CN111840581B - 一种用于诊断脑梗死的核磁共振造影剂及其应用 - Google Patents

一种用于诊断脑梗死的核磁共振造影剂及其应用 Download PDF

Info

Publication number
CN111840581B
CN111840581B CN202010779178.6A CN202010779178A CN111840581B CN 111840581 B CN111840581 B CN 111840581B CN 202010779178 A CN202010779178 A CN 202010779178A CN 111840581 B CN111840581 B CN 111840581B
Authority
CN
China
Prior art keywords
magnetic resonance
nuclear magnetic
contrast agent
resonance contrast
parts
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
CN202010779178.6A
Other languages
English (en)
Other versions
CN111840581A (zh
Inventor
刘鹤
董妍
苗慧
冯华
尹燕伟
李海燕
于海娇
周洋
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.)
Mudanjiang Medical University
Original Assignee
Mudanjiang Medical University
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 Mudanjiang Medical University filed Critical Mudanjiang Medical University
Priority to CN202010779178.6A priority Critical patent/CN111840581B/zh
Publication of CN111840581A publication Critical patent/CN111840581A/zh
Application granted granted Critical
Publication of CN111840581B publication Critical patent/CN111840581B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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
    • A61K49/06—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
    • A61K49/14—Peptides, e.g. proteins
    • 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
    • A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
    • 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
    • A61K49/103—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being acyclic, e.g. DTPA
    • A61K49/105—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being acyclic, e.g. DTPA the metal complex being Gd-DTPA
    • 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
    • A61K49/108—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 the metal complex being Gd-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
    • 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
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1833—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with 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
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1851—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
    • A61K49/1857—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA
    • A61K49/186—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA the organic macromolecular compound being polyethyleneglycol [PEG]
    • 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
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1866—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
    • 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)
  • Nanotechnology (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Radiology & Medical Imaging (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Biophysics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

本发明涉及一种用于诊断脑梗死的核磁共振造影剂及其应用，所述核磁共振造影剂由PEG氨基修饰的核磁共振造影剂脂质体纳米颗粒及任选的纤维蛋白靶向多肽制备而成，显示了明显的脑梗死患处靶向特性，显著增强了脑梗死患处的核磁共振显像效果。

Description

一种用于诊断脑梗死的核磁共振造影剂及其应用
技术领域
本发明属于诊断试剂领域，具体涉及一种用于诊断脑梗死的核磁共振造影剂及其应用。
背景技术
核磁共振成像(Nuclear Magnetic Resonance Imaging，NMRI)，又称自旋成像、磁共振成像，是利用核磁共振原理，依据所释放的能量在物质内部不同结构环境中不同的衰减，通过外加梯度磁场检测所发射出的电磁波，即可得知构成这一物体原子核的位置和种类，据此可以绘制成物体内部的结构图像。快速变化的梯度磁场的应用，大大加快了核磁共振成像的速度，使该技术在临床诊断、科学研究的应用成为现实，极大地推动了医学、神经生理学和认知神经科学的迅速发展。
由于人体不同组织，或正常组织与病变组织弛豫时间相互重叠,差别太小且易波动,容易导致成像模糊及分辨不清,甚至会造成漏诊或误诊，核磁共振造影剂的出现很好的解决了这个问题,从1983年Weinmann和Brasch等首次将钆喷酸葡胺(Gd-DTPA)运用于脑部肿瘤的诊断，1987年通过美国FDA认证后，核磁共振造影剂目前已经广泛使用于临床。核磁共振造影剂的作用机理就是通过缩短质子弛豫时间T1或T2,从而提高不同组织间或病变的信号差异，达到使原有图像更加清晰。
心脑血管疾病是我国成年人群的首要致死病因，且发病率仍在上升，并具有年轻化的趋势。脑梗死为常见的心脑血管疾病之一，又称缺血性脑卒中或中风，为多种原因所导致的局部脑组织区域血液供应障碍，可导致脑组织缺血缺氧性病变坏死，轻者会导致偏瘫、失语、失认，重者会直接危及患者的生命。脑梗死发病后的6小时内及时进行治疗，可有效挽救患者的生命，降低后遗症的发生率，因此也被称为脑梗死治疗的黄金时段。脑梗死的及时治疗要以及时诊断、及时发现脑梗死血管的位置为首要前提，虽然核磁共振及核磁共振造影剂，已经广泛应用于心脑血管疾病的诊断，但传统的核磁共振造影剂，如钆螯合物，不具有靶向性、半衰期短、弛豫效能低，且由于脑梗死部位血流受限，严重影响了传统的核磁共振造影剂向脑梗死部位的递送，也无法实现造影剂在脑梗死部位的有效聚集，大大削弱了传统核磁共振造影剂对脑梗死诊断的增强效果。
为了获取具有靶向性的核磁共振造影剂，人们尝试在钆造影剂结构上添加抗体等靶向分子，如抗P-选择素功能域单抗，虽然取得了一定的靶向效果，但其制备方法复杂、保存条件高、使用成本高，大大限制了其应用。纤维蛋白靶向造影剂也已经被用于动脉血栓的核磁共振检测，如有文献报道了环状纤维蛋白结合肽EP-2014R、靶向纤维蛋白α链的多肽TP850、纤连蛋白、凝血因子XIII等可用于动脉粥样硬化、冠状动脉血栓和经动脉血栓及静脉血栓的磁共振成像研究，但由于其分子量大、脂溶性低，不易穿过血脑屏障，且脑毛细血管壁上存在非常丰富的水解酶，使得血液中的多肽类物质被迅速降解而失活，使得相应造影剂的靶向性功能减弱，甚至失效。
本发明旨在提供一种脑靶向性效果明显改善的诊断脑梗死的核磁共振造影剂。
发明内容
本发明的目的是提供一种用于诊断脑梗死的核磁共振造影剂及其应用。
一方面，本发明提供了一种用于诊断脑梗死的核磁共振造影剂，所述核磁共振造影剂由PEG氨基修饰的核磁共振造影剂脂质体纳米颗粒及任选的纤维蛋白靶向多肽制备而成；
优选的，所述核磁共振造影剂由PEG氨基修饰的核磁共振造影剂脂质体纳米颗粒和纤维蛋白靶向多肽制备而成；
优选的，所述核磁共振造影剂选自T1核磁共振造影剂或T2核磁共振造影剂；
优选的，所述T1核磁共振造影剂选自：钆喷酸葡胺(Gd-DTPA)或钆特酸葡胺(Gd-DOTA)；所述T2核磁共振造影剂选自：超顺磁性氧化铁(SPIO)；
优选的，所述纤维蛋白靶向多肽选自：胸腺五肽、胸腺肽α1、RGD肽、KRDS肽或其混合物；更优选的，所述纤维蛋白靶向多肽选自：胸腺肽α1与KRDS肽的混合物；优选的，所述胸腺肽α1与KRDS肽的重量比为：3-8：1-5；更优选的，所述胸腺肽α1与KRDS肽的重量比为：5：3。
优选的，所述PEG氨基修饰的核磁共振造影剂脂质体纳米颗粒中PEG氨基选自：DSPE-PEG(2000)Amine、4臂-氨基-聚乙二醇或6臂-氨基-聚乙二醇。
优选的，所述PEG氨基与纤维蛋白靶向多肽的摩尔比为1:2-8；更优选的，所述PEG氨基与纤维蛋白靶向多肽的摩尔比为1:3-7；最优选的，所述PEG氨基与纤维蛋白靶向多肽的摩尔比为1:4。
另一方面，本发明提供了PEG氨基修饰的核磁共振造影剂脂质体纳米颗粒与纤维蛋白靶向多肽的组合在制备用于诊断脑梗死的核磁共振造影剂中的用途。
优选的，所述核磁共振造影剂选自T1核磁共振造影剂或T2核磁共振造影剂；
优选的，所述T1核磁共振造影剂选自：钆喷酸葡胺(Gd-DTPA)或钆特酸葡胺(Gd-DOTA)；所述T2核磁共振造影剂选自：超顺磁性氧化铁(SPIO)；
优选的，所述纤维蛋白靶向多肽选自：胸腺五肽、胸腺肽α1、RGD肽、KRDS肽或其混合物；更优选的，所述纤维蛋白靶向多肽选自：胸腺肽α1与KRDS肽的混合物；优选的，所述胸腺肽α1与KRDS肽的重量比为：3-8：1-5；更优选的，所述胸腺肽α1与KRDS肽的重量比为：5：3。
优选的，所述PEG氨基修饰的核磁共振造影剂脂质体纳米颗粒中PEG氨基选自：DSPE-PEG(2000)Amine、4臂-氨基-聚乙二醇或6臂-氨基-聚乙二醇。
优选的，所述PEG氨基与纤维蛋白靶向多肽的摩尔比为1:2-8；更优选的，所述PEG氨基与纤维蛋白靶向多肽的摩尔比为1:3-7；最优选的，所述PEG氨基与纤维蛋白靶向多肽的摩尔比为1:4。
再一个方面，本发明提供了一种诊断脑梗死的核磁共振造影剂的制备方法，其包括以下步骤：
(1)脂质体纳米颗粒的制备：按配方量称取卵磷脂、胆固醇、PEG氨基溶于氯仿溶液中，搅拌均匀后，置于旋转蒸发仪中，水浴55℃条件下旋转成膜，真空干燥后添加核磁共振造影剂溶液后制得脂质体乳液，经超速离心获得PEG氨基修饰的核磁共振造影剂脂质体纳米颗粒；
(2)任选的纤维蛋白靶向多肽的缀合：按量称取步骤(1)制得的PEG氨基修饰的核磁共振造影剂脂质体纳米颗粒与纤维蛋白靶向多肽，20-30℃条件下于注射用水中共同孵育5-15min，即得本发明诊断脑梗死的核磁共振造影剂。
本发明有益效果
本发明通过PEG氨基修饰的核磁共振造影剂脂质体纳米颗粒并优选的添加纤维蛋白靶向多肽有效提高了核磁共振造影剂的血脑屏障的通过率，实现了核磁共振造影剂在脑梗死部位的富集，显著增强了脑梗死的核磁共振显像效果，可以明显降低核磁共振造影剂所需剂量，在实现及时诊断脑梗死、及时发现脑梗死血管的位置，为脑梗死的及时治疗提供条件的基础上，还有利于降低成本、避免造影剂副作用的发生。
具体实施方式
在下文中更详细地描述了本发明以有助于对本发明的理解。
实施例1：一种诊断脑梗死的核磁共振造影剂
DSPE-PEG(2000)Amine2份、钆喷酸葡胺15份、卵磷脂80份、胆固醇15份、注射用水适量，按照以下步骤制备：
按配方量称取卵磷脂、胆固醇、DSPE-PEG(2000)Amine溶于氯仿溶液中，搅拌均匀后，置于旋转蒸发仪中，水浴55℃条件下旋转成膜，真空干燥后添加钆喷酸葡胺溶液后制得脂质体乳液，经超速离心获得PEG氨基修饰的核磁共振造影剂脂质体纳米颗粒，即得本发明诊断脑梗死的核磁共振造影剂。
实施例2：一种诊断脑梗死的核磁共振造影剂
4臂-氨基-聚乙二醇2份、钆喷酸葡胺15份、卵磷脂80份、胆固醇15份、注射用水适量，按照实施例1方法制备即得。
实施例3：一种诊断脑梗死的核磁共振造影剂
6臂-氨基-聚乙二醇2份、钆喷酸葡胺15份、卵磷脂80份、胆固醇15份、注射用水适量，按照实施例1方法制备即得。
实施例4：一种诊断脑梗死的核磁共振造影剂
4臂-氨基-聚乙二醇2份、钆喷酸葡胺15份、卵磷脂80份、胆固醇15份、胸腺五肽8份、注射用水适量，按照以下步骤制备：
(1)脂质体纳米颗粒的制备：按配方量称取卵磷脂、胆固醇、4臂-氨基-聚乙二醇溶于氯仿溶液中，搅拌均匀后，置于旋转蒸发仪中，水浴55℃条件下旋转成膜，真空干燥后添加钆喷酸葡胺溶液后制得脂质体乳液，经超速离心获得PEG氨基修饰的核磁共振造影剂脂质体纳米颗粒；
(2)纤维蛋白靶向多肽的缀合：按量称取步骤(1)制得的PEG氨基修饰的核磁共振造影剂脂质体纳米颗粒与胸腺五肽，25℃条件下于注射用水中共同孵育10min，即得本发明诊断脑梗死的核磁共振造影剂。
实施例5：一种诊断脑梗死的核磁共振造影剂
4臂-氨基-聚乙二醇2份、钆喷酸葡胺15份、卵磷脂80份、胆固醇15份、胸腺肽α18份、注射用水适量，按照实施例4步骤制备即得。
实施例6：一种诊断脑梗死的核磁共振造影剂
4臂-氨基-聚乙二醇2份、钆喷酸葡胺15份、卵磷脂80份、胆固醇15份、RGD肽8份、注射用水适量，按照实施例4步骤制备即得。
实施例7、一种诊断脑梗死的核磁共振造影剂
4臂-氨基-聚乙二醇2份、钆喷酸葡胺15份、卵磷脂80份、胆固醇15份、KRDS肽8份、注射用水适量，按照实施例4步骤制备即得。
实施例8：一种诊断脑梗死的核磁共振造影剂
4臂-氨基-聚乙二醇2份、钆喷酸葡胺15份、卵磷脂80份、胆固醇15份、胸腺肽α15份、KRDS肽3份、注射用水适量，按照实施例4步骤制备即得。
对比例1：一种诊断脑梗死的核磁共振造影剂
钆喷酸葡胺15份、卵磷脂80份、胆固醇15份，注射用水适量，按照实施例1方法制备即得。
对比例2：一种诊断脑梗死的核磁共振造影剂
钆喷酸葡胺15份、卵磷脂80份、胆固醇15份、胸腺五肽8份、注射用水适量，按照实施例4步骤制备即得。
对比例3：一种诊断脑梗死的核磁共振造影剂
4臂-氨基-聚乙二醇2份、钆喷酸葡胺15份、卵磷脂80份、胆固醇15份、胸腺五肽2份、注射用水适量，按照实施例4方法制备即得。
对比例4：一种诊断脑梗死的核磁共振造影剂
4臂-氨基-聚乙二醇2份、钆喷酸葡胺15份、卵磷脂80份、胆固醇15份、胸腺五肽20份、注射用水适量，按照实施例4方法制备即得。
效果例1：本发明诊断脑梗死的核磁共振造影剂的靶向效果
1.1实验物质：
实施例1-8及对比例1-4所述超声造影剂及钆喷酸葡胺注射液。
1.2实验方法：
12周龄雄性昆明小鼠42只，体重35-40g，适应性饲养1d后随机分为：模型组、对照组、实施例1-8组及对比例1-4组，每组3只。小鼠经10％水合氯醛麻醉后，剪开脑部皮肤后固定，在小鼠左脑前后卤间，使用孔径为2mm的屏蔽纸紧贴颅骨，其中孔的右缘距正中线1mm。各组小鼠均使用冷光源紧贴颅骨照射20min。各组小鼠尾静脉注射相应的核磁共振造影剂，注射剂量以钆喷酸葡胺计均为0.2mmol/kg体重，其中对照组注射等量钆喷酸葡胺注射液，模型组注射等体积生理盐水。给药4h后小鼠断颈处死，取脑组织，经生理盐水冲洗干净后滤纸吸干，加入1mL浓硝酸，于60℃水浴条件下硝化12h，使用电感耦合等离子体-发射光谱法测定各组小鼠脑组织所含的钆浓度，以对照组小鼠脑组织中钆喷酸葡胺的含量为基准，计算各组小鼠脑组织中钆喷酸葡胺含量的相对于对照组的增减比例，具体实验结果见表1。
1.3实验结果
对比例1实验结果显示，将钆喷酸葡胺制备成脂质体有利于提升钆喷酸葡胺的脑靶向性效果，其可能的原因为通过制备成脂质体增加了其脂溶性，从而有利于钆喷酸葡胺透过血脑屏障，从而增强其脑梗死部位的靶向性；实施例1-3的实验结果显示了单独使用DSPE-PEG(2000)Amine修饰的钆喷酸葡胺脂质体纳米颗粒的脑梗死部位靶向性相对于钆喷酸葡胺注
表1.本发明诊断脑梗死的核磁共振造影剂的脑靶向性效果
组别 钆浓度(以对照组为基准)
模型组 0
实施例1 1.263
实施例2 1.462
实施例3 1.479
实施例4 3.518
实施例5 3.679
实施例6 2.741
实施例7 2.858
实施例8 4.635
对比例1 1.154
对比例2 1.166
对比例3 2.087
对比例4 3.629
对照组 1
射液明显改善，脑组织中钆浓度提高了26.3％,且4臂-氨基-聚乙二醇、6臂-氨基-聚乙二醇修饰的钆喷酸葡胺脂质体纳米颗粒脑靶向性更强，相对于DSPE-PEG(2000)Amine提高了约15％。实施例4-8组实验结果显示，通过在PEG氨基修饰的钆喷酸葡胺脂质体纳米颗粒表面缀合纤维蛋白靶向多肽，使得钆喷酸葡胺脂质体纳米颗粒的脑梗死部位靶向性出现了非常显著性的增加，且尤其以缀合胸腺肽α1与KRDS肽混合物的实施例8组脑靶向性提升效果最为优异，相对于钆喷酸葡胺注射液提升了3.635倍，从而可以显著增强脑梗死部位的核磁共振显像效果，有利于及时诊断脑梗死、及时发现脑梗死血管的位置，为脑梗死的及时治疗提供条件。对比例2组实验结果显示了在未添加PEG氨基的情况下在钆喷酸葡胺脂质体纳米颗粒中添加纤维蛋白靶向多肽后其脑靶向效果并未显示改善，其可能的原因是由于纤维蛋白靶向多肽不能与钆喷酸葡胺脂质体纳米颗粒实现有效缀合，从而无法通过纤维蛋白靶向多肽增强钆喷酸葡胺脂质体纳米颗粒的脑梗死部位的靶向性。对比例3-4组的实验结果显示了PEG氨基与纤维蛋白靶向多肽的比例与其脑组织靶向性效果具有明显关系，且当纤维蛋白靶向多肽用量超过一定比例后其脑组织靶向性增强效果明显减弱，其可能的原因是纤维蛋白靶向多肽在钆喷酸葡胺脂质体纳米颗粒表面的缀合位点饱和，多余的纤维蛋白靶向多肽由于无法实现与钆喷酸葡胺脂质体纳米颗粒表面的有效缀合，从而无法发挥脑梗死部位的靶向效果，且随着纤维蛋白靶向多肽结合数量的增加，钆喷酸葡胺脂质体纳米颗粒的体积明显增加，也不利于其通过血脑屏障。
以上描述了本发明优选实施方式，然其并非用以限定本发明。本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。

Claims (4)

1.一种用于诊断脑梗死的核磁共振造影剂，其特征在于，由PEG氨基修饰的核磁共振造影剂脂质体纳米颗粒及纤维蛋白靶向多肽制备而成；具体组成为：4臂-氨基-聚乙二醇2份、钆喷酸葡胺15份、卵磷脂80份、胆固醇15份、胸腺肽α1 5份、KRDS肽3份、注射用水适量。
2.权利要求1所述的诊断脑梗死的核磁共振造影剂的制备方法，其特征在于包括以下步骤：
(1)脂质体纳米颗粒的制备：按配方量称取卵磷脂、胆固醇、PEG氨基溶于氯仿溶液中，搅拌均匀后，置于旋转蒸发仪中，水浴55℃条件下旋转成膜，真空干燥后添加核磁共振造影剂溶液后制得脂质体乳液，经超速离心获得PEG氨基修饰的核磁共振造影剂脂质体纳米颗粒；
(2)纤维蛋白靶向多肽的缀合：按量称取步骤(1)制得的PEG氨基修饰的核磁共振造影剂脂质体纳米颗粒与纤维蛋白靶向多肽，20-30℃条件下于注射用水中共同孵育5-15min，即得。
3.权利要求1所述的核磁共振造影剂在制备用于诊断脑梗死的核磁共振造影剂中的用途。
4.根据权利要求3 所述的用途，其特征在于，所述PEG氨基与纤维蛋白靶向多肽的摩尔比为1:2-8。
CN202010779178.6A 2020-08-05 2020-08-05 一种用于诊断脑梗死的核磁共振造影剂及其应用 Active CN111840581B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010779178.6A CN111840581B (zh) 2020-08-05 2020-08-05 一种用于诊断脑梗死的核磁共振造影剂及其应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010779178.6A CN111840581B (zh) 2020-08-05 2020-08-05 一种用于诊断脑梗死的核磁共振造影剂及其应用

Publications (2)

Publication Number Publication Date
CN111840581A CN111840581A (zh) 2020-10-30
CN111840581B true CN111840581B (zh) 2022-12-09

Family

ID=72971415

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010779178.6A Active CN111840581B (zh) 2020-08-05 2020-08-05 一种用于诊断脑梗死的核磁共振造影剂及其应用

Country Status (1)

Country Link
CN (1) CN111840581B (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115721739B (zh) * 2022-12-09 2024-05-31 牡丹江医学院 一种用于肾盂肾炎核磁造影的造影剂及其应用
CN115944751B (zh) * 2022-12-09 2023-10-31 牡丹江医学院附属红旗医院 一种用于诊断脑血栓的核磁共振造影剂及其应用

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1287833A2 (en) * 2001-08-20 2003-03-05 Fuji Photo Film Co., Ltd. Liposome containing hydrophobic iodine compound and X-ray contrast medium comprising said liposome
WO2005048987A1 (en) * 2003-11-21 2005-06-02 Fuji Photo Film Co., Ltd. Contrast medium comprising liposomes containing hydrophobic chelate compound
JP2006335745A (ja) * 2005-06-06 2006-12-14 Fujifilm Holdings Corp リポソームを含むｍｒｉ造影剤
CN101301479A (zh) * 2007-05-08 2008-11-12 上海华明高技术（集团）有限公司 用于磁共振成像诊断的肿瘤靶向显影组合物及其制备方法
CN102028959A (zh) * 2009-09-25 2011-04-27 上海华明高技术（集团）有限公司 用于磁共振诊断的肿瘤靶向顺磁性脂质体及其制备方法
ES2381950A1 (es) * 2010-11-08 2012-06-04 Servizo Galego De Saúde (Sergas) Liposomas con anticuerpos contra marcadores de la zona peri-infarto cerebral.
CN103990151A (zh) * 2014-06-09 2014-08-20 北京大学 一种磁共振成像造影剂及其制备方法和应用
CN110639031A (zh) * 2019-11-12 2020-01-03 广州市番禺区中心医院(广州市番禺区人民医院、广州市番禺区心血管疾病研究所) 一种t1增强核磁共振纳米造影剂的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5512294A (en) * 1994-08-05 1996-04-30 Li; King C. Targeted polymerized liposome contrast agents
GB0920304D0 (en) * 2009-11-20 2010-01-06 Medical Res Council Novel liposome nanoparticles for tumour magnetic resonance imaging
CN105983106B (zh) * 2015-06-11 2019-08-09 杨庆宪 Il-13修饰的含钆螯合物脂质体靶向磁共振成像对比剂及其制备方法和应用
CN108096587A (zh) * 2018-01-28 2018-06-01 上海舜纳生物科技有限公司 一种用于急性胰腺炎磁共振成像的脂质体及其制备与应用

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1287833A2 (en) * 2001-08-20 2003-03-05 Fuji Photo Film Co., Ltd. Liposome containing hydrophobic iodine compound and X-ray contrast medium comprising said liposome
WO2005048987A1 (en) * 2003-11-21 2005-06-02 Fuji Photo Film Co., Ltd. Contrast medium comprising liposomes containing hydrophobic chelate compound
JP2006335745A (ja) * 2005-06-06 2006-12-14 Fujifilm Holdings Corp リポソームを含むｍｒｉ造影剤
CN101301479A (zh) * 2007-05-08 2008-11-12 上海华明高技术（集团）有限公司 用于磁共振成像诊断的肿瘤靶向显影组合物及其制备方法
CN102028959A (zh) * 2009-09-25 2011-04-27 上海华明高技术（集团）有限公司 用于磁共振诊断的肿瘤靶向顺磁性脂质体及其制备方法
ES2381950A1 (es) * 2010-11-08 2012-06-04 Servizo Galego De Saúde (Sergas) Liposomas con anticuerpos contra marcadores de la zona peri-infarto cerebral.
CN103990151A (zh) * 2014-06-09 2014-08-20 北京大学 一种磁共振成像造影剂及其制备方法和应用
CN110639031A (zh) * 2019-11-12 2020-01-03 广州市番禺区中心医院(广州市番禺区人民医院、广州市番禺区心血管疾病研究所) 一种t1增强核磁共振纳米造影剂的制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"In Vivo Theranostics at the Peri-Infarct Region in Cerebral Ischemia";Jesús Agulla等;《Theranostics》;20131212;第4卷(第1期);摘要，第101页至第102页左栏第1段 *
纳米载药系统应用于缺血性脑卒中的研究进展;吴雅云等;《中国药房》;20180530(第10期);第1段，第1426页右栏至第1427页左栏第1段 *

Also Published As

Publication number Publication date
CN111840581A (zh) 2020-10-30

Similar Documents

Publication Publication Date Title
Huang et al. Repurposing ferumoxytol: Diagnostic and therapeutic applications of an FDA-approved nanoparticle
Shevtsov et al. Targeting experimental orthotopic glioblastoma with chitosan-based superparamagnetic iron oxide nanoparticles (CS-DX-SPIONs)
US5213788A (en) Physically and chemically stabilized polyatomic clusters for magnetic resonance image and spectral enhancement
CN111840581B (zh) 一种用于诊断脑梗死的核磁共振造影剂及其应用
TW205006B (zh)
US20060204443A1 (en) Methods for tumor treatment using dendrimer conjugates
JPH06506468A (ja) メラニン系画像強調剤
JPH04501218A (ja) 受容体媒介エンドサイト―シス型ｍｒｉ造影剤
Hofmann et al. Mechanism of gadophrin‐2 accumulation in tumor necrosis
Chin et al. Collagenase‐cleavable peptide Amphiphile micelles as a novel Theranostic strategy in atherosclerosis
CN113398286B (zh) 一种靶向载铁氧体多功能纳米粒及其制备方法和应用
WO2023082786A1 (zh) 前列腺癌靶向磁共振造影剂及应用
TWI590832B (zh) 核磁共振對比增強顯影劑
JPH07505638A (ja) 磁気共鳴イメージングの方法および組成物
CN108245688A (zh) 肝细胞癌诊断试剂及其制备方法
Zhuang et al. Dynamic changes of inflammation and apoptosis in cerebral ischemia‑reperfusion injury in mice investigated by ferumoxytol‑enhanced magnetic resonance imaging
CN103041408A (zh) 核-壳型纳米造影剂、其制备方法及应用
CN103041407A (zh) 核-壳型纳米造影剂、其制备方法及应用
Li et al. Safe and efficient magnetic resonance imaging of acute myocardial infarction with gadolinium-doped carbon dots
Gong et al. A dual ligand targeted nanoprobe with high MRI sensitivity for diagnosis of breast cancer
WO2000071169A2 (en) Magnetic resonance tracking of magnetically labeled cells
Cai et al. A transferrin-target magnetic/fluorescent dual-mode probe significantly enhances the diagnosis of non-small cell lung cancer
Yao et al. A folate-conjugated dual-modal fluorescent magnetic resonance imaging contrast agent that targets activated macrophages in vitro and in vivo
CN101474414B (zh) 高分子包裹磁性纳米粒子造影剂的制备及应用
Suganuma et al. Rare case with metastatic involvement of hypothalamo-pituitary and pineal body presenting as hypopituitarism and diabetes insipidus

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