21/6456—Spatial resolved fluorescence measurements; Imaging
-
- 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
- C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms
-
- 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
- C09K2211/1092—Heterocyclic compounds characterised by ligands containing sulfur as the only heteroatom
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
- Y02E10/00—Energy generation through renewable energy sources
- Y02E10/50—Photovoltaic [PV] energy
- Y02E10/549—Organic PV cells
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Physics & Mathematics (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Analytical Chemistry (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Optics & Photonics (AREA)
- Acoustics & Sound (AREA)
- Radiology & Medical Imaging (AREA)
- Biomedical Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Materials Engineering (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明公开了一种有机小分子近红外二区荧光染料，并公开了该染料及其纳米颗粒水溶液的制备方法和应用。本发明基于吡咯并吡咯二酮单元合成了一种新型有机小分子荧光材料，此设计合成步骤简单，结构特征明显。通过纳米共沉淀方法制得具有良好水溶性、生物相容性及靶向性的纳米颗粒，该纳米颗粒具有优良的近红外二区荧光成像、光声成像、光动力及光热转换性能，可用于近红外二区荧光成像/光声成像指导下的光热/光动力联合治疗试剂的制备，为单一波长激发的NIR‑II荧光成像引导的光疗开辟新的领域。
Description
技术领域
本发明属于生物医药工程技术领域，更具体地，涉及一种有机小分子近红外二区荧光染料及其制备方法和应用。
背景技术
目前，癌症治疗主要采用外科手术来切除肿瘤，同时辅以发射性疗法治疗，而对严重或扩散性的肿瘤则采用化学药物治疗。但由于化疗对治疗目标靶体的选择性差，在杀伤癌细胞的同时也会损伤正常组织和细胞，为此光动力疗法(PDT)以及光热疗法(PTT)开始被尝试用作治疗恶性肿瘤的新技术。光学动力治疗是以光/光敏剂/氧气彼此共同作用为基础的一种新型疾病治疗手段。其原理是利用摄入的药物发生光动力学以及酶化反应产生多种活性氧(ROS)，从而对蛋白质、核酸等生物大分子产生破坏作用，产生细胞毒性，造成细胞器损伤，导致细胞死亡，进而破坏靶组织以达到治疗目的。基于单线态氧的光动力治疗需要足够的氧气供给，这限制了该治疗方式在缺乏氧病灶的治疗。光热疗法(PTT)成为近几年发展起来的一种具有临床应用前景的肿瘤技术，其过程是利用光热诊疗试剂选择性地富集于病灶部位，然后利用组织穿透力较强、光毒性较低的近红外光对其进行照射，光热治疗试剂吸收光能并转化为热能，使其肿瘤部位温度升高，从而杀死肿瘤细胞，达到治疗肿瘤的目的。相比于传统的肿瘤治疗方法，PTT的优势包括：(1)可以选择性的让激光照射肿瘤部位，避免了全身效应，从而达到微创治疗的目的；(2)当肿瘤区域的温度达到42℃以上时，癌细胞会因为蛋白质变性等因素的影响而导致死亡，且肿瘤细胞比正常细胞对温度更加敏感，从而在一定温度范围内可以选择性地杀死癌细胞而正常细胞不受影响；(3)侵入性小。但是，单一的PTT治疗往往会导致热休克反应，因此，光热及光动力两种技术的联合治疗被视作是一种可行性的策略。然而，大多数已报道的光诊疗剂往往受到多种因素的限制，包括较差的生物相容性、较低的近红外吸收能力以及不理想的治疗效果。同时，肿瘤治疗过程中往往需要多次注射药物并进行光照，这导致许多不必要的副作用同时增加患者体内毒性。
随着纳米技术的不断发展，大量纳米材料被制备用于光热治疗中。其中，金纳米材料包括金纳米棒、纳米笼、纳米片和复合纳米结构是目前应用最广泛的光热治疗试剂。然而这些无机纳米材料固有的生物毒性和不可降解性一定程度上都限制了它们在临床上的实际应用。相比于无机纳米材料的生物毒性，有机材料因其具有与生物组织类似的元素组成，被认为是比无机纳米颗粒有更好的生物相容性。其中，小分子NIR-II荧光染料凭借其具有良好的生物相容性，优越的光学性能，快速的代谢能力是理想的候选方案。此外，小分子NIR-II有机荧光团的内在多功能性也赋予了它们的PTT和PDT效应。但是现有的NIR-II荧光染料大多结构复杂，合成困难。
基于此，有必要开发一种新型的有机小分子NIR-II荧光染料，为实现临床应用的高性能纳米诊疗试剂的设计开发提供全新的方向。
发明内容
本发明的目的是针对以上不足，提供一种新型的有机小分子近红外二区(NIR-II)荧光染料，并提供该染料及其纳米颗粒水溶液的制备方法，其纳米颗粒具有良好的水溶性和生物相容性和靶向性，同时具有近红外二区荧光成像能力，和良好的光热及光动力效果。
本发明的另一个目的在于提供了该新型有机小分子近红外二区(NIR-II)荧光染料在近红外二区荧光成像和光声成像中的应用，及其在近红外二区荧光成像指导下的光热/光动力联合治疗的试剂中的应用。
为实现上述目的，本发明是通过以下技术方案实现的：
一种有机小分子近红外二区荧光染料，该染料的主要成分为吡咯并吡咯二酮单元衍生物，其结构式为：
一种上述有机小分子近红外二区荧光染料的制备方法，包括以下步骤：
将4-溴邻苯二胺和2,5-二(2-辛基十二烷基)-3,6-二(5-硼酸频哪醇酯噻吩基)-吡咯并吡咯二酮，与磷催化剂、钯催化剂混合，抽真空，通氮气，随后加入溶剂和碱性溶液，在85～95℃反应45～50h，将得到的粗产物旋干，旋粉提纯即得。
其合成路线为：
优选地，上述制备方法，所述4-溴邻苯二胺、2,5-二(2-辛基十二烷基)-3,6-二(5-硼酸频哪醇酯噻吩基)-吡咯并吡咯二酮、磷催化剂和钯催化剂的摩尔比为(3～5):1：(0.1～0.2)：(0.2～0.3)。
优选地，上述制备方法中，所述磷催化剂选用三(邻甲基苯基)磷，钯催化剂选用三(二亚苄基丙酮)二钯(Pd2(Dba)3)。
优选地，上述制备方法中，所述溶剂为无水甲苯，碱性溶液为1mol/L的K3PO4溶液。
一种上述有机小分子近红外二区荧光染料的纳米颗粒水溶液，是通过将所述的有机小分子近红外二区荧光染料与两亲性分子通过纳米共沉淀方法制得的，包括以下步骤：
将上述的吡咯并吡咯二酮单元衍生物和Pluronic F127溶解于四氢呋喃后，加入水，超声震荡3～5min；
去除溶液中的四氢呋喃，然后经水相滤膜过滤、离心机超滤，制得有机小分子近红外二区荧光染料的纳米颗粒水溶液。
上述方法制备的纳米颗粒水溶液，其最大光吸收波长为635nm±10nm。
上述方法制备的纳米颗粒水溶液，其最大荧光发射波长为1000nm±10nm。
一种上述的有机小分子近红外二区荧光染料在近红外二区荧光成像中的应用，所述应用是指该有机小分子近红外二区荧光染料的纳米颗粒水溶液作为近红外二区荧光成像造影剂。
一种上述的有机小分子近红外二区荧光染料在光声成像中的应用，所述应用是指该有机小分子近红外二区荧光染料的纳米颗粒水溶液作为光声成像造影剂。
一种上述的有机小分子近红外二区荧光染料在制备光热/光动力联合治疗试剂中的应用，所述应用是指该新型有机小分子近红外二区荧光染料的纳米颗粒水溶液用于制备肿瘤靶向光热/光动力联合治疗试剂。
与现有技术相比，本发明的有益效果为：
本发明基于吡咯并吡咯二酮单元合成了一种新型有机小分子NIR-II荧光材料，其设计合成步骤简单，结构特征明显。
本发明所述的有机小分子NIR-II染料通过简单的纳米共沉淀方法制备得到具有良好水溶性、生物相容性及靶向性的纳米颗粒，该纳米颗粒具有优良的近红外二区荧光成像能力、光声成像能力、光动力及光热转换性能，可以用于近红外二区荧光成像/光声成像指导下的光热/光动力联合治疗试剂的制备。
本发明的有机小分子NIR-II染料可以用于成像和光疗，对肿瘤细胞表现良好的抑制率，为单一波长激发的NIR-II荧光成像引导的光疗开辟新的领域，提供了新的策略，同时实现了肿瘤的有效治疗。
附图说明
图1为实施例所制备的有机小分子NIR-II荧光染料的纳米颗粒水溶液的紫外谱图。
图2为实施例所制备的有机小分子NIR-II荧光染料的纳米颗粒水溶液的荧光谱图。
图3为实施例所制备的有机小分子NIR-II荧光染料的纳米颗粒的DLS图。
图4为实施例所制备的有机小分子NIR-II荧光染料的纳米颗粒水溶液的近红外二区荧光成像图。
图5为实施例所制备的有机小分子NIR-II荧光染料的纳米颗粒水溶液的光声成像图。
图6为不同浓度的有机小分子NIR-II荧光染料的纳米颗粒水溶液在同一功率光照下的光热变化图。
图7为相同浓度的有机小分子NIR-II荧光染料的纳米颗粒水溶液在不同功率光照下的光热变化图。
图8为一定浓度的有机小分子NIR-II荧光染料的纳米颗粒水溶液在1W/m2光照下DPBF的414nm紫外吸收强度随时间变化图。
具体实施方式
下面将结合附图和具体实验方法对本发明做更详细地描述。以下实施例仅用于更加清楚地说明本发明的技术方案，而不能以此来限制本发明的保护范围。
本发明的实施所使用的试剂皆为市购，所使用的仪器分别为：
近红外二窗荧光成像仪：NIRvana 640-Princeton instrument
红外热成像仪：TESTO869
激光器：MDL-IH-808-1.5W-PSU-II-LED
1.一种有机小分子近红外二区荧光染料，该染料的主要成分为吡咯并吡咯二酮单元衍生物，其结构式为：
所述有机小分子近红外二区(NIR-II)荧光染料的合成路线为：
具体制备步骤如下：
称取85mg的4-溴邻苯二胺和100mg的2,5-二(2-辛基十二烷基)-3,6-二(5-硼酸频哪醇酯噻吩基)-吡咯并吡咯二酮(摩尔比5：1)，20mg三(邻甲基苯基)磷，10mg三(二亚苄基丙酮)二钯(Pd2(Dba)3)(摩尔比1:3)加入到两口烧瓶中，抽真空，通氮气。随后加入无水甲苯30mL，2mL的K3PO4溶液(1mol/L)，油浴锅内90℃反应48h，将得到的粗产物旋干，旋粉过柱子提纯，得到目标产物(约110mg，产率59.5％)。
2.上述有机小分子近红外二区荧光染料的纳米颗粒水溶液的制备方法如下：
称取1mg有机小分子NIR-II染料和20mg Pluronic F127溶于1mL四氢呋喃(THF)中，将溶液放入细胞粉碎仪器中，迅速加入5mL水，超声环境中迅速震荡3min。鼓吹氮气去除溶液中的THF，然后使用水相滤膜过滤得到水溶液纳米颗粒，最后通过离心机超滤得到定量的纳米颗粒水溶液。其紫外吸收光谱如图1所示，荧光光谱图如图2所示，所得到的纳米颗粒的粒径大小如图3所示。
3.有机小分子NIR-II荧光染料的纳米颗粒水溶液用于近红外二区荧光成像
配制浓度为0.1mg/ml的上述纳米颗粒水溶液1ml，放置于小离心管中，在近红外二区荧光成像仪下，用波长为808nm的激光激发，得到近红外二区荧光成像，如图4所示，结果表明该纳米颗粒具有优异的红外二区荧光成像能力。
4.有机小分子NIR-II荧光染料的纳米颗粒水溶液用于光声成像
配置浓度为1mg/mL的纳米颗粒水溶液，溶于200μL小试管，在光声成像仪进行成像测试，结果如图5所示。
5.有机小分子NIR-II荧光染料的纳米颗粒水溶液光热/光动力测试
(1)纳米颗粒光热测试：
研究不同溶液浓度及不同光功率密度下纳米颗粒水溶液的光热性能。
分别配置浓度梯度为20μg/ml、40μg/ml、60μg/ml、80μg/ml和100μg/ml的纳米颗粒水溶液，使用激光(660nm，1W/cm2)照射，由红外相机记录溶液温度随时间变化的趋势，如图6所示，采用相同的激光功率照射下，纳米颗粒水溶液温度上随着浓度的增大而不断升高。
接着，分别用功率密度为0.25W/cm2、0.5W/cm2、0.75W/cm2及1W/cm2的激光(660nm)照射具有相同浓度的纳米颗粒溶液，并检测溶液温度随时间变化曲线，如图7所示，表明随着激光功率密度增加，纳米颗粒溶液温度增加越明显。
(2)光动力性能的测试：
在比色皿中加入纳米颗粒水溶液，再滴加入DPBF的乙醇溶液，分别用光功率密度为0.25W/cm2、0.5W/cm2及1W/m2的激光(730nm)间断照射，每次光照20s，并记录DPBF在414nm处的紫外吸收峰的变化，图8为1W/m2光照下DPBF特征峰414nm处的紫外吸收峰随时间的变化趋势。DPBF在414nm处的吸收峰随着激光的不断照射有明显降低，从而反映光照过程产生了单线态氧。另外随着光功率密度越大，DPBF在414nm处的吸收峰下降的幅度越大，表明该纳米颗粒具有较好的光动力性能。
以上已经描述了本发明的各实施例，上述说明是示例性的，并非穷尽性的，并且也不限于所披露的各实施例。在不偏离所说明的各实施例的范围和技术原理的情况下，对于本技术领域的普通技术人员来说许多修改和变更都是显而易见的，这些修改和变更也应视为本发明的保护范围。
Claims (10)
1.一种有机小分子近红外二区荧光染料，其特征在于，该染料的主要成分为吡咯并吡咯二酮单元衍生物，其结构式为：
2.一种有机小分子近红外二区荧光染料的制备方法，其特征在于，包括以下步骤：
将4-溴邻苯二胺和2,5-二(2-辛基十二烷基)-3,6-二(5-硼酸频哪醇酯噻吩基)-吡咯并吡咯二酮，与磷催化剂、钯催化剂混合，抽真空，通氮气，随后加入溶剂和碱性溶液，在85～95℃反应45～50h，将得到的粗产物旋干，旋粉提纯即得。
3.根据权利要求2所述的有机小分子近红外二区荧光染料的制备方法，其特征在于，所述4-溴邻苯二胺、2,5-二(2-辛基十二烷基)-3,6-二(5-硼酸频哪醇酯噻吩基)-吡咯并吡咯二酮、磷催化剂和钯催化剂的摩尔比为(3～5):1：(0.1～0.2)：(0.2～0.3)。
4.根据权利要求2所述的有机小分子近红外二区荧光染料的制备方法，其特征在于，所述磷催化剂为三(邻甲基苯基)磷，钯催化剂为三(二亚苄基丙酮)二钯。
5.根据权利要求2所述的有机小分子近红外二区荧光染料的制备方法，其特征在于，所述溶剂为无水甲苯，碱性溶液为1mol/L的K3PO4溶液。
6.一种权利要求1所述的有机小分子近红外二区荧光染料的纳米颗粒水溶液，其特征在于，是通过纳米共沉淀方法制得的，包括以下步骤：
将权利要求1所述的吡咯并吡咯二酮单元衍生物和Pluronic F127溶解于四氢呋喃后，加入水，超声震荡3～5min；
去除溶液中的四氢呋喃，然后经水相滤膜过滤、离心机超滤，制得有机小分子近红外二区荧光染料的纳米颗粒水溶液。
7.根据权利要求6所述的有机小分子近红外二区荧光染料的纳米颗粒水溶液，其特征在于，其最大光吸收波长为635nm±10nm。
8.根据权利要求6所述的有机小分子近红外二区荧光染料的纳米颗粒水溶液，其特征在于，其最大荧光发射波长为1000nm±10nm。
9.一种权利要求1所述的有机小分子近红外二区荧光染料在近红外二区荧光成像和/或光声成像中的应用。
10.一种权利要求1所述的有机小分子近红外二区荧光染料在制备光热/光动力联合治疗试剂中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111105760.5A CN113773667B (zh) | 2021-09-22 | 2021-09-22 | 有机小分子近红外二区荧光染料及其制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111105760.5A CN113773667B (zh) | 2021-09-22 | 2021-09-22 | 有机小分子近红外二区荧光染料及其制备方法和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113773667A true CN113773667A (zh) | 2021-12-10 |
| CN113773667B CN113773667B (zh) | 2023-05-09 |
Family
ID=78852472
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111105760.5A Active CN113773667B (zh) | 2021-09-22 | 2021-09-22 | 有机小分子近红外二区荧光染料及其制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113773667B (zh) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114349756A (zh) * | 2021-12-15 | 2022-04-15 | 南京邮电大学 | 一种aie有机小分子及其制备方法和应用 |
| CN114591729A (zh) * | 2022-03-01 | 2022-06-07 | 南京邮电大学 | 一种近红外IIb荧光探针、纳米粒子及其制备方法和应用 |
| CN114836197A (zh) * | 2022-04-25 | 2022-08-02 | 南京邮电大学 | 一种提高近红外二区有机纳米粒子荧光量子产率的方法 |
| CN114989174A (zh) * | 2022-06-02 | 2022-09-02 | 南京邮电大学 | 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 |
| CN114984249A (zh) * | 2022-03-18 | 2022-09-02 | 湖南大学 | 一种兼具近红外二区荧光成像、近红外光激发的光动力治疗纳米药物及其制备方法 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105829454A (zh) * | 2013-12-19 | 2016-08-03 | 默克专利股份有限公司 | 染料化合物 |
| CN108864106A (zh) * | 2018-07-17 | 2018-11-23 | 南京邮电大学 | 新型近红外二区有机小分子荧光探针的制备与应用 |
| CN110917348A (zh) * | 2019-12-09 | 2020-03-27 | 南京邮电大学 | 荧光/光声成像及光疗一体化靶向纳米诊疗剂及其构建与应用 |
-
2021
- 2021-09-22 CN CN202111105760.5A patent/CN113773667B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105829454A (zh) * | 2013-12-19 | 2016-08-03 | 默克专利股份有限公司 | 染料化合物 |
| CN108864106A (zh) * | 2018-07-17 | 2018-11-23 | 南京邮电大学 | 新型近红外二区有机小分子荧光探针的制备与应用 |
| CN110917348A (zh) * | 2019-12-09 | 2020-03-27 | 南京邮电大学 | 荧光/光声成像及光疗一体化靶向纳米诊疗剂及其构建与应用 |
Non-Patent Citations (1)
| Title |
|---|
| SIMON TANG 等: "Protein-induced fluorescence enhancement of two-photon excitable water-soluble diketopyrrolopyrroles", 《ORG. BIOMOL. CHEM.》 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114349756A (zh) * | 2021-12-15 | 2022-04-15 | 南京邮电大学 | 一种aie有机小分子及其制备方法和应用 |
| CN114349756B (zh) * | 2021-12-15 | 2024-02-20 | 南京邮电大学 | 一种aie有机小分子及其制备方法和应用 |
| CN114591729A (zh) * | 2022-03-01 | 2022-06-07 | 南京邮电大学 | 一种近红外IIb荧光探针、纳米粒子及其制备方法和应用 |
| CN114591729B (zh) * | 2022-03-01 | 2023-11-14 | 南京邮电大学 | 一种近红外IIb荧光探针、纳米粒子及其制备方法和应用 |
| CN114984249A (zh) * | 2022-03-18 | 2022-09-02 | 湖南大学 | 一种兼具近红外二区荧光成像、近红外光激发的光动力治疗纳米药物及其制备方法 |
| CN114984249B (zh) * | 2022-03-18 | 2023-07-28 | 湖南大学 | 一种兼具近红外二区荧光成像、近红外光激发的光动力治疗纳米药物及其制备方法 |
| CN114836197A (zh) * | 2022-04-25 | 2022-08-02 | 南京邮电大学 | 一种提高近红外二区有机纳米粒子荧光量子产率的方法 |
| CN114836197B (zh) * | 2022-04-25 | 2023-12-12 | 南京邮电大学 | 一种提高近红外二区有机纳米粒子荧光量子产率的方法 |
| CN114989174A (zh) * | 2022-06-02 | 2022-09-02 | 南京邮电大学 | 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 |
| CN114989174B (zh) * | 2022-06-02 | 2023-07-28 | 南京邮电大学 | 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113773667B (zh) | 2023-05-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108864106B (zh) | 近红外二区有机小分子荧光探针的制备与应用 | |
| CN113773667B (zh) | 有机小分子近红外二区荧光染料及其制备方法和应用 | |
| CN110898222B (zh) | 一种基于a-d-a型有机分子/双亲性高分子复合纳米粒子的制备方法及应用 | |
| CN112516337B (zh) | 近红外二区有机共轭聚合物荧光探针的制备方法及其应用 | |
| CN114213419B (zh) | 一种兼具荧光成像和i型光动力/光热杀伤癌细胞活性的荧光探针及其制备方法和应用 | |
| CN109464677B (zh) | 一种用于肿瘤靶向诊疗的近红外光控纳米颗粒及制备方法 | |
| KR20080095182A (ko) | 고분자 유도체-광감작제 복합체를 이용한 새로운 광역학치료제 | |
| CN114106581B (zh) | 一种有机小分子染料、j聚集纳米粒子及其制备方法和应用 | |
| CN109498808A (zh) | 一种通过静电组装可控合成CuS@EPO纳米材料的方法 | |
| CN110856747A (zh) | 一种过氧化氢激活的光敏剂及其制备方法与应用 | |
| CN111686250A (zh) | 一种线粒体靶向的光热治疗剂及其制备和应用 | |
| CN112409365A (zh) | 3-磺酸基丙烷巯基修饰酞菁及其制备方法与在制药领域的应用 | |
| Yan et al. | Single-laser excitation synergistic photo-and chemodynamic therapy system based on persistent luminescence nanoparticles | |
| CN113683602B (zh) | 一种用于缺氧肿瘤多模态治疗的七甲川花菁小分子和制备方法及应用 | |
| CN112156186B (zh) | 红外染料敏化氮化碳三元异质结纳米材料及其制备方法和应用 | |
| CN114984249B (zh) | 一种兼具近红外二区荧光成像、近红外光激发的光动力治疗纳米药物及其制备方法 | |
| CN116426275B (zh) | 一种荧光硅量子点及其制备方法和应用 | |
| CN115819446B (zh) | 一种酞菁-荧光素有机光热剂及其制备方法与在有机近红外光热治疗抗肿瘤药物中的应用 | |
| CN113321646B (zh) | 同时具有光动力/光热性能的有机光敏脂质纳米粒子，制备方法和应用 | |
| CN117402174A (zh) | 有机小分子光学诊疗试剂、纳米粒子及其制备方法和应用 | |
| CN115160496A (zh) | 一种谷胱甘肽激活的聚降冰片烯光敏剂及其制备方法和应用 | |
| CN118307560A (zh) | 一种用于肿瘤诊疗一体化的有机光敏剂及其制备与应用 | |
| CN118005652A (zh) | 一种近红外二区荧光共轭有机小分子及其制备方法与应用 | |
| CN116444513A (zh) | 一种具有过氧化氢酶活性用于肿瘤协同光疗的有机小分子化合物 | |
| Loya et al. | Carbon dots in anticancer detection and therapy |
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 |