WO2017063258A1 - 用于恶性肿瘤和心脑血管相关疾病早期快速检测及多模态成像的金属离子试剂和影像制剂 - Google Patents

用于恶性肿瘤和心脑血管相关疾病早期快速检测及多模态成像的金属离子试剂和影像制剂 Download PDF

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WO2017063258A1
WO2017063258A1 PCT/CN2015/096309 CN2015096309W WO2017063258A1 WO 2017063258 A1 WO2017063258 A1 WO 2017063258A1 CN 2015096309 W CN2015096309 W CN 2015096309W WO 2017063258 A1 WO2017063258 A1 WO 2017063258A1
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metal ion
ions
imaging
ion reagent
reagent
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French (fr)
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王雪梅
赵春秋
杜天宇
任发
来兰梅
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东南大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations

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  • the invention relates to the field of medical imaging, in particular to a metal ion reagent and an imaging preparation for early detection and multimodal imaging of malignant tumors and cardiovascular and cerebrovascular diseases.
  • Cancer also known as malignant tumor, has become the biggest killer of human health and life in the 21st century.
  • the discovery of malignant tumors mainly depends on imaging techniques such as imaging, pathology and conventional tumor markers.
  • the existing imaging methods commonly used to diagnose tumors mainly include MRI (magnetic resonance imaging), SPECT (single photon emission tomography), PET (positron emission tomography), but these methods have certain limitations, although Clinically applied for many years, but lack of sufficient sensitivity and specificity, more importantly, it is difficult to find tumors early.
  • the early detection of cancerous sites and timely targeted therapy is one of the most effective treatments for cancer. In order to improve the survival rate and quality of life of cancer patients, it is one of the efforts of people to study more advanced diagnostic methods and preparations to achieve accurate and timely diagnosis and treatment of cancer.
  • fluorescence imaging has the characteristics of low price and fast imaging. It also has molecular-level sensitive single-molecule imaging and can mark and trace tumor growth.
  • fluorescence imaging technology can measure the tumor growth of various cancer models, monitor the changes of cancer cells in cancer treatment in real time, and quantitatively detect the in situ tumors, metastases and spontaneous tumors of mice in a non-invasive manner.
  • Multi-modal imaging technology combining fluorescence imaging with CT imaging, magnetic resonance imaging, ultrasound imaging and photoelectric imaging can effectively utilize the advantages of various imaging technologies, complement each other, and have great advantages in early, real-time and rapid diagnosis of malignant tumors. Application prospects.
  • how to find a multimodal imaging preparation that can be used for several imaging methods at the same time has become a new challenge. Many problems such as poor targeting of the preparation, high toxicity in the body, poor stability and weak signal intensity in the body. Waiting for it to be solved.
  • the present invention provides a metal for early detection and multimodal imaging of malignant tumors and cardiovascular and cerebrovascular related diseases in view of various technical defects for early detection of malignant tumors and cardiovascular and cerebrovascular diseases.
  • An ionic reagent capable of synthesizing an imaging preparation for multimodal imaging in situ in a diseased cell such as a tumor, and performing non-invasive real-time dynamic high-sensitivity rapid tracing and monitoring of the lesion site to achieve malignancy
  • the detection method is simple and easy.
  • the metal ion reagent for early detection and multimodal imaging of malignant tumors and cardiovascular and cerebrovascular diseases is an aqueous solution containing metal ions, and the metal ions are composed of iron ions or ferrous ions and magnesium.
  • the metal ions are composed of iron ions or ferrous ions and magnesium.
  • the molar ratio of iron ions or ferrous ions to other metal ions is 5 to 1:1.
  • the metal ion reagent of the present invention contains ferrous ions or iron ions, and the ferrous ions or iron ions cooperate with other metal ions, and the other metal ions are at least one of magnesium ions, transition metal ions, rare earth metal ions and noble metal ions.
  • the molar ratio of iron ions or ferrous ions to other metal ions in the metal ion reagent is 5 to 1:1, where metal ions other than iron ions or ferrous ions in the metal ion reagent are used. Calculated as a whole.
  • the rare earth metal ion is one of or a mixture of cerium ions and cerium ions.
  • the noble metal ion is a mixture of one or both of gold ions, silver ions, and platinum ions.
  • the metal ion is prepared by one or both of an iron ion or a ferrous ion and a magnesium ion, a transition metal ion, a rare earth metal ion and a noble metal ion.
  • the metal ion is prepared by one or both of iron ions or ferrous ions and magnesium ions, strontium ions, zinc ions, strontium ions, strontium ions, gold ions, silver ions, and platinum ions.
  • the combined metal ion combination may be iron ions, barium ions and zinc ions; zinc ions, gold ions and ferrous ions; barium ions and ferrous ions; gold ions, silver ions and iron ions; zinc ions and ferrous iron Ion; etc.
  • the metal ion reagent has a concentration of iron ions or ferrous ions of 5 to 10 mmol/L.
  • concentration and amount of the metal ion reagent depend on the intended use.
  • the metal ion is provided by a water-soluble compound containing a corresponding metal ion
  • a cerium ion is provided by a soluble cerium-containing ionic compound such as cerium acetate, cerium nitrate, sorghum sulfate or the like
  • soluble zinc-containing ionic compounds such as zinc chloride, zinc nitrate, zinc gluconate, zinc sulfate, etc.
  • gold ions are composed of soluble gold ion-containing compounds such as chloroauric acid, tetraammonium octachloride, gold chloride, and the like.
  • gold chloride, gold monochloride, etc. silver ions are provided by soluble silver-containing compounds such as silver ammonia, silver nitrate, etc.; soluble by cerium ion-containing compounds such as cerium nitrate, barium sulfate, cerium chloride, fluorinated Provided by barium, strontium carbonate, barium acetate, etc.; iron or ferrous ions are provided by soluble iron or ferrous ion-containing compounds such as ferric nitrate, ferric chloride, ferrous nitrate, ferrous chloride, and the like.
  • the metal ion reagent of the present invention is prepared by dissolving a metal ion-containing compound in water, and the water may be ultrapure water.
  • the specific preparation measures are as follows:
  • metal ions manganesium ions, transition metal ions, noble metal ions and rare earth metal ions, selected according to specific formula
  • Other metal ions are respectively dissolved in ultrapure water, and are all formulated to a certain concentration (5-10 mmol).
  • Testing fluids such as blood or serum
  • urine using a mixture of other metal ions (magnesium ions, transition metal ions, noble metal ions, and rare earth metal ions) and iron or ferrous ions.
  • metal ions magnesium ions, transition metal ions, noble metal ions, and rare earth metal ions
  • iron or ferrous ions iron or ferrous ions.
  • the invention also provides an imaging preparation for early rapid detection and multimodal imaging of malignant tumors and cardiovascular and cerebrovascular diseases, which is synthesized by in situ biological action at the lesion site by the metal ion reagent.
  • the lesion site is a lesion site of liver cancer, lung cancer, cervical cancer, leukemia, osteosarcoma, brain tumor or leukemia; for cardiovascular and cerebrovascular related diseases, the lesion site is stroke or Alzheimer's disease. The location of the lesion.
  • the invention provides the application of the metal ion reagent for early detection and multimodal imaging of malignant tumors and cardiovascular and cerebrovascular diseases in targeted multimodal imaging of malignant tumors and cardiovascular and cerebrovascular diseases.
  • 0.05-0.2 ml metal ion reagent is injected into the control model mouse and the tumor model mouse through the tail vein injection or local injection.
  • the ionic reagent can be rapidly enriched in the lesions of the mouse and the image preparation is synthesized in situ.
  • the model mice are imaged using a small animal living fluorescence imager, CT imager, ultrasound imager and MRI.
  • the imaging time window is 1 to 72 hours.
  • the invention also provides the use of the metal ion reagent for early detection and multimodal imaging of malignant tumors and cardiovascular and cerebrovascular diseases in the preparation of contrast agents.
  • the contrast agent is used in multimodal imaging detection of malignant tumors and cardiovascular and cerebrovascular related diseases.
  • the metal ion reagent and the image preparation of the invention adopt a transition metal ion, a rare earth metal ion and a noble metal ion which are excellent in biocompatibility, and cooperate with iron ions or ferrous ions to realize a fixed-point action with a target bioactive molecule. Accurate targeted markers and rapid imaging detection of relevant lesions enable highly sensitive and rapid tracking and monitoring of non-invasive, real-time dynamics in vivo.
  • the metal ion reagent and the image preparation of the invention have no biological side effects, and the detection method is simple and convenient, and effectively avoids the biological toxicity caused by the chemical reagent and the nano material stabilizer introduced in the synthesis process of the traditional nano material, and avoids the organism.
  • the metal ion reagent and the imaging preparation of the invention can be applied to multimodal imaging detection of malignant tumors and cardiovascular and cerebrovascular diseases, and the imaging effect is good.
  • the results show that CT, MRI, fluorescence, ultrasound, photoacoustic and Raman spectroscopy (SERS) imaging can quickly identify and detect the pathogenesis of malignant tumors and cardiovascular and cerebrovascular diseases, and enrich the area to achieve targeted lesions. Precise marking.
  • the metal ion reagent and the imaging preparation of the present invention can realize early, rapid, multimodal (CT, ultrasound, fluorescence, photoacoustic, MRI, etc.) imaging detection of cancer and cardiovascular and cerebrovascular diseases.
  • the invention can realize the imaging of malignant tumors and cardiac and cerebrovascular diseases related lesions without damage, in situ and real-time dynamic targeting, and perform multi-scale and multi-modal simultaneous diagnosis and accurate targeted positioning and treatment, and has broad medical application. prospect.
  • Example 1 is a graph showing the results of fluorescence imaging analysis of a cervical cancer model mouse in Example 1 at a time point of 24 hours;
  • Fig. 2 is a graph showing the results of MRI imaging analysis of a cervical cancer model mouse in Example 1 at a time point of 24 hours.
  • the specific steps include:
  • the metal ion reagent of the present embodiment was used to test body fluids (such as blood or serum) or urine, and the results showed that the optical and electrochemical properties of the tumor experimental group changed significantly after the metal ion reagent was added, and the normal control There were no significant changes in the group.
  • the body fluid comes from normal people and leukemia patients, and the urine comes from normal nude mice and tumor model nude mice.
  • the tumor model nude mice are liver cancer (HepG2 cell line) and cervical cancer (Hela cell line), and the tumor implantation method is subcutaneous subcutaneous tumor.
  • Optical detection methods include ultraviolet absorption spectroscopy and fluorescence spectroscopy, and electrochemical detection methods include cyclic voltammetry and differential voltammetry.
  • Fluorescence imaging analysis of tumor model mice using the metal ion reagent of the present embodiment the specific steps include:
  • the tumor implantation method is subcutaneous subcutaneous tumor.
  • the CT model of the tumor model mouse is analyzed by using the metal ion reagent of the embodiment, and the specific steps include:
  • the tumor implantation method is subcutaneous subcutaneous tumor.
  • the MRI imaging analysis of the tumor model mouse is performed by using the metal ion reagent of the embodiment, and the specific steps include:
  • the tumor implantation method is subcutaneous subcutaneous tumor.
  • Imaging with a small animal MRI imager and qualitatively and quantitatively analyzing it was performed by an MRI (7.0T) imager at different time points such as 1 hour, 4 hours, 8 hours, 12 hours, 24 hours, and 48 hours, and then the experimental model rats were treated with 5% isoflurane. Gas anesthesia, placed on the small animal living MRI imager operating platform, select the lesion area of nude mice, and collect images.
  • MRI 7.0T
  • the specific steps include:
  • the compound zinc gluconate was dissolved in ultrapure water to prepare a solution having a concentration of 10 mmol/L; and the zinc gluconate solution was mixed with a 10 mmol/L aqueous solution of ferrous chloride in a volume of 1:3 to obtain a metal ion reagent.
  • metal ion reagents for testing body fluids such as blood or serum
  • body fluids such as blood or serum
  • urine showed that the optical and electrochemical properties of the tumor experimental group changed significantly after the addition of the metal ion reagent, while the normal control group showed no significant change.
  • the body fluid comes from normal people and leukemia patients, and the urine comes from normal nude mice and tumor model nude mice.
  • Tumor model The nude mice are liver cancer (HepG2 cell line) and cervical cancer (Hela cell line), and the tumor implantation method is subcutaneous subcutaneous tumor.
  • Optical detection methods include ultraviolet absorption spectroscopy and fluorescence spectroscopy, and electrochemical detection methods include cyclic voltammetry and differential voltammetry.
  • the tumor model mice were subjected to fluorescence imaging analysis using the metal ion reagent of the present example, and the fluorescence imaging analysis method was the same as in Example 1.
  • Tumor model mice were subjected to CT imaging analysis using the metal ion reagent of the present example, and the CT imaging analysis method was the same as in Example 1.
  • the tumor model mice were subjected to MRI imaging analysis using the metal ion reagent of the present example, and the MRI imaging analysis method was the same as in Example 1.
  • the specific steps include:
  • the compound chloroauric acid and silver nitrate were respectively dissolved in ultrapure water, and were prepared into a solution having a concentration of 10 mmol/L; the chloroauric acid solution and the silver nitrate solution were mixed in an equal ratio and then mixed with 10 mmol/L of ferric chloride aqueous solution. The volume is 1:2 mixed to obtain a metal ion reagent.
  • metal ion reagents for testing body fluids such as blood or serum
  • body fluids such as blood or serum
  • urine showed that the optical and electrochemical properties of the tumor experimental group changed significantly after the addition of the metal ion reagent, while the normal control group showed no significant change.
  • the body fluid comes from normal people and leukemia patients, and the urine comes from normal nude mice and tumor model nude mice.
  • the tumor model nude mice are liver cancer (HepG2 cell line) and cervical cancer (Hela cell line), and the tumor implantation method is subcutaneous subcutaneous tumor.
  • Optical detection methods include ultraviolet absorption spectroscopy and fluorescence spectroscopy, and electrochemical detection methods include cyclic voltammetry and differential voltammetry.
  • the tumor model mice were subjected to fluorescence imaging analysis using the metal ion reagent of the present example, and the fluorescence imaging analysis method was the same as in Example 1.
  • Tumor model mice were subjected to CT imaging analysis using the metal ion reagent of the present example, and the CT imaging analysis method was the same as in Example 1.
  • the tumor model mice were subjected to MRI imaging analysis using the metal ion reagent of the present example, and the MRI imaging analysis method was the same as in Example 1.
  • the specific steps include:
  • the compound cerium nitrate was dissolved in ultrapure water to prepare a solution having a concentration of 10 mmol/L; the cerium nitrate solution was mixed with a 10 mmol/L aqueous solution of ferrous chloride in a volume of 1:5 to obtain a metal ion reagent.
  • metal ion reagents for testing body fluids such as blood or serum
  • body fluids such as blood or serum
  • urine showed that the optical and electrochemical properties of the tumor experimental group changed significantly after the addition of the metal ion reagent, while the normal control group showed no significant change.
  • the body fluid comes from normal people and leukemia patients, and the urine comes from normal nude mice and tumor model nude mice.
  • the tumor model nude mice are liver cancer (HepG2 cell line) and cervical cancer (Hela cell line), and the tumor implantation method is subcutaneous subcutaneous tumor.
  • Optical detection methods include ultraviolet absorption spectroscopy and fluorescence spectroscopy, and electrochemical detection methods include cyclic voltammetry and differential voltammetry.
  • the tumor model mice were subjected to fluorescence imaging analysis using the metal ion reagent of the present example, and the fluorescence imaging analysis method was the same as in Example 1.
  • Tumor model mice were subjected to CT imaging analysis using the metal ion reagent of the present example, and the CT imaging analysis method was the same as in Example 1.
  • the tumor model mice were subjected to MRI imaging analysis using the metal ion reagent of the present example, and the MRI imaging analysis method was the same as in Example 1.
  • the specific steps include:
  • the compound zinc chloride and chloroauric acid are respectively dissolved in ultrapure water, and are prepared into a solution having a concentration of 10 mmol/L; the zinc chloride and the chloroauric acid solution are mixed in an equal volume and 10 mmol/L of the aqueous solution of ferrous chloride.
  • the metal ion reagent was obtained by mixing in a volume of 1:4.
  • metal ion reagents for testing body fluids such as blood or serum
  • body fluids such as blood or serum
  • urine showed that the optical and electrochemical properties of the tumor experimental group changed significantly after the addition of the metal ion reagent, while the normal control group showed no significant change.
  • the body fluid comes from normal people and leukemia patients, and the urine comes from normal nude mice and tumor model nude mice.
  • the tumor model nude mice are liver cancer (HepG2 cell line) and cervical cancer (Hela cell line), and the tumor implantation method is subcutaneous subcutaneous tumor.
  • Optical detection methods include ultraviolet absorption spectroscopy and fluorescence spectroscopy, and electrochemical detection methods include cyclic voltammetry And differential volt-ampere pulse method.
  • the tumor model mice were subjected to fluorescence imaging analysis using the metal ion reagent of the present example, and the fluorescence imaging analysis method was the same as in Example 1.
  • Tumor model mice were subjected to CT imaging analysis using the metal ion reagent of the present example, and the CT imaging analysis method was the same as in Example 1.
  • the tumor model mice were subjected to MRI imaging analysis using the metal ion reagent of the present example, and the MRI imaging analysis method was the same as in Example 1.
  • the specific steps include:
  • the compound zinc chloride and barium sulfate are respectively dissolved in ultrapure water, and are prepared into a solution having a concentration of 10 mmol/L; the zinc chloride solution and the barium sulfate are mixed in a ratio and then mixed with a 10 mmol/L aqueous solution of ferric chloride according to the volume. Mix 1:1 to obtain a metal ion reagent.
  • Fluorescence imaging analysis of the senile dementia model mouse using the metal ion reagent of the present embodiment the specific steps include:
  • the fluorescence intensity of the lesions in the Alzheimer's disease model increased first and then decreased with time, indicating that the ions and other preparations in the reagents can be specifically synthesized or enriched in the lesion area, and then gradually metabolized.
  • the fluorescence intensity showed that the model rats with large age of Alzheimer's disease were more enriched and the fluorescence intensity was larger, indicating that the lesions were deeper.
  • the specific steps include:
  • the results show that the signal can be clearly detected in the head region of the model mouse. Different from the tissue density of the head, a granular high-density material can be seen, indicating that the metal ion reagent is targeted to specific aggregation within the brain and is related.
  • the protein binds and is reduced to a fluorescent and magnetic material (image preparation).
  • the MRI imaging analysis of the senile dementia model mouse is carried out by using the metal ion reagent of the embodiment, and the specific steps include:
  • Imaging with a small animal MRI imager and qualitatively and quantitatively analyzing it was performed by an MRI (7.0T) imager at different time points such as 1 hour, 4 hours, 8 hours, 12 hours, 24 hours, and 48 hours, and then the experimental model rats were treated with 5% isoflurane. Gas anesthesia, placed on the small animal living MRI imager operating platform, select the model mouse head area, and collect images.
  • MRI 7.0T
  • the results show that the signal can be clearly detected in the head region of the model mouse. Different from the tissue density of the head, a granular high-density material can be seen, indicating that the metal ion reagent is targeted to specific aggregation within the brain and is related.
  • the protein binds and is reduced to a fluorescent and magnetic material (image preparation).
  • the specific steps include:
  • the compound zinc gluconate and chloroauric acid were dissolved in ultrapure water, and each was prepared into a solution with a concentration of 10 mmol/L; the ratio of zinc gluconate and chloroauric acid was mixed, and then mixed with 10 mmol/L aqueous solution of ferrous chloride.
  • the metal ion reagent is obtained by mixing according to a volume of 1:1.
  • Fluorescence imaging analysis of stroke model mice using the metal ion reagent of the present embodiment the specific steps include:
  • CT imaging analysis of stroke model mice using the metal ion reagent of the present embodiment the specific steps include:
  • the model of the head injury area of the model mouse can clearly detect the signal. Different from the tissue density of the head, a granular high-density material can be seen, indicating that the metal ion reagent targets specific aggregation in the damaged area inside the brain. , reduced to fluorescent and magnetic materials (image preparation).
  • the MRI imaging analysis of the stroke model mice is carried out by using the metal ion reagent of the embodiment, and the specific steps include:
  • Imaging with a small animal MRI imager and qualitatively and quantitatively analyzing it was performed by an MRI (7.0T) imager at different time points such as 1 hour, 4 hours, 8 hours, 12 hours, 24 hours, and 48 hours, and then the experimental model rats were treated with 5% isoflurane. Gas anesthesia, placed on the small animal living MRI imager operating platform, select the model mouse head area, and collect images.
  • MRI 7.0T
  • the head region of the model mouse can clearly detect the signal. Different from the tissue density of the head, a granular high-density material can be seen, indicating that the metal ion reagent targets specific aggregation in the damaged region inside the brain. Reduction to fluorescent and magnetic materials (image preparation).
  • the compound ferric chloride is dissolved in ultrapure water to prepare a solution having a concentration of 10 mmol/L, that is, an iron ion reagent.
  • Fluorescence imaging analysis of tumor model mice using the iron ion reagent of the present embodiment the specific steps include:
  • the tumor implantation method is subcutaneous subcutaneous tumor.

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Abstract

一种用于恶性肿瘤和心脑血管相关疾病早期快速检测及多模态成像的金属离子试剂和影像制剂。所述金属离子试剂为含金属离子的水溶液，金属离子由铁离子或亚铁离子与镁离子、过渡金属离子、稀土金属离子和贵金属离子中的至少一种配制而成；过渡金属离子为铈离子、锌离子中的一种或两种的混合物；铁离子或亚铁离子与其他金属离子的摩尔比为5～1:1。

Description

用于恶性肿瘤和心脑血管相关疾病早期快速检测及多模态成像的金属离子试剂和影像制剂 技术领域
本发明涉及医学成像领域，尤其涉及一种用于恶性肿瘤和心脑血管相关疾病早期快速检测及多模态成像的金属离子试剂和影像制剂。
背景技术
癌症，又称恶性肿瘤，已经成为二十一世纪影响人类身体健康及生命的最大杀手。临床医疗工作中，恶性肿瘤的发现主要依赖于影像学、病理学及常规肿瘤标志等检查技术。现有的常用于诊断肿瘤的影像学方法主要包括MRI(核磁共振成像)，SPECT(单光子发射断层成像)，PET(正电子发射断层成像)，但这些方法均有一定的局限性，虽在临床上应用多年，却缺乏足够的敏感度和特异度，更重要的是难以早期发现肿瘤。若能早期发现癌变位点并及时对其进行靶向治疗是目前为止针对癌症最有效的治疗方法之一。为了提高肿瘤患者的存活率和生活质量，研究更先进的诊断方法及制剂，来实现准确、及时的癌症早期诊断及治疗一直是人们努力的方向之一。
随着生物医学研究的不断深入，可视化的生物成像技术在生命科学和医学领域扮演着越来越重要的角色，相比于其它生物成像技术而言，荧光成像具有价格低廉、成像快速的特点，并具有分子水平的敏感性单分子成像，并能对肿瘤的生长进行标记和示踪。此外，荧光成像技术可以对各种癌症模型的肿瘤生长情况进行测量，实时监测癌症治疗中癌细胞的变化；定量的对小鼠整体原位瘤、转移瘤及自发瘤进行无创伤地的检测。
将荧光成像与CT成像、核磁共振成像、超声成像以及光电成像结合的多模态成像技术，可以有效的利用各种成像技术的优势，取长补短，在恶性肿瘤的早期、实时、快速诊断中具有巨大的应用前景。然而如何寻找到一种可以同时用于几种成像手段的多模态成像制剂也成为了新的挑战，许多问题比如制剂的靶向性不好，体内毒性大，稳定性差以及体内的信号强度弱等都亟待解决。
发明内容
发明目的：针对现有的针对于恶性肿瘤和心脑血管相关疾病早期检测的种种技术缺陷，本发明提供了一种用于恶性肿瘤和心脑血管相关疾病早期快速检测及多模态成像的金属离子试剂，该金属离子试剂能够在肿瘤等病变细胞内原位合成用于多模态成像的影像制剂，可非侵入式的对病灶部位进行实时动态的高灵敏快速示踪和监测，实现对恶性肿瘤和心脑血管相关疾病早期、快速、多模态成像检测，且无生物毒副作用，检测方法简便易行。
为达到上述目的，本发明是通过以下的技术方案来实现的：
本发明所述的用于恶性肿瘤和心脑血管相关疾病早期快速检测及多模态成像的金属离子试剂，其为含有金属离子的水溶液，所述的金属离子由铁离子或亚铁离子与镁离子、过渡金属离子、稀土金属离子和贵金属离子中的至少一种配制而成；其中，所述的过渡金属离子为铈离子、锌离子中的一种或两种的混合物；金属离子试剂中，铁离子或亚铁离子与其他金属离子的摩尔比为5～1:1。
本发明金属离子试剂中含有亚铁离子或铁离子，亚铁离子或铁离子与其他金属离子相配合发挥作用，其他金属离子为镁离子、过渡金属离子、稀土金属离子和贵金属离子中的至少一种。本领域技术人员可以理解，金属离子试剂中，铁离子或亚铁离子与其他金属离子的摩尔比为5～1:1，此处，是将金属离子试剂中铁离子或亚铁离子以外的金属离子作为整体来计算。
所述的稀土金属离子为铕离子、镧离子中的一种或两种的混合物。
所述的贵金属离子为金离子、银离子、铂离子中的一种或两种的混合物。
优选的，所述的金属离子由铁离子或亚铁离子与镁离子、过渡金属离子、稀土金属离子和贵金属离子中的一种或两种配制而成。
优选的，所述的金属离子由铁离子或亚铁离子与镁离子、铈离子、锌离子、铕离子、镧离子、金离子、银离子、铂离子中的一种或两种配制而成。进一步的，配制的金属离子组合可以为铁离子、铕离子和锌离子；锌离子、金离子和亚铁离子；铕离子和亚铁离子；金离子、银离子和铁离子；锌离子和亚铁离子；等。
优选的，金属离子试剂中，铁离子或亚铁离子的浓度为5～10mmol/L。金属离子试剂的浓度及使用量根据使用对象而定。
本发明的金属离子试剂中，金属离子由可溶于水的含相应金属离子的化合物提供，如，铈离子由可溶性的含铈离子化合物如醋酸铈、硝酸铈、硫酸高铈等提供；锌离子由可溶性的含锌离子化合物如氯化锌、硝酸锌、葡萄糖酸锌、硫酸锌等提供；金离子由可溶性的含金离子的化合物如氯金酸、八氯化四金、氯化金、三氯化金、一氯化金等提供；银离子由可溶性的含银化合物如银氨、硝酸银等提供；铕由可溶性的含铕离子的化合物如硝酸铕、硫酸铕、氯化铕、氟化铕、碳酸铕、醋酸铕等提供；铁离子或亚铁离子由可溶性的含铁离子或亚铁离子的化合物如硝酸铁、氯化铁、硝酸亚铁、氯化亚铁等提供。
本发明的金属离子试剂由含金属离子的化合物溶于水制成，水可采用超纯水。具体制备措施如下：
将其他金属离子(镁离子、过渡金属离子、贵金属离子及稀土金属离子，根据具体的配方进行选择)分别溶于超纯水，均配制成一定的浓度(5～10mmol)。将其他金属离子(过渡金属离子、贵金属离子及稀土金属离子)与铁离子或亚铁离子溶液按照体积比1:1至1:5之间的比例混合溶于超纯水，均配制成一定的浓度(5～10mmol)。
利用已配制的其他金属离子(镁离子、过渡金属离子、贵金属离子及稀土金属离子)与铁离子或亚铁离子的混合检测试剂对体液(如血液或血清等)或者尿液进行测试，结果显示，恶性肿瘤和心脑血管相关疾病实验组的光学以及电化学特性发生了显著的变化，而正常对照组无明显变化。
本发明还提供了一种用于恶性肿瘤和心脑血管相关疾病早期快速检测及多模态成像的影像制剂，由所述的金属离子试剂在病灶部位通过原位生物作用定点合成。
对于恶性肿瘤，所述的病灶部位为肝癌、肺癌、宫颈癌、白血病、骨肉瘤、脑瘤或白血病的病灶部位；对于心脑血管相关疾病，所述的病灶部位为脑卒中或老年痴呆症的病灶部位。
本发明提供了所述的用于恶性肿瘤和心脑血管相关疾病早期快速检测及多模态成像的金属离子试剂在恶性肿瘤和心脑血管相关疾病靶向多模态成像的应用。以肿瘤模型鼠为例说明其应用步骤，该金属离子制剂用于肿瘤靶向成像时，将0.05～0.2ml金属离子试剂通过尾静脉注射或局部注射到对照组模型鼠和肿瘤模型鼠体内，金属离子试剂可快速在鼠的病灶部位富集并原位合成影像制剂，使用小动物活体荧光成像仪、CT成像仪、超声成像仪以及MRI对模型鼠进行成像，成像时间窗为1～72小时。
本发明还提供了所述的用于恶性肿瘤和心脑血管相关疾病早期快速检测及多模态成像的金属离子试剂在制备造影剂中的应用。
所述造影剂用于恶性肿瘤和心脑血管相关疾病多模态成像检测中。
与现有技术相比，本发明的有益效果为：
(1)本发明金属离子试剂、影像制剂采用生物相容性优良的过渡金属离子、稀土金属离子及贵金属离子等，与铁离子或亚铁离子相配合，通过与靶向生物活性分子定点作用实现相关病灶部位的精准靶向标记与快速成像检测，可进行活体非侵入式的实时动态的高灵敏快速示踪和监测。(2)本发明的金属离子试剂、影像制剂无生物毒副作用，检测方法简便易行，有效避免了传统纳米材料合成过程中引入的化学试剂以及纳米材料稳定剂对有机体造成的生物毒性，同时避免了传统纳米材料易被网状内皮系统捕获后被清除从而不能到达病灶组织的缺点，以便实现活体靶向成像分析。(3)本发明的金属离子试剂、影像制剂可应用于恶性肿瘤和心脑血管相关疾病的多模态成像检测中，成像效果好。结果表明：通过CT、MRI、荧光、超声、光声以及拉曼光谱(SERS)成像等能快速识别检测恶性肿瘤和心脑血管相关疾病发病部位并富集在该区域，实现靶向病灶部位的精准标记。以上结果说明本发明金属离子试剂、影像制剂可以实现对癌症和心脑血管相关疾病的早期、快速、多模态(CT、超声、荧光、光声以及MRI等)成像检测。本发明可实现无损伤、原位、实时动态靶向的恶性肿瘤和心脑血管相关疾病病灶部位成像，进行多尺度与多模态的同步诊断及准确靶向定位与治疗，具有广阔的医学应用前景。
附图说明
图1为实施例1中宫颈癌模型鼠时间点为24小时的荧光成像分析结果图；
图2为实施例1中宫颈癌模型鼠时间点为24小时的MRI成像分析结果图。
具体实施方式
下面结合具体实施例，进一步阐明本发明，应理解这些实施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
1、金属离子试剂的制备
制备生物相容性优良的金属离子试剂，具体步骤包括：
将化合物氯化锌、硫酸铕分别溶于超纯水，均配制成浓度为10mmol/L的溶液；将氯化锌溶液、硫酸铕等比例混合后再与10mmol/L的氯化铁水溶液(氯化铁用超纯水溶解)按照体积1:1混合，得金属离子试剂。
2、体外测试
应用本实施例的金属离子试剂对体液(如血液或血清等)或者尿液进行测试，结果显示，肿瘤实验组的光学以及电化学特性在金属离子试剂加入后发生了显著的变化，而正常对照组无明显变化。
其中，体液来自于正常人和白血病人，尿液来自正常裸鼠和肿瘤模型裸鼠。肿瘤模型裸鼠为肝癌(HepG2细胞系)及宫颈癌(Hela细胞系)，植瘤方式为腋下皮下植瘤。光学检测方法包括紫外吸收光谱测定和荧光光谱测定，电化学检测方法包括循环伏安法和差分伏安脉冲法。
3、荧光成像分析
应用本实施例的金属离子试剂对肿瘤模型鼠进行荧光成像分析，具体步骤包括：
(1)构建肝癌(HepG2细胞系)的肿瘤模型鼠及宫颈癌(Hela细胞系)的肿瘤模型鼠，植瘤方式为腋下皮下植瘤。
(2)将0.1mL无菌的金属离子试剂，通过尾静脉和皮下注射到肿瘤模型鼠上。
(3)利用活体荧光成像仪进行成像并对其进行定性及定量分析。具体为，利用活体荧光成像仪成像，分别选取1小时、4小时、8小时、12小时、24小时、48小时等不同时间点，然后将该实验模型鼠用5％异氟烷进行气体麻醉，将其置于小动物活体成像仪操作平台上，选择420nm和480nm波长激发采集图像。
结果显示，模型鼠的腋下肿瘤区域的荧光强度随着时间呈现先增加后减弱的变化，说明影像制剂可以特异性的原位合成或者富集在病变区域，而后又逐渐代谢。
4、CT成像分析
应用本实施例的金属离子试剂对肿瘤模型鼠进行CT成像分析，具体步骤包括：
(1)构建肝癌(HepG2细胞系)的肿瘤模型鼠及宫颈癌(Hela细胞系)的肿瘤模型鼠，植瘤方式为腋下皮下植瘤。
(2)将0.1mL无菌的金属离子试剂，通过尾静脉和皮下注射到肿瘤模型鼠上。
(3)利用小动物CT成像仪进行成像并对其进行定性及定量分析。具体为，利用CT成像仪成像，分别选取1小时、4小时、8小时、12小时、24小时、48小时等不同时间点，然后将该实验模型鼠用5％异氟烷进行气体麻醉，将其置于小动物活体CT成像仪操作平台上，选择裸鼠的腋下肿瘤区域，采集图像。
结果显示，模型鼠的腋下肿瘤区域可以明显的检测到信号，不同于肿瘤内部的组织密度，可以看到颗粒状的高密度材料，说明金属离子试剂在肿瘤内部靶向特异性聚集，并且还原成为荧光和磁性材料(影像制剂)。
5、MRI成像分析
应用本实施例的金属离子试剂对肿瘤模型鼠进行MRI成像分析，具体步骤包括：
(1)构建肝癌(HepG2细胞系)的肿瘤模型鼠及宫颈癌(Hela细胞系)的肿瘤模型鼠，植瘤方式为腋下皮下植瘤。
(2)将0.1mL无菌的金属离子试剂，通过尾静脉和皮下注射到肿瘤模型鼠上。
(3)利用小动物MRI成像仪进行成像并对其进行定性及定量分析。具体为，利用MRI(7.0T)成像仪成像，分别选取1小时、4小时、8小时、12小时、24小时、48小时等不同时间点，然后将该实验模型鼠用5％异氟烷进行气体麻醉，将其置于小动物活体MRI成像仪操作平台上，选择裸鼠的病变区域，采集图像。
结果显示，模型鼠的腋下肿瘤区域可以明显的检测到信号，不同于肿瘤内部的组织密度，可以看到颗粒状的高密度材料，说明金属离子试剂在肿瘤内部靶向特异性聚集，并且还原成为荧光和磁性材料(影像制剂)。
实施例2
1、金属离子试剂的制备
制备生物相容性优良的金属离子试剂，具体步骤包括：
将化合物葡萄糖酸锌溶于超纯水，配制成浓度为10mmol/L的溶液；将葡萄糖酸锌溶液与10mmol/L的氯化亚铁水溶液按照体积1:3混合，得金属离子试剂。
2、体外测试
利用金属离子试剂对体液(如血液或血清等)或者尿液进行测试，结果显示，肿瘤实验组的光学以及电化学特性在金属离子试剂加入后发生了显著的变化，而正常对照组无明显变化。
其中，体液来自于正常人和白血病人，尿液来自正常裸鼠和肿瘤模型裸鼠。肿瘤模 型裸鼠为肝癌(HepG2细胞系)及宫颈癌(Hela细胞系)，植瘤方式为腋下皮下植瘤。光学检测方法包括紫外吸收光谱测定和荧光光谱测定，电化学检测方法包括循环伏安法和差分伏安脉冲法。
3、荧光成像分析
应用本实施例的金属离子试剂对肿瘤模型鼠进行荧光成像分析，荧光成像分析方法同实施例1。
结果显示，肿瘤模型鼠病变区域荧光强度随着时间呈现先增加后减弱的变化，说明影像制剂可以特异性的原位合成或者富集在病变区域，而后又逐渐代谢。与实施例1中的荧光强度相比，本实施例的荧光强度有所减弱。
4、CT成像分析
应用本实施例的金属离子试剂对肿瘤模型鼠进行CT成像分析，CT成像分析方法同实施例1。
结果显示，肿瘤模型鼠的病变区域可以明显的检测到信号，不同于肿瘤内部的组织密度，可以看到颗粒状的高密度材料，说明金属离子试剂在肿瘤内部靶向特异性聚集，并且还原成为荧光和磁性材料(影像制剂)。与实施例1相比，本实施例中的颗粒衬度更好，分布更加均匀。
5、MRI成像分析
应用本实施例的金属离子试剂对肿瘤模型鼠进行MRI成像分析，MRI成像分析方法同实施例1。
结果显示，肿瘤模型鼠的病变区域可以明显的检测到信号，不同于肿瘤内部的组织密度，可以看到颗粒状的高密度材料，说明金属离子试剂在肿瘤内部靶向特异性聚集，并且还原成为荧光和磁性材料(影像制剂)。与实施例1相比，本实施例中的颗粒衬度更好，分布更加均匀。
实施例3
1、金属离子试剂的制备
制备生物相容性优良的金属离子试剂，具体步骤包括：
将化合物氯金酸、硝酸银分别溶于超纯水，均配制成浓度为10mmol/L的溶液；将氯金酸溶液、硝酸银溶液等比例混合后再与10mmol/L的氯化铁水溶液按照体积1:2混合，得金属离子试剂。
2、体外测试
利用金属离子试剂对体液(如血液或血清等)或者尿液进行测试，结果显示，肿瘤实验组的光学以及电化学特性在金属离子试剂加入后发生了显著的变化，而正常对照组无明显变化。
其中，体液来自于正常人和白血病人，尿液来自正常裸鼠和肿瘤模型裸鼠。肿瘤模型裸鼠为肝癌(HepG2细胞系)及宫颈癌(Hela细胞系)，植瘤方式为腋下皮下植瘤。光学检测方法包括紫外吸收光谱测定和荧光光谱测定，电化学检测方法包括循环伏安法和差分伏安脉冲法。
3、荧光成像分析
应用本实施例的金属离子试剂对肿瘤模型鼠进行荧光成像分析，荧光成像分析方法同实施例1。
结果显示，肿瘤模型鼠病变区域荧光强度随着时间呈现先增加后减弱的变化，说明影像制剂可以特异性的原位合成或者富集在病变区域，而后又逐渐代谢。
4、CT成像分析
应用本实施例的金属离子试剂对肿瘤模型鼠进行CT成像分析，CT成像分析方法同实施例1。
结果显示，肿瘤模型鼠的病变区域可以明显的检测到信号，不同于肿瘤内部的组织密度，可以看到颗粒状的高密度材料，说明金属离子试剂在肿瘤内部靶向特异性聚集，并且还原成为荧光和磁性材料(影像制剂)。与实施例1相比，本实施例中的颗粒衬度更好，分布更加均匀。
5、MRI成像分析
应用本实施例的金属离子试剂对肿瘤模型鼠进行MRI成像分析，MRI成像分析方法同实施例1。
结果显示，肿瘤模型鼠的病变区域可以明显的检测到信号，不同于肿瘤内部的组织密度，可以看到颗粒状的高密度材料，说明金属离子试剂在肿瘤内部靶向特异性聚集，并且还原成为荧光和磁性材料(影像制剂)。
实施例4
1、金属离子试剂的制备
制备生物相容性优良的金属离子试剂，具体步骤包括：
将化合物硝酸铕溶于超纯水，配制成浓度为10mmol/L的溶液；将硝酸铕溶液与10mmol/L的氯化亚铁水溶液按照体积1:5混合，得金属离子试剂。
2、体外测试
利用金属离子试剂对体液(如血液或血清等)或者尿液进行测试，结果显示，肿瘤实验组的光学以及电化学特性在金属离子试剂加入后发生了显著的变化，而正常对照组无明显变化。
其中，体液来自于正常人和白血病人，尿液来自正常裸鼠和肿瘤模型裸鼠。肿瘤模型裸鼠为肝癌(HepG2细胞系)及宫颈癌(Hela细胞系)，植瘤方式为腋下皮下植瘤。 光学检测方法包括紫外吸收光谱测定和荧光光谱测定，电化学检测方法包括循环伏安法和差分伏安脉冲法。
3、荧光成像分析
应用本实施例的金属离子试剂对肿瘤模型鼠进行荧光成像分析，荧光成像分析方法同实施例1。
结果显示，肿瘤模型鼠病变区域荧光强度随着时间呈现先增加后减弱的变化，说明影像制剂可以特异性的原位合成或者富集在病变区域，而后又逐渐代谢。
4、CT成像分析
应用本实施例的金属离子试剂对肿瘤模型鼠进行CT成像分析，CT成像分析方法同实施例1。
结果显示，肿瘤模型鼠的病变区域可以明显的检测到信号，不同于肿瘤内部的组织密度，可以看到颗粒状的高密度材料，说明金属离子试剂在肿瘤内部靶向特异性聚集，并且还原成为荧光和磁性材料(影像制剂)。
5、MRI成像分析
应用本实施例的金属离子试剂对肿瘤模型鼠进行MRI成像分析，MRI成像分析方法同实施例1。
结果显示，肿瘤模型鼠的病变区域可以明显的检测到信号，不同于肿瘤内部的组织密度，可以看到颗粒状的高密度材料，说明金属离子试剂在肿瘤内部靶向特异性聚集，并且还原成为荧光和磁性材料(影像制剂)。与实施例1相比，本实施例中的颗粒衬度更好，分布更加均匀。
实施例5
1、金属离子试剂的制备
制备生物相容性优良的金属离子试剂，具体步骤包括：
将化合物氯化锌、氯金酸分别溶于超纯水，均配制成浓度为10mmol/L的溶液；将氯化锌、氯金酸溶液等体积混合后与10mmol/L的氯化亚铁水溶液按照体积1:4混合，得金属离子试剂。
2、体外测试
利用金属离子试剂对体液(如血液或血清等)或者尿液进行测试，结果显示，肿瘤实验组的光学以及电化学特性在金属离子试剂加入后发生了显著的变化，而正常对照组无明显变化。
其中，体液来自于正常人和白血病人，尿液来自正常裸鼠和肿瘤模型裸鼠。肿瘤模型裸鼠为肝癌(HepG2细胞系)及宫颈癌(Hela细胞系)，植瘤方式为腋下皮下植瘤。光学检测方法包括紫外吸收光谱测定和荧光光谱测定，电化学检测方法包括循环伏安法 和差分伏安脉冲法。
3、荧光成像分析
应用本实施例的金属离子试剂对肿瘤模型鼠进行荧光成像分析，荧光成像分析方法同实施例1。
结果显示，肿瘤模型鼠病变区域荧光强度随着时间呈现先增加后减弱的变化，说明影像制剂可以特异性的原位合成或者富集在病变区域，而后又逐渐代谢。
4、CT成像分析
应用本实施例的金属离子试剂对肿瘤模型鼠进行CT成像分析，CT成像分析方法同实施例1。
结果显示，肿瘤模型鼠的病变区域可以明显的检测到信号，不同于肿瘤内部的组织密度，可以看到颗粒状的高密度材料，说明金属离子试剂在肿瘤内部靶向特异性聚集，并且还原成为荧光和磁性材料(影像制剂)。
5、MRI成像分析
应用本实施例的金属离子试剂对肿瘤模型鼠进行MRI成像分析，MRI成像分析方法同实施例1。
结果显示，肿瘤模型鼠的病变区域可以明显的检测到信号，不同于肿瘤内部的组织密度，可以看到颗粒状的高密度材料，说明金属离子试剂在肿瘤内部靶向特异性聚集，并且还原成为荧光和磁性材料(影像制剂)。对比实施例1，本实施例中的颗粒衬度更好，分布更加均匀。
实施例6
1、金属离子试剂的制备
制备生物相容性优良的金属离子试剂，具体步骤包括：
将化合物氯化锌、硫酸铕分别溶于超纯水，均配制成浓度为10mmol/L的溶液；将氯化锌溶液、硫酸铕等比例混合后再与10mmol/L的氯化铁水溶液按照体积1:1混合，得金属离子试剂。
2、荧光成像分析
应用本实施例的金属离子试剂对老年痴呆模型鼠进行荧光成像分析，具体步骤包括：
(1)构建不同月龄的老年痴呆模型鼠。
(2)将0.1mL无菌的金属离子试剂，通过尾静脉和皮下注射到老年痴呆模型鼠上。
(3)利用活体荧光成像仪进行成像并对其进行定性及定量分析。具体为，利用活体荧光成像仪成像，分别选取1小时、4小时、8小时、12小时、24小时、48小时等不同时间点，然后将该实验模型鼠用5％异氟烷进行气体麻醉，将其置于小动物活体成像仪操作平台上，选择420nm和480nm波长激发采集图像。
结果显示，老年痴呆症模型鼠上病变区域的荧光强度随着时间呈现先增加后减弱的变化，说明试剂中的离子等制剂可以特异性的原位合成或者富集在病变区域，而后又逐渐代谢。同时荧光强度显示相同条件下，老年痴呆症月龄大的模型鼠富集的更多，荧光强度更大，说明病变的程度更深。
3、CT成像分析
应用本实施例的金属离子试剂对老年痴呆症模型鼠进行CT成像分析，具体步骤包括：
(1)构建老年痴呆模型鼠。
(2)将0.1mL无菌的金属离子试剂，通过尾静脉和皮下注射到老年痴呆模型鼠上。
(3)利用小动物CT成像仪进行成像并对其进行定性及定量分析。具体为，利用CT成像仪成像，分别选取1小时、4小时、8小时、12小时、24小时、48小时等不同时间点，然后将该实验模型鼠用5％异氟烷进行气体麻醉，将其置于小动物活体CT成像仪操作平台上，选择模型鼠的头部区域，采集图像。
结果显示，模型鼠的头部区域可以明显的检测到信号，不同于头部的组织密度，可以看到颗粒状的高密度材料，说明金属离子试剂在脑内部靶向特异性聚集，并与相关蛋白结合，还原成为荧光和磁性材料(影像制剂)。
4、MRI成像分析
应用本实施例的金属离子试剂对老年痴呆模型鼠进行MRI成像分析，具体步骤包括：
(1)构建老年痴呆模型鼠。
(2)将0.1mL无菌的金属离子试剂，通过尾静脉和皮下注射到老年痴呆模型鼠上。
(3)利用小动物MRI成像仪进行成像并对其进行定性及定量分析。具体为，利用MRI(7.0T)成像仪成像，分别选取1小时、4小时、8小时、12小时、24小时、48小时等不同时间点，然后将该实验模型鼠用5％异氟烷进行气体麻醉，将其置于小动物活体MRI成像仪操作平台上，选择模型鼠的头部区域，采集图像。
结果显示，模型鼠的头部区域可以明显的检测到信号，不同于头部的组织密度，可以看到颗粒状的高密度材料，说明金属离子试剂在脑内部靶向特异性聚集，并与相关蛋白结合，还原成为荧光和磁性材料(影像制剂)。
实施例7
1、金属离子试剂的制备
制备生物相容性优良的金属离子试剂，具体步骤包括：
将化合物葡萄糖酸锌、氯金酸分别溶于超纯水，均配制成浓度为10mmol/L的溶液；将葡萄糖酸锌、氯金酸等比例混合后再与10mmol/L的氯化亚铁水溶液按照体积1:1混合，得金属离子试剂。
2、荧光成像分析
应用本实施例的金属离子试剂对卒中模型鼠进行荧光成像分析，具体步骤包括：
(1)利用血管损伤诱发构建脑卒中模型鼠。
(2)将0.1mL无菌的金属离子试剂，通过尾静脉和皮下注射到卒中模型鼠上。
(3)利用活体荧光成像仪进行成像并对其进行定性及定量分析。具体为，利用活体荧光成像仪成像，分别选取1小时、4小时、8小时、12小时、24小时、48小时等不同时间点，然后将该实验模型鼠用5％异氟烷进行气体麻醉，将其置于小动物活体成像仪操作平台上，选择420nm和480nm波长激发采集图像。
结果显示，卒中模型鼠上病变区域的荧光强度随着时间呈现先增加后减弱的变化，说明试剂中的离子等制剂可以特异性的原位合成或者富集在缺血缺氧的病变区域，而后又逐渐代谢。
3、CT成像分析
应用本实施例的金属离子试剂对卒中模型鼠进行CT成像分析，具体步骤包括：
(1)利用血管损伤诱发构建脑卒中模型鼠。
(2)将0.1mL无菌的金属离子试剂，通过尾静脉和皮下注射到卒中模型鼠上。
(3)利用小动物CT成像仪进行成像并对其进行定性及定量分析。具体为，利用CT成像仪成像，分别选取1小时、4小时、8小时、12小时、24小时、48小时等不同时间点，然后将该实验模型鼠用5％异氟烷进行气体麻醉，将其置于小动物活体CT成像仪操作平台上，选择模型鼠的头部区域，采集图像。
结果显示，模型鼠的头部损伤区域可以明显的检测到信号，不同于头部的组织密度，可以看到颗粒状的高密度材料，说明金属离子试剂在脑内部的损伤区域靶向特异性聚集，还原成为荧光和磁性材料(影像制剂)。
4、MRI成像分析
应用本实施例的金属离子试剂对卒中模型鼠进行MRI成像分析，具体步骤包括：
(1)利用血管损伤诱发构建脑卒中模型鼠。
(2)将0.1mL无菌的金属离子试剂，通过尾静脉和皮下注射到卒中模型鼠。
(3)利用小动物MRI成像仪进行成像并对其进行定性及定量分析。具体为，利用MRI(7.0T)成像仪成像，分别选取1小时、4小时、8小时、12小时、24小时、48小时等不同时间点，然后将该实验模型鼠用5％异氟烷进行气体麻醉，将其置于小动物活体MRI成像仪操作平台上，选择模型鼠的头部区域，采集图像。
结果显示，模型鼠的头部区域可以明显的检测到信号，不同于头部的组织密度，可以看到颗粒状的高密度材料，说明金属离子试剂在脑内部的损伤区域靶向特异性聚集，还原成为荧光和磁性材料(影像制剂)。
对比例1
将化合物氯化铁溶于超纯水，配制成浓度为10mmol/L的溶液，即铁离子试剂。
应用本实施例的铁离子试剂对肿瘤模型鼠进行荧光成像分析，具体步骤包括：
(1)构建肝癌(HepG2细胞系)的肿瘤模型鼠及宫颈癌(Hela细胞系)的肿瘤模型鼠，植瘤方式为腋下皮下植瘤。
(2)将0.1mL无菌的铁离子试剂，通过尾静脉和皮下注射到肿瘤模型鼠上。
(3)利用活体荧光成像仪进行成像并对其进行定性及定量分析。具体为，利用活体荧光成像仪成像，分别选取1小时、4小时、8小时、12小时、24小时、48小时等不同时间点，然后将该实验模型鼠用5％异氟烷进行气体麻醉，将其置于小动物活体成像仪操作平台上，选择420nm和480nm波长激发采集图像。
结果显示，模型鼠的腋下肿瘤区域在1～72小时内没有明显的荧光信号产生，说明单独的氯化铁溶液并不能应用于活体荧光成像。

Claims (8)

  1. 一种用于恶性肿瘤和心脑血管相关疾病早期快速检测及多模态成像的金属离子试剂，其为含有金属离子的水溶液，其特征在于，所述的金属离子由铁离子或亚铁离子与镁离子、过渡金属离子、稀土金属离子和贵金属离子中的至少一种配制而成；其中，所述的过渡金属离子为铈离子、锌离子中的一种或两种的混合物；金属离子试剂中，铁离子或亚铁离子与其他金属离子的摩尔比为5～1:1。
  2. 如权利要求1所述的金属离子试剂，其特征在于，所述的稀土金属离子为铕离子、镧离子中的一种或两种的混合物。
  3. 如权利要求1所述的金属离子试剂，其特征在于，所述的贵金属离子为金离子、银离子、铂离子中的一种或两种的混合物。
  4. 如权利要求1所述的金属离子试剂，其特征在于，金属离子试剂中，铁离子或亚铁离子的浓度为5～10mmol/L。
  5. 一种用于恶性肿瘤和心脑血管相关疾病早期快速检测及多模态成像的影像制剂，其特征在于，由如权利要求1～4任一项所述的金属离子试剂在病灶部位通过原位生物作用定点合成。
  6. 如权利要求5所述的用于恶性肿瘤和心脑血管相关疾病早期快速检测及多模态成像的影像制剂，其特征在于，病灶源自肝癌、肺癌、宫颈癌、白血病、骨肉瘤、脑瘤、白血病、脑卒中或老年痴呆症。
  7. 如权利要求1～4任一项所述的用于恶性肿瘤和心脑血管相关疾病早期快速检测及多模态成像的金属离子试剂在恶性肿瘤及心脑血管相关疾病靶向多模态成像的应用。
  8. 如权利要求1～4任一项所述的用于恶性肿瘤和心脑血管相关疾病早期快速检测及多模态成像的金属离子试剂在制备造影剂中的应用。
PCT/CN2015/096309 2015-10-14 2015-12-03 用于恶性肿瘤和心脑血管相关疾病早期快速检测及多模态成像的金属离子试剂和影像制剂 WO2017063258A1 (zh)

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