CN111135313A - 一种近红外染料共配位型纳米配位聚合物及其制备方法和应用 - Google Patents
一种近红外染料共配位型纳米配位聚合物及其制备方法和应用 Download PDFInfo
- Publication number
- CN111135313A CN111135313A CN202010072870.5A CN202010072870A CN111135313A CN 111135313 A CN111135313 A CN 111135313A CN 202010072870 A CN202010072870 A CN 202010072870A CN 111135313 A CN111135313 A CN 111135313A
- Authority
- CN
- China
- Prior art keywords
- ncp
- infrared dye
- coordination
- type nano
- coordination polymer
- 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
- 239000013256 coordination polymer Substances 0.000 title claims abstract description 25
- 229920001795 coordination polymer Polymers 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 20
- 239000000463 material Substances 0.000 claims abstract description 16
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 11
- 238000007626 photothermal therapy Methods 0.000 claims abstract description 10
- 238000002512 chemotherapy Methods 0.000 claims abstract description 9
- 238000003745 diagnosis Methods 0.000 claims abstract description 7
- 238000003384 imaging method Methods 0.000 claims abstract description 4
- 230000008685 targeting Effects 0.000 claims abstract description 4
- 239000003446 ligand Substances 0.000 claims abstract description 3
- 229910052751 metal Inorganic materials 0.000 claims abstract description 3
- 239000002184 metal Substances 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 claims description 36
- 229940109262 curcumin Drugs 0.000 claims description 27
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 claims description 27
- GRAVJJAQKJDGPM-UHFFFAOYSA-N 3-[2-[7-[3-(2-carboxyethyl)-1,1-dimethylbenzo[e]indol-3-ium-2-yl]hepta-2,4,6-trienylidene]-1,1-dimethylbenzo[e]indol-3-yl]propanoic acid;bromide Chemical compound [Br-].OC(=O)CCN1C2=CC=C3C=CC=CC3=C2C(C)(C)\C1=C/C=C/C=C/C=C/C1=[N+](CCC(O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C GRAVJJAQKJDGPM-UHFFFAOYSA-N 0.000 claims description 14
- 239000011259 mixed solution Substances 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- 235000012754 curcumin Nutrition 0.000 claims description 9
- 239000004148 curcumin Substances 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- GPNNOCMCNFXRAO-UHFFFAOYSA-N 2-aminoterephthalic acid Chemical compound NC1=CC(C(O)=O)=CC=C1C(O)=O GPNNOCMCNFXRAO-UHFFFAOYSA-N 0.000 claims description 8
- 235000019441 ethanol Nutrition 0.000 claims description 8
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 8
- 239000012498 ultrapure water Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 4
- HRCJAFGUEPMJIR-UHFFFAOYSA-K gadolinium(3+);triacetate;hexahydrate Chemical compound O.O.O.O.O.O.[Gd+3].CC([O-])=O.CC([O-])=O.CC([O-])=O HRCJAFGUEPMJIR-UHFFFAOYSA-K 0.000 claims description 4
- 238000003333 near-infrared imaging Methods 0.000 claims description 4
- 229960000304 folic acid Drugs 0.000 claims description 3
- 239000011724 folic acid Substances 0.000 claims description 3
- 229910021645 metal ion Inorganic materials 0.000 claims description 3
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 208000003445 Mouth Neoplasms Diseases 0.000 claims description 2
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 2
- 229930012538 Paclitaxel Natural products 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 2
- 229960002685 biotin Drugs 0.000 claims description 2
- 235000020958 biotin Nutrition 0.000 claims description 2
- 239000011616 biotin Substances 0.000 claims description 2
- 229940127093 camptothecin Drugs 0.000 claims description 2
- -1 camptothecin compound Chemical class 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 2
- 229960004316 cisplatin Drugs 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 2
- 235000019152 folic acid Nutrition 0.000 claims description 2
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 229960001592 paclitaxel Drugs 0.000 claims description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 21
- 239000003814 drug Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000000799 fluorescence microscopy Methods 0.000 abstract description 3
- 230000010354 integration Effects 0.000 abstract description 3
- 230000004048 modification Effects 0.000 abstract description 3
- 238000012986 modification Methods 0.000 abstract description 3
- 230000033228 biological regulation Effects 0.000 abstract description 2
- 238000002601 radiography Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 238000011580 nude mouse model Methods 0.000 description 5
- 241000699660 Mus musculus Species 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 238000002583 angiography Methods 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940044683 chemotherapy drug Drugs 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 239000002616 MRI contrast agent Substances 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 208000007660 Residual Neoplasm Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 210000001099 axilla Anatomy 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 201000000760 cerebral cavernous malformation Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005760 tumorsuppression Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K49/0032—Methine dyes, e.g. cyanine dyes
-
- 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
- A61K49/0052—Small organic 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
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/12—Macromolecular compounds
- A61K49/126—Linear polymers, e.g. dextran, inulin, PEG
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y20/00—Nanooptics, e.g. quantum optics or photonic crystals
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y25/00—Nanomagnetism, e.g. magnetoimpedance, anisotropic magnetoresistance, giant magnetoresistance or tunneling magnetoresistance
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nanotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Physics & Mathematics (AREA)
- Biomedical Technology (AREA)
- Radiology & Medical Imaging (AREA)
- General Physics & Mathematics (AREA)
- Biophysics (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- Medical Informatics (AREA)
- Molecular Biology (AREA)
- General Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Manufacturing & Machinery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Optics & Photonics (AREA)
- Composite Materials (AREA)
- Materials Engineering (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本发明公开了一种近红外染料共配位型纳米配位聚合物及其制备方法和应用，该纳米配位聚合物以具有核磁响应型的金属Gd3+为节点，采用近红外染料与传统框架材料双配体共配位，并利用其多孔特性负载抗肿瘤药物，同时，进一步表面修饰赋予其良好的生物相容性和肿瘤靶向性。本发明制备的纳米配位聚合物具备良好的近红外荧光成像与核磁造影成像特性，能够实现良好的近红外光调控和pH敏感药物释放，实现多模成像引导的光热/化疗诊疗一体化。
Description
技术领域
本发明属于生物医用材料技术领域，具体涉及一种近红外染料共配位型纳米配位聚合物及其制备方法和应用。
背景技术
多数恶性肿瘤通过单一手术治疗的方式无法根治，需要化疗根除机体内残余的肿瘤细胞，从而提高外科手术的治愈率。然而，化疗药物选择性差，往往造成严重的全身毒副作用。光热治疗（PTT）是一种非侵入性的肿瘤治疗方法，主要是利用光热试剂在近红外光（NIR）照射下将光能转换为热能，高温（大于42℃）直接杀死肿瘤细胞，全身毒副作用小。将PTT与化疗结合，通过不同的抑瘤机制实现光热/化疗协同抗肿瘤作用。
癌症的早期诊断与治疗同样重要。近红外荧光成像技术具有组织穿透能力强、灵敏度高、检测时间短等特点，是一种常见的肿瘤诊断方法，但近红外染料存在稳定性差、体内半衰期短等缺点。核磁共振成像（MRI）具有良好的空间分辨率、高软组织对比度和大的穿透深度，但由于检测部位环境差异，灵敏度较低，通常利用MRI造影剂进一步提高图像质量。
要实现肿瘤的精准诊断与治疗，首先要将诊断试剂与抗肿瘤药物靶向输送到肿瘤组织。纳米配位聚合物（NCP）可改变药物在体内的分布、靶向输送药物到肿瘤组织、控制药物释放、降低全身毒副作用。NCP是通过中心金属离子或中心金属团簇与有机配体通过自组装相互连接形成的一类无定形结构材料，它具有无机和有机材料的优势，例如有序介孔结构、组成及尺寸可调控、功能多样性、生物安全性好和可快速代谢等。
本发明结合近红外染料Cypate（Cy）的荧光成像与光热作用、Gd3+离子的核磁成像及NCP的特点，构建一种近红外染料共配位型纳米配位聚合物，实现光热/化疗/近红外成像/核磁造影诊疗一体化。
发明内容
本发明在于提供一种近红外染料共配位型纳米配位聚合物及其制备方法和应用，该纳米配位聚合物可主动靶向肿瘤组织，实现近红外荧光成像、核磁造影功能，并能发挥光热/化疗协同抗肿瘤作用，实现恶性肿瘤的多模式诊疗一体化。
为实现上述目的，本发明采用如下技术方案：
一种近红外染料共配位型纳米配位聚合物，以 Gd3+为中心金属离子，近红外染料Cypate和2-氨基对苯二甲酸为双配体，共配位合成Cy-NCP材料，再负载抗肿瘤药物合成抗肿瘤药物@Cy-NCP，最后在NCP材料表面修饰COOH-PEG-靶向基团。
所述的抗肿瘤药物为顺铂、紫杉醇、姜黄素、蒽环类化合物、喜树碱类化合物中的任意一种。
所述的COOH-PEG-靶向基团为叶酸、生物素、RGD、抗体中的任一种。
金属Gd3+、2-氨基对苯二甲酸、Cypate的摩尔比为1:(0.1-1):(0.01-1)；Cy-NCP与抗肿瘤药物的质量比为1:(0.25-2)；抗肿瘤药物@Cy-NCP与COOH-PEG-靶向基团的质量比为1:(0.2-1)。、
制备所述的近红外染料共配位型纳米配位聚合物的方法，包括以下步骤：
（1）将六水合醋酸钆和Cypate加入DMF/乙醇混合溶液，再加入2-氨基对苯二甲酸与PVP，于反应釜中反应1-24 h，反应温度为40-240℃，冷却至室温后，离心收集产物，并依次用DMF/乙醇混合溶液、无水乙醇洗涤三次，离心收集产物,即得Cy-NCP材料；
（2）将抗肿瘤药物溶解于无水乙醇中，并加入步骤（1）制备得到的Cy-NCP材料，室温避光反应8-48 h，离心收集产物，再依次用无水乙醇、超纯水洗涤两遍，离心收集产物，得到抗肿瘤药物@Cy-NCP；
（3）将步骤（2）获得的抗肿瘤药物@Cy-NCP、COOH-PEG-靶向基团、NHS与EDC溶解于pH=7.4的MES溶液中，室温避光反应6-24 h，离心收集产物，并用超纯水清洗三遍，离心收集得到抗肿瘤药物@Cy-NCP/主动靶向基团。
进一步地，将近红外染料共配位型纳米配位聚合物应用于制备抗乳腺癌、口腔癌、肝癌、肺癌或宫颈癌的光热/化疗/近红外成像/核磁造影诊疗一体化载体中。
本发明的优点在于：制备的近红外染料共配位型纳米配位聚合物可将近红外染料和化疗药物主动靶向输送到肿瘤部位，增强肿瘤细胞对药物的摄取。在肿瘤组织实现近红外成像、核磁造影功能的同时，还具有良好的近红外光调控和pH敏感药物释放作用，可实现多模成像引导的光热/化疗诊疗一体化。
附图说明：
图1为实施例2制备的Cy-NCP的扫描电镜结果。
图2为实施例4的近红外染料共配位型纳米配位聚合物体外释放结果。
图3为实施例4的近红外染料共配位型纳米配位聚合物细胞摄取结果。
图4为实施例4的近红外染料共配位型纳米配位聚合物对KB荷瘤裸鼠抑瘤实验结果。
具体实施方式：
为了使本发明所述的内容更加便于理解，下面结合具体实施方式对本发明所述的技术方案做进一步的说明，但是本发明不仅限于此。
实施例1：Cy-NCP材料的合成方法
将50 mg六水合醋酸钆和1 mg Cypate加入30 mL DMF/乙醇（V:V=5:3）混合溶液，再加入7.3 mg 2-氨基对苯二甲酸与680 mg PVP，混合溶液置于反应釜中，60℃反应10 h；冷却至室温，12000r,10min离心收集产物,并依次用DMF/乙醇混合溶液（V:V=5:3）、无水乙醇洗涤三次，12000r,10min离心收集产物,即得Cy-NCP。
实施例2：Cy-NCP材料的合成方法
将50 mg六水合醋酸钆和5 mg Cypate加入30 mL DMF/乙醇（V:V=5:3）混合溶液，再加入12.3 mg 2-氨基对苯二甲酸与680 mg PVP，混合溶液置于反应釜中，140℃反应4 h，冷却至室温，12000r,10min离心收集产物,并依次用DMF/乙醇混合溶液（V:V=5:3）、无水乙醇洗涤三次，12000r,10min离心收集产物,即得Cy-NCP。
合成Cy-NCP材料的扫描电镜结果如图1所示，Cy-NCP为球形，粒径分布在60-120nm，分散较均匀。
实施例3：CCM@Cy-NCP/FA的合成方法
（1）将25 mg姜黄素（CCM）溶于25 mL无水乙醇，再加入50 mg实施例2制备的Cy-NCP，室温避光反应24 h，10000r,10min离心收集产物，再依次用无水乙醇、超纯水洗涤两遍，10000r,10min离心收集产物，得到CCM@Cy-NCP。
（2）将10 mg CCM@Cy-NCP、2.5 mg COOH-PEG-叶酸（FA）、1.4 mg NHS与2.3 mg EDC溶解于10 mL的MES溶液（pH=7.4）,室温避光反应16 h，10000r,10min离心收集产物，并用超纯水清洗三遍，离心收集得到CCM@Cy-NCP/FA。
MES溶液的配制：将19.5gMES粉末溶于三蒸水，移至容量瓶中并定容至1 L，调节pH=7.4，置于4℃保存备用。
实施例4：CCM@Cy-NCP/FA的合成方法
（1）将50 mg CCM溶于25 mL无水乙醇，再加入50 mg实施例2制备的Cy-NCP，室温避光反应24 h，10000r,10min离心收集产物，再依次用无水乙醇、超纯水洗涤两遍，10000r,10min离心收集产物，得到CCM@Cy-NCP。
（2）将10 mg CCM@Cy-NCP、5 mg COOH-PEG-FA、1.4 mg NHS与2.3 mg EDC溶解于10mL的MES溶液（pH=7.4）,室温避光反应16 h，10000r,10min离心收集产物，并用超纯水清洗三遍，10000r,10min离心收集得到CCM@Cy-NCP/FA。
实施例5：近红外染料共配位型纳米配位聚合物的体外释放实验
将3.58 mg实施例4制备的CCM@Cy-NCP/FA置于15 mL 含有0.1 wt%吐温-80的PBS溶液（pH=5.5或7.4），采用785 nm的近红外激光照射5 min，于37℃、100 rpm/min条件释放，对照组无激光照射；分别于0、1、2、4、8、12、24、36、48 h取出2 mL释放液，同时补充2 mL新鲜的释放介质；取出的释放液采用紫外分光光度计测试CCM的释放量，并计算CCM的累积释放率。
结果如图2所示表明，在pH=5.5的PBS溶液，释放48 h时，激光照射组中CCM的累计释放量为81%，明显高于无激光照射的对照组（释放量为62.5%）；而激光照射组在pH=7.4时，CCM的释放量为38%，明显低于pH=5.5时CCM的释放量。这是因为CCM@Cy-NCP/FA具有近红外和pH响应性释放功能。
实施例6：近红外染料共配位型纳米配位聚合物的细胞摄取实验
取对数生长期的KB细胞，用含10%胎牛血清的RPMI-1640培养基稀释，以1×106细胞/孔的密度接种于6孔培养板，37℃培养过夜，弃去培养基，PBS (10mM, pH=7.2-7.4) 洗涤，分别于避光条件下加入2 mL含游离Cypate、实施例4制备的产物CCM@Cy-NCP和CCM@Cy-NCP/FA溶液的培养基（Cypate终浓度为15 µg/mL），培养2 h后弃培养基，1mLPBS清洗2次，500μL胰酶消化，300-500μLPBS重悬，采用流式细胞仪分析。
结果如图3所示，与游离Cypate相比，NCP组的荧光强度明显增强，这表明NCP改善了细胞对Cypate的摄取。此外，CCM@Cy-NCP/FA的荧光强度明显高于CCM@Cy-NCP，这是因为NCP经过主动靶向基团FA修饰，促进了细胞对材料的摄取。
实施例7：近红外染料共配位型纳米配位聚合物对KB荷瘤裸鼠的抑瘤实验
KB荷瘤裸鼠模型的建立：取对数生长期的KB细胞，PBS洗涤、消化后收集细胞，经0.9%NaCl注射液重悬并稀释成浓度为1×108细胞/mL的单细胞悬液，于裸鼠右腋皮下注射1×107个细胞/只。取肿瘤约80-100 mm3的荷瘤裸鼠分组，分别按Cypate剂量7.5 mg/kg给药，给药1 d后，激光照射组用785 nm近红外光照射4 min，对照组无激光照射。实验期间，每天测量肿瘤体积。
结果如图4所示，在14 d时，生理盐水组具有显著的肿瘤生长，NCP组对肿瘤体积增长呈现不同程度的抑制作用。其中，CCM@Cy-NCP/FA组的抑制作用强于无FA修饰的CCM@Cy-NCP组；激光照射后，CCM@Cy-NCP/FA组对肿瘤的抑瘤作用明显增强。这说明CCM@Cy-NCP/FA激光照射组具有良好的体内抑瘤效果，明显增强了光热/化疗协同抗肿瘤作用，提高了疗效。
以上所述仅为本发明的较佳实施例，凡依本发明申请专利范围所做的均等变化与修饰，皆应属本发明的涵盖范围。
Claims (6)
1.一种近红外染料共配位型纳米配位聚合物，其特征在于：以 Gd3+为中心金属离子，近红外染料Cypate和2-氨基对苯二甲酸为双配体，共配位合成Cy-NCP材料，再负载抗肿瘤药物合成抗肿瘤药物@Cy-NCP，最后在NCP材料表面修饰COOH-PEG-靶向基团。
2.根据权利要求1所述近红外染料共配位型纳米配位聚合物，其特征在于：所述的抗肿瘤药物为顺铂、紫杉醇、姜黄素、蒽环类化合物、喜树碱类化合物中的任意一种。
3.根据权利要求1所述近红外染料共配位型纳米配位聚合物，其特征在于：所述的COOH-PEG-靶向基团为叶酸、生物素、RGD、抗体中的任一种。
4.根据权利要求1所述近红外染料共配位型纳米配位聚合物，其特征在于：金属Gd3+、2-氨基对苯二甲酸、Cypate的摩尔比为1:(0.1-1):(0.01-1)；Cy-NCP与抗肿瘤药物的质量比为1:(0.25-2)；抗肿瘤药物@Cy-NCP与COOH-PEG-靶向基团的质量比为1:(0.2-1)。
5.一种制备如权利要求1-4任意一项所述的近红外染料共配位型纳米配位聚合物的方法，其特征在于：包括以下步骤：
（1）将六水合醋酸钆和Cypate加入DMF/乙醇混合溶液，再加入2-氨基对苯二甲酸与PVP，于反应釜中反应1-24 h，反应温度为40-240℃，冷却至室温后，离心收集产物，并依次用DMF/乙醇混合溶液、无水乙醇洗涤三次，离心收集产物，即得Cy-NCP材料；
（2）将抗肿瘤药物溶解于无水乙醇中，并加入步骤（1）制备得到的Cy-NCP材料，室温避光反应8-48 h，离心收集产物，再依次用无水乙醇、超纯水洗涤两遍，离心收集产物，得到抗肿瘤药物@Cy-NCP；
（3）将步骤（2）获得的抗肿瘤药物@Cy-NCP、COOH-PEG-靶向基团、NHS与EDC溶解于pH=7.4的MES溶液中，室温避光反应6-24 h，离心收集产物，并用超纯水清洗三遍，离心收集得到抗肿瘤药物@Cy-NCP/主动靶向基团。
6.一种如权利要求1所述的近红外染料共配位型纳米配位聚合物在制备抗乳腺癌、口腔癌、肝癌、肺癌或宫颈癌的光热/化疗/近红外成像/核磁造影诊疗一体化载体中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010072870.5A CN111135313B (zh) | 2020-01-22 | 2020-01-22 | 一种近红外染料共配位型纳米配位聚合物及其制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010072870.5A CN111135313B (zh) | 2020-01-22 | 2020-01-22 | 一种近红外染料共配位型纳米配位聚合物及其制备方法和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111135313A true CN111135313A (zh) | 2020-05-12 |
| CN111135313B CN111135313B (zh) | 2021-07-27 |
Family
ID=70526931
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010072870.5A Active CN111135313B (zh) | 2020-01-22 | 2020-01-22 | 一种近红外染料共配位型纳米配位聚合物及其制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111135313B (zh) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113155930A (zh) * | 2021-05-29 | 2021-07-23 | 福建医科大学 | 一种多重信号放大技术检测白血病干细胞肿瘤标志物cd123的电化学免疫传感方法 |
| CN113289015A (zh) * | 2021-05-13 | 2021-08-24 | 华中科技大学 | 调节光敏剂聚集程度的方法、纳米配位聚合物及其制备方法和应用 |
| CN113546170A (zh) * | 2021-07-21 | 2021-10-26 | 福州大学 | 一种无载体纳米诊疗剂及其制备方法和应用 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108619511A (zh) * | 2018-04-20 | 2018-10-09 | 山东大学 | 一种基于阿糖胞苷小分子前药的金属有机框架载药系统的制备方法和应用 |
-
2020
- 2020-01-22 CN CN202010072870.5A patent/CN111135313B/zh active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108619511A (zh) * | 2018-04-20 | 2018-10-09 | 山东大学 | 一种基于阿糖胞苷小分子前药的金属有机框架载药系统的制备方法和应用 |
Non-Patent Citations (2)
| Title |
|---|
| YAWEI LI等: ""Facile synthesis of a metal–organic framework nanocarrier for NIR imaging-guided photothermal therapy"", 《BIOMATER. SCI.》 * |
| ZHIMEI HE等: ""Acid-degradable gadolinium-based nanoscale coordination polymer: A potential platform for targeted drug delivery and potential magnetic resonance imaging"", 《NANO RESEARCH》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113289015A (zh) * | 2021-05-13 | 2021-08-24 | 华中科技大学 | 调节光敏剂聚集程度的方法、纳米配位聚合物及其制备方法和应用 |
| CN113289015B (zh) * | 2021-05-13 | 2023-02-21 | 华中科技大学 | 调节光敏剂聚集程度的方法、纳米配位聚合物及其制备方法和应用 |
| CN113155930A (zh) * | 2021-05-29 | 2021-07-23 | 福建医科大学 | 一种多重信号放大技术检测白血病干细胞肿瘤标志物cd123的电化学免疫传感方法 |
| CN113155930B (zh) * | 2021-05-29 | 2023-05-12 | 福建医科大学 | 一种多重信号放大技术检测白血病干细胞肿瘤标志物cd123的电化学免疫传感方法 |
| CN113546170A (zh) * | 2021-07-21 | 2021-10-26 | 福州大学 | 一种无载体纳米诊疗剂及其制备方法和应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111135313B (zh) | 2021-07-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111135313B (zh) | 一种近红外染料共配位型纳米配位聚合物及其制备方法和应用 | |
| Lu et al. | Nanoscale metal–organic frameworks for therapeutic, imaging, and sensing applications | |
| Sun et al. | In situ synthesis of graphene oxide/gold nanorods theranostic hybrids for efficient tumor computed tomography imaging and photothermal therapy | |
| Yang et al. | Recent advances in nanosized metal organic frameworks for drug delivery and tumor therapy | |
| Pan et al. | A combination of glioma in vivo imaging and in vivo drug delivery by metal–organic framework based composite nanoparticles | |
| CN103893128B (zh) | 一种肿瘤治疗复合纳米材料及其制备 | |
| CN107812200B (zh) | Bsa-钆离子络合物包载的空心金纳米壳及制备方法 | |
| Sun et al. | MnO 2 nanoflowers as a multifunctional nano-platform for enhanced photothermal/photodynamic therapy and MR imaging | |
| CN111760024A (zh) | 一种渗透增强型金纳米簇载药靶向制剂及其制法和应用 | |
| Zhang et al. | Mitochondrial targeted melanin@ mSiO2 yolk-shell nanostructures for NIR-Ⅱ-driven photo-thermal-dynamic/immunotherapy | |
| CN111358964A (zh) | 磁性八面体铂掺杂金纳米壳、其制备方法和应用 | |
| CN114848854B (zh) | 一种131i-hsa-icg纳米颗粒及其制备方法和应用 | |
| CN113941010A (zh) | 一种协同no气体治疗并增强声动力治疗效果的纳米粒及其制备方法与应用 | |
| CN113559064A (zh) | 一种新型自供氧脂质体纳米粒及其制备方法与应用 | |
| Chen et al. | A multifunctional SN38-conjugated nanosystem for defeating myelosuppression and diarrhea induced by irinotecan in esophageal cancer | |
| Ouyang et al. | Efficient improvement in chemo/photothermal synergistic therapy against lung cancer using Bi@ Au nano-acanthospheres | |
| Guan et al. | Iron oxide-based enzyme mimic nanocomposite for dual-modality imaging guided chemical phototherapy and anti-tumor immunity against immune cold triple-negative breast cancer | |
| CN118045178A (zh) | 一种中空二氧化锰包覆硫化铜纳米药物载体及用其制备肝癌靶向肽修饰纳米药物的方法 | |
| Tang et al. | Glutathione depletion-mediated in situ transformation of Prussian blue nanocubes for enhanced tumor-specific imaging and photoimmunotherapy | |
| CN117338925A (zh) | 双光治疗的白蛋白载药纳米粒在制备用于治疗宫颈癌药物中的应用 | |
| CN115192708B (zh) | 负载抗肿瘤药物的纳米复合材料、纳米载药体系及制备与应用 | |
| CN112546025A (zh) | 一种Ce6@CMCS-DSP-IPI549抗肿瘤纳米传递系统的制备方法 | |
| CN111686250A (zh) | 一种线粒体靶向的光热治疗剂及其制备和应用 | |
| CN113769087B (zh) | 仿生预淬灭双光敏剂共组装纳米粒及其制备和应用 | |
| CN108324958A (zh) | 一种紫红素18-脂质体纳米囊泡的制备方法以及在制备用于治疗肿瘤药物中的应用 |
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 |