CN113087877B - 近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂及其制备方法与应用 - Google Patents

近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂及其制备方法与应用 Download PDF

Info

Publication number
CN113087877B
CN113087877B CN202110369366.6A CN202110369366A CN113087877B CN 113087877 B CN113087877 B CN 113087877B CN 202110369366 A CN202110369366 A CN 202110369366A CN 113087877 B CN113087877 B CN 113087877B
Authority
CN
China
Prior art keywords
conjugated polymer
water
infrared
nano
soluble conjugated
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
Application number
CN202110369366.6A
Other languages
English (en)
Other versions
CN113087877A (zh
Inventor
黄艳琴
江珊珊
盛况
潘立祥
刘兴奋
范曲立
黄维
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing University of Posts and Telecommunications
Original Assignee
Nanjing University of Posts and Telecommunications
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Nanjing University of Posts and Telecommunications filed Critical Nanjing University of Posts and Telecommunications
Priority to CN202110369366.6A priority Critical patent/CN113087877B/zh
Publication of CN113087877A publication Critical patent/CN113087877A/zh
Application granted granted Critical
Publication of CN113087877B publication Critical patent/CN113087877B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G61/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
    • C08G61/12—Macromolecular compounds containing atoms other than carbon in the main chain of the macromolecule
    • C08G61/122—Macromolecular compounds containing atoms other than carbon in the main chain of the macromolecule derived from five- or six-membered heterocyclic compounds, other than imides
    • C08G61/123—Macromolecular compounds containing atoms other than carbon in the main chain of the macromolecule derived from five- or six-membered heterocyclic compounds, other than imides derived from five-membered heterocyclic compounds
    • C08G61/126—Macromolecular compounds containing atoms other than carbon in the main chain of the macromolecule derived from five- or six-membered heterocyclic compounds, other than imides derived from five-membered heterocyclic compounds with a five-membered ring containing one sulfur atom in the ring
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A61K47/6931—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
    • A61K47/6935—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
    • 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
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0089—Particulate, powder, adsorbate, bead, sphere
    • A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
    • A61K49/0093—Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2261/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
    • C08G2261/10—Definition of the polymer structure
    • C08G2261/12—Copolymers
    • C08G2261/124—Copolymers alternating
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2261/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
    • C08G2261/10—Definition of the polymer structure
    • C08G2261/14—Side-groups
    • C08G2261/141—Side-chains having aliphatic units
    • C08G2261/1412—Saturated aliphatic units
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2261/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
    • C08G2261/10—Definition of the polymer structure
    • C08G2261/14—Side-groups
    • C08G2261/142—Side-chains containing oxygen
    • C08G2261/1424—Side-chains containing oxygen containing ether groups, including alkoxy
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2261/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
    • C08G2261/10—Definition of the polymer structure
    • C08G2261/14—Side-groups
    • C08G2261/142—Side-chains containing oxygen
    • C08G2261/1426—Side-chains containing oxygen containing carboxy groups (COOH) and/or -C(=O)O-moieties
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2261/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
    • C08G2261/10—Definition of the polymer structure
    • C08G2261/18—Definition of the polymer structure conjugated
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2261/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
    • C08G2261/30—Monomer units or repeat units incorporating structural elements in the main chain
    • C08G2261/32—Monomer units or repeat units incorporating structural elements in the main chain incorporating heteroaromatic structural elements in the main chain
    • C08G2261/322—Monomer units or repeat units incorporating structural elements in the main chain incorporating heteroaromatic structural elements in the main chain non-condensed
    • C08G2261/3223—Monomer units or repeat units incorporating structural elements in the main chain incorporating heteroaromatic structural elements in the main chain non-condensed containing one or more sulfur atoms as the only heteroatom, e.g. thiophene
    • 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
    • C09K2211/14—Macromolecular compounds
    • C09K2211/1408—Carbocyclic compounds
    • C09K2211/1425—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
    • C09K2211/14—Macromolecular compounds
    • C09K2211/1441—Heterocyclic
    • C09K2211/1458—Heterocyclic containing sulfur as the only heteroatom
    • 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
    • C09K2211/14—Macromolecular compounds
    • C09K2211/1441—Heterocyclic
    • C09K2211/1466—Heterocyclic containing nitrogen as the only heteroatom

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nanotechnology (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Polymers & Plastics (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Materials Engineering (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

本发明公开了一种近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂及其制备方法与应用，水溶性共轭聚合物以非取代吡咯并吡咯二酮(DPP)衍生物和窄带隙二卤代芳烃单体采用有机金属催化的直接芳基化聚合(DHAP)反应进行交替共聚获得，并通过纳米沉淀法获得纳米材料。该纳米材料吸收波长处于近红外一区(NIR‑Ⅰ650‑950nm)，发射位于近红外二区(NIR‑Ⅱ1000‑1700nm)，具有良好的水溶性和生物相容性、出色的光热转化能力以及单线态氧产率，可以实现近红外二区荧光成像，并有效地抑制肿瘤细胞的生长。

Description

近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂及其制 备方法与应用
技术领域
本发明属于荧光成像、光疗技术领域，具体涉及一种近红外二区水溶性共轭聚合物纳米光疗试剂的制备方法,以及其在近红外二区成像、光热/光动力协同治疗中的应用。
背景技术
癌症是世界范围内对人类健康最主要的威胁之一。传统的手术和放疗、化疗结合可以控制肿瘤生长，但也存在着巨大的毒副作用。在荧光成像指导下通过光疗治疗癌症是很有前景的新兴治疗方法。
共轭聚合物作为荧光成像和光疗材料，具有很多优势：如化学结构易于修饰、可定制的近红外吸收和良好的光电特性。水溶性共轭聚合物是指在主链上引入带有离子型官能团侧链或者接枝亲水侧链,使共轭聚合物的水溶性和生物相容性得到较大提高，同时还保留了共轭聚合物良好的光电特性，如：优良的半导体性能和光稳定性、高摩尔消光系数等。
研究表明，近红外吸收的材料用于生物诊疗具有以下优点:(1)相对于短波长的光，生物组织对近红外波段的吸收比较小，有利于治疗更深处的生物组织；(2)这一波段的光对于正常细胞的损伤更小，避免了一定程度的光致损伤。近红外二区(NIR-Ⅱ)荧光成像技术是用近红外一区(NIR-Ⅰ650-950nm)的激发光照射被检测生物组织，激发组织里的荧光基团发出NIR-Ⅱ光，随后收集光信号并根据信号的强度还原出组织的图像。相较于传统NIR-Ⅰ荧光成像技术(激发光和发射光波长都在NIR-Ⅰ区域)在实际应用过程中只能探测到1mm深度的组织信息，NIR-Ⅱ荧光成像技术因其利用更长波长的荧光，减少了生物组织的光散射与吸收，大大降低了背景噪音，具有更深的组织穿透深度(可达cm)和更高的对比度。
光疗包括光动力和光热治疗。光动力治疗(photodynamic therapy，PDT)是利用光敏剂(PS)作为治疗药物，在合适的光激发条件下，光敏剂将能量转移给三线态的氧气分子(3O2)产生单线态氧(1O2)。单线态氧具有细胞毒性，能够破坏细胞或血管，最终使有机体、细胞或生物分子发生机能及形态变化而致死。共轭小分子(如卟啉衍生物)、共轭聚合物(如聚芴苯衍生物)等有机光电子材料都可以作为光敏剂用于肿瘤等疾病的光动力治疗。
光热治疗(photothermal therapy，PTT)利用在近红外区具有强吸收的材料将光能转化为热能，达到癌细胞不能承受的温度从而杀死癌细胞。光热治疗具有疗效高、副作用小、特异性好、可控性好、对周围正常组织的副作用低的优点。一个优良的光热试剂必须满足两个条件：①在组织穿透性强的近红外区具有高的光吸收率、光稳定性以及光热转换效率：②具有良好的生物相容性和肿瘤靶向性。单独的有机共轭小分子应用于光热治疗存在一些不足，如热作用下其光学性质不稳定、易发生光漂白，通过静脉给药之后药物很快会被排出体外等。大量研究发现，当这些小分子与其他高分子以聚集体形式形成纳米胶束或者胶囊时，小分子的稳定性被有效提高，所以小分子在肿瘤部位的聚集量增多，光热效果显著增加。近年来，聚苯胺、聚吡咯、聚噻吩、聚多巴胺等在近红外区域有较强吸收的共轭聚合物也被应用于光热治疗。
发明内容
发明目的：为了克服现有技术中存在的不足，本发明提供一种近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂及其制备方法与应用，水溶性共轭聚合物以非取代吡咯并吡咯二酮(DPP)衍生物和窄带隙二卤代芳烃单体采用有机金属催化的直接芳基化聚合(DHAP)反应进行交替共聚获得，并通过纳米沉淀法获得纳米材料。DHAP反应是二卤代芳烃单体和非取代芳烃单体之间的交叉偶联聚合，其优点是不需要制备具有有机金属功能的单体，具有较高的原子经济性，副产物低毒性，比传统交叉偶联聚合更环保。该纳米材料吸收波长处于近红外一区(NIR-Ⅰ650-950nm)，发射位于近红外二区(NIR-Ⅱ1000-1700nm)，具有良好的水溶性和生物相容性、出色的光热转化能力以及单线态氧产率，可以实现近红外二区荧光成像，并有效地抑制肿瘤细胞的生长，是一种优良的诊疗试剂。实现近红外二区荧光成像，在光热、光动力治疗时对生物体的光损伤小、对生物组织的穿透能力更强，光热转化效率和单线态氧产率较高，从而使其在荧光成像指导的光热、光动力联合治疗方面有着潜在的广泛应用前景。
技术方案：为实现上述目的，本发明采用的技术方案为：
一种近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂，通过分子的主链和侧链结构设计使其具有良好的生物相容性和近红外二区荧光发射性质，疏水部分为聚合物的共轭主链，亲水部分为其取代侧链，通过纳米沉淀法进行分子自组装形成纳米诊疗剂，具有较高的光热转化效率和单线态氧产率，体现出良好的肿瘤细胞抑制能力。因此该纳米光疗试剂由两亲性的水溶性的共轭聚合物通过分子自组装形成纳米光疗试剂，所述水溶性共轭聚合物的化学结构式如下：
Figure BDA0003008696580000031
其中，2,5位取代的吡咯并吡咯二酮衍生物(DPP)为电子受体，简称A，噻吩为π-共轭桥，窄带隙芳烃Ar为另一种电子受体，简称A’，得到一种结构为A-π-A’的疏水共轭主链，疏水共轭主链的聚合度n为大于1的自然数；吡咯并吡咯二酮衍生物(DPP)2,5位取代亲水侧链上聚乙二醇(PEG)的聚合度x为大于或等于10的自然数；
所述窄带隙芳烃Ar为噻吩并[3,2-b]噻吩基团或为2,5-双(2-乙基己基)-3,6-二(噻吩-2-基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮基团。
在本发明中，所述的近红外二区荧光发射水溶性共轭聚合物，其中两种典型的结构为：
当窄带隙芳烃Ar为噻吩并[3,2-b]噻吩单体基团，x为大于20的自然数时，所述水溶性共轭聚合物的结构如下：
Figure BDA0003008696580000041
当窄带隙芳烃Ar为2,5-双(2-乙基己基)-3,6-二(噻吩-2-基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮单体基团，x为大于20的自然数时，所述水溶性共轭聚合物的结构如下：
Figure BDA0003008696580000051
优选的：由两亲性的水溶性共轭聚合物通过纳米沉淀法进行分子自组装形成纳米光疗试剂。
一种近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂的制备方法为：
1)采用简单环保的DHAP聚合反应，通过双组分交替共聚的方法先合成近红外二区荧光发射水溶性共轭聚合物，其中的双组分分别为接枝亲水性大分子PEG链的非取代吡咯并吡咯二酮衍生物单体和窄带隙二卤代芳烃；
2)由步骤1)制备得到的水溶性共轭聚合物可以通过纳米沉淀法得到近红外二区荧光发射水溶性共轭聚合物纳米颗粒。
水溶性共轭聚合物的制备方法为：
1)在碳链上接枝亲水性大分子PEG链，获得具有良好水溶性的非取代DPP衍生物单体。
2)采用DHAP反应，通过A+B双组分交替共聚的方法合成水溶性共轭聚合物,其中A为非取代DPP衍生物单体，B为二卤代芳烃。
3)由步骤2)制备得到的水溶性共轭聚合物通过纳米沉淀法获得纳米光疗试剂。
具体包括以下步骤：
步骤1)，将3,6-二(噻吩-2-基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮和1,6-二溴己烷的按物质的量比为1:9-11投料，合成出2,5-双(6-溴己基)-3,6-二(噻吩-2-基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮；
步骤2)，通过羧甲基化单甲氧基聚乙二醇(mPEG-COOH)和四丁基氢氧化铵按物质的量比为1:4-6反应得到活化的大分子PEG链；
步骤3)，在2,5-双(6-溴己基)-3,6-二(噻吩-2-基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮碳链末端接枝活化的大分子PEG链，进一步增加单体水溶性，DPP衍生物和PEG链物质的量比为1:0.9-1.1。
步骤4)，将接枝了PEG链的DPP衍生物单体和窄带隙二卤代芳烃按物质的量比为1:0.9-1.1投料，经有机金属醋酸钯催化剂催化聚合，反应10小时后得到近红外二区水溶性共轭聚合物，再经纳米沉淀法制备成纳米颗粒。
所述纳米沉淀法包括以下步骤：
步骤1)，将共轭聚合物溶于极性有机溶剂DMSO中,浓度控制在0.8-1.2mg/mL，然后将DMSO溶液在超声状态下滴加到纯水中，体积比约为1:0.9-1.1，搅拌均匀；
步骤2)，接着在冰水浴中用尖头型超声仪间隔性超声10min，超声功率为55％，每超声10s间隔2s；
步骤3)，室温搅拌3小时后移入透析袋中，在纯水中透析24小时；
步骤4)，用0.45μm滤孔的滤膜过滤后，取滤液冷冻干燥除水，得到纳米诊疗剂。
一种近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂的应用，应用于肿瘤细胞，在近红外激光照射下实现二区荧光成像，并产生光热效应和单线态氧，产生肿瘤抑制效果，实现肿瘤治疗。
本发明相比现有技术，具有以下有益效果：
在本发明中制备得到一种近红外二区发射水溶性共轭聚合物纳米光疗试剂。该纳米光疗试剂具有良好的水溶性和生物相容性，可用近红外一区激发，二区成像，在减小光损伤和提高光疗穿透深度方面有较大的优势，并且具有出色的光热转化能力以及单线态氧产率，可以有效地抑制肿瘤细胞的生长，在光疗方面有着潜在的广泛应用前景。
附图说明
图1.为本发明制备的水溶性共轭聚合物纳米粒子P1 NPs的可见-近红外吸收与近红外二区荧光发射光谱，其中，图1(a)为可见-近红外吸收光谱，图1(b)为近红外二区荧光发射光谱。
图2.为本发明制备的水溶性共轭聚合物P1的单线态氧测试(以1,3-二苯基异苯并呋喃(DPBF)作为单线态氧指示剂，以亚甲基蓝(MB)作为标准对照)，其中，图2(a)为DPBF的吸收随P1光照时间变化图，图2(b)为DPBF在吸收峰值处吸收分别随P1和MB光照时间变化的曲线。
图3.为本发明制备的水溶性共轭聚合物P1的光热转化效率测试，其中，图3(a)为P1水溶液单次循环温度随时间变化曲线，图3(b)为-lnθ与时间线性关系。
图4.为本发明制备的水溶性共轭聚合物纳米粒子P1 NPs的透射电镜(TEM)图。
图5.为本发明制备的水溶性共轭聚合物纳米粒子P1 NPs的暗毒性与光毒性测试，其中，图5(a)为P1 NPs的暗毒性测试，图5(b)为P1 NPs的光毒性测试。
具体实施方式
下面结合附图和具体实施例，进一步阐明本发明，应理解这些实例仅用于说明本发明而不用于限制本发明的范围，在阅读了本发明之后，本领域技术人员对本发明的各种等价形式的修改均落于本申请所附权利要求所限定的范围。
实施例
1)通过以下方法制备DPP衍生物单体M1。将mPEG-COOH(0.2g，0.1mmol，分子量2000)和四丁基氢氧化铵(0.13g，0.5mmol)加入到去离子水(50mL)中，加热至40℃反应12h。反应结束后，透析(用1000截留分子量透析袋除去四丁基氢氧化铵)，冷冻干燥(除去水)得到粗产物白色固体C1。将3,6-二(噻吩-2-基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮(0.3g，1mmol)、NaH(0.24g，10mmol)加入到超干DMF(20mL)中，抽真空通氮气，加热到85℃活化1h后，再加入1,6-二溴己烷(2.43g，10mmol)，升温至100℃下反应24h。反应结束后柱层析提纯得到C2。
将C2(0.0627g，0.1mmol)和C1(0.45g，0.2mmol)加入到四氢呋喃(30mL)和丙酮(10mL)的混合溶剂中，加热至40℃反应24h。反应结束后，旋蒸除去溶剂，加入去离子水溶解，抽滤，将滤液用透析袋(截留分子量3500)透析72h，冷冻干燥得到红色固体M1。
Figure BDA0003008696580000071
Figure BDA0003008696580000081
2)通过以下方法制备水溶性共轭聚合物P1。在氮气保护下，将M1(223.23mg，0.05mmol)、M2(34.12mg，0.05mmol)、无水碳酸钾(13.82mg，0.1mmol)、特戊酸(3.06mg，0.03mmol)和醋酸钯(1.12g，0.005mmol)加入到DMA(5mL)中，加热至110℃反应10h。反应结束后，加入去离子水溶解，抽滤，将滤液用透析袋(截留分子量8000)透析72h，冷冻干燥得到固体。
Figure BDA0003008696580000082
4)在808nm近红外激光照射下，将步骤1)、2)中制备的水溶性共轭聚合物纳米粒子(P1NPs)进行近红外二区荧光发射光谱、细胞外单线态氧产率(30mW/cm2)光热转化效率(1W/cm2)和形貌粒径测试，从图1中可知P1 NPs近红外二区荧光发射在1100nm-1300nm，从图2中可知P1单线态氧产率为34.97％，从图3中可知光热转换效率为37.5％，从图4中可知P1 NPs为30nm左右的球形形貌；再以HeLa细胞为模型，以MTT为指示剂进行细胞的暗毒性、光毒性测试(1W/cm2)，从图5中可知P1 NPs在无光照时没有毒性，在光照时能达到80％左右肿瘤细胞抑制率。
本发明采用接枝了亲水性大分子PEG链的吡咯并吡咯二酮(DPP)衍生物和窄带隙的电子受体，通过DHAP反应进行双组分交替共聚，有效实现了共轭聚合物的近红外二区荧光发射。吡咯并吡咯二酮(DPP)摩尔吸光系数和荧光量子效率高，很容易实现近红外吸收，耐热、耐光照，具有良好的光热转化效率以及一定的单线态氧产生能力，而且结构易修饰，其两侧连接噻吩基团，可以通过重原子效应(硫原子)增加激子系间穿越能力，提高三线态激子含量，增加了单线态氧产生能力，在有机电子器件以及生物探针领域有广泛应用。然而，在生物医药领域，DPP的水溶性和靶向性仍然是一个巨大的挑战。所以，引入亲水基团对DPP进行修饰或者制成纳米颗粒等方法被广泛研究。亲水性的聚乙二醇，由于具有水溶性、生物相容性、生物可降解性和易于化学修饰等特点，可以与DPP偶联形成具有高水溶性的单体用于聚合，而且引入了氧、氮原子这样的杂原子，杂原子效应可能会进一步提高单线态氧的产率，从而提高光动力治疗的效果。另外，光热效果通过扩充血管通透性为光动力提供了更多的氧气进而有相互促进的作用，二者结合一体化治疗可以实现无创性的高效肿瘤治疗。而且，将两亲性共轭聚合物制成纳米粒子，容易通过渗透增强和保留(EPR)效应富集于肿瘤组织，从而改善肿瘤靶向性。
以上所述仅是本发明的优选实施方式，应当指出：对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (6)

1.一种近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂，其特征在于：由两亲性的水溶性共轭聚合物通过分子自组装形成纳米光疗试剂，所述水溶性共轭聚合物的化学结构式如下：
Figure FDA0003468561560000011
其中，2,5位取代的吡咯并吡咯二酮衍生物(DPP)为电子受体，简称A，噻吩为π-共轭桥，窄带隙芳烃Ar为另一种电子受体，简称A’，得到一种结构为A-π-A’的疏水共轭主链，疏水共轭主链的聚合度n为大于1的自然数；吡咯并吡咯二酮衍生物(DPP)2,5位取代亲水侧链上聚乙二醇(PEG)的聚合度x为大于或等于10的自然数；
所述窄带隙芳烃Ar为噻吩并[3,2-b]噻吩基团或为2,5-双(2-乙基己基)-3,6-二(噻吩-2-基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮基团。
2.根据权利要求1所述的近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂，其特征在于：当窄带隙芳烃Ar为噻吩并[3,2-b]噻吩单体基团，x为大于20的自然数时，所述水溶性共轭聚合物的结构如下：
Figure FDA0003468561560000021
3.根据权利要求1所述的近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂，其特征在于：当窄带隙芳烃Ar为2,5-双(2-乙基己基)-3,6-二(噻吩-2-基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮单体基团，x为大于20的自然数时，所述水溶性共轭聚合物的结构如下：
Figure FDA0003468561560000031
4.根据权利要求1所述的近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂，其特征在于：由两亲性的水溶性共轭聚合物通过纳米沉淀法进行分子自组装形成纳米光疗试剂。
5.一种如权利要求1所述的近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂的制备方法，其特征在于，包括以下步骤：
步骤1)，将3,6-二(噻吩-2-基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮和1,6-二溴己烷的按物质的量比为1:9-11投料，合成出2,5-双(6-溴己基)-3,6-二(噻吩-2-基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮；
步骤2)，通过羧甲基化单甲氧基聚乙二醇(mPEG-COOH)和四丁基氢氧化铵反应得到活化的大分子PEG链；
步骤3)，在2,5-双(6-溴己基)-3,6-二(噻吩-2-基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮碳链末端接枝活化的大分子PEG链；
步骤4)，将接枝了PEG链的DPP衍生物单体和窄带隙二卤代芳烃，经有机金属醋酸钯催化剂催化聚合，反应后得到近红外二区水溶性共轭聚合物，再经纳米沉淀法制备成纳米颗粒。
6.根据权利要求5所述的近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂的制备方法，其特征在于，所述纳米沉淀法包括以下步骤：
步骤1)，将共轭聚合物溶于极性有机溶剂DMSO中,浓度控制在0.8-1.2mg/mL，然后将DMSO溶液在超声状态下滴加到纯水中，搅拌均匀；
步骤2)，接着在冰水浴中用尖头型超声仪间隔性超声；
步骤3)，室温搅拌后移入透析袋中，在纯水中透析；
步骤4)，用滤膜过滤后，取滤液冷冻干燥除水，得到纳米诊疗剂。
CN202110369366.6A 2021-04-06 2021-04-06 近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂及其制备方法与应用 Active CN113087877B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110369366.6A CN113087877B (zh) 2021-04-06 2021-04-06 近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂及其制备方法与应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110369366.6A CN113087877B (zh) 2021-04-06 2021-04-06 近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂及其制备方法与应用

Publications (2)

Publication Number Publication Date
CN113087877A CN113087877A (zh) 2021-07-09
CN113087877B true CN113087877B (zh) 2022-03-01

Family

ID=76674743

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110369366.6A Active CN113087877B (zh) 2021-04-06 2021-04-06 近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂及其制备方法与应用

Country Status (1)

Country Link
CN (1) CN113087877B (zh)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113861391A (zh) * 2021-10-08 2021-12-31 桂林理工大学 一种用于近红外二区成像的双给体共轭聚合物及应用
CN113956446B (zh) * 2021-10-12 2023-07-28 中国科学院大学 一种用于治疗乏氧肿瘤的半导体聚合物、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
CN114921245B (zh) * 2022-04-28 2024-04-02 澳门大学 近红外碳点及其制备方法和应用
CN115093548B (zh) * 2022-06-29 2024-05-10 南京邮电大学 一种自降解共轭聚合物、纳米粒子及其制备方法和应用
CN115215996B (zh) * 2022-07-21 2023-05-05 浙江省人民医院 Pdtp-tbz及其纳米制剂与治疗脑胶质瘤的应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111205438B (zh) * 2020-02-27 2022-03-04 南京邮电大学 一种近红外吸收水溶性共轭聚合物光疗试剂及其制备与应用
CN112494663B (zh) * 2020-11-18 2022-06-17 南京邮电大学 一种多模态纳米诊疗试剂及其制备方法和应用

Also Published As

Publication number Publication date
CN113087877A (zh) 2021-07-09

Similar Documents

Publication Publication Date Title
CN113087877B (zh) 近红外二区荧光发射水溶性共轭聚合物纳米光疗试剂及其制备方法与应用
Yin et al. Organic semiconducting polymer amphiphile for near-infrared-II light-triggered phototheranostics
Liu et al. Photosensitizer cross-linked nano-micelle platform for multimodal imaging guided synergistic photothermal/photodynamic therapy
Han et al. Theranostic reduction-sensitive gemcitabine prodrug micelles for near-infrared imaging and pancreatic cancer therapy
Gao et al. Molecular engineering of near-infrared light-responsive BODIPY-based nanoparticles with enhanced photothermal and photoacoustic efficiencies for cancer theranostics
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
CN109529034B (zh) 近红外二区共轭纳米粒子及其制备方法和应用
CN109503455B (zh) 一种以四苯乙烯吲哚衍生物为光敏剂的纳米复合材料及制备方法和在肿瘤治疗方面的应用
Deng et al. Zwitterionic diketopyrrolopyrrole for fluorescence/photoacoustic imaging guided photodynamic/photothermal therapy
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
CN110787305B (zh) 一种含聚集诱导发光基团的供体-受体类近红外ii区荧光分子的白蛋白纳米制剂
Jiang et al. Diketopyrrolopyrrole: An emerging phototherapy agent in fighting cancer
CN110433294B (zh) 基于偶氮苯的乏氧响应性胶束及其制备方法和应用
WO2019027370A1 (en) POLYMERIC NANOPARTICLES FOR MOLECULAR IMAGING WITH RESIDUAL LUMINESCENCE
Jiang et al. Polymerization-induced photothermy: A non-donor-acceptor approach to highly effective near-infrared photothermal conversion nanoparticles
Chen et al. The self-assembly of a hybrid photosensitizer for the synergistically enhanced photodynamic/photothermal therapy
Bao et al. Mussel-inspired functionalization of semiconducting polymer nanoparticles for amplified photoacoustic imaging and photothermal therapy
Zhang et al. A single-wavelength NIR-triggered polymer for in situ generation of peroxynitrite (ONOO−) to enhance phototherapeutic efficacy
Huang et al. A hierarchical supramolecular nanozyme platform for programming tumor-specific PDT and catalytic therapy
Tang et al. Organic disulfide-modified folate carbon dots for tumor-targeted synergistic chemodynamic/photodynamic therapy
Lu et al. Conjugated‐Polymer‐Based Photodynamic Therapy
CN110917348A (zh) 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
He et al. Tumor-targeting semiconducting polymer nanoparticles: efficient adjuvant photothermal therapy using ultra-low laser power inhibits recurrences after breast-conserving surgery
CN110152021A (zh) 一种具备癌细胞内靶向给药能力的药物载体系统及其制备方法
Deng et al. Molecular engineering of organic small-molecule photothermal agents by changing the donor group for photothermal therapy and photoacoustic imaging of tumors

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