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WO2018153349A1 - Mmt-gd-dtpa complex and synthetic method and use thereof in magnetic resonance diagnosis of digestive tract - Google Patents

Mmt-gd-dtpa complex and synthetic method and use thereof in magnetic resonance diagnosis of digestive tract Download PDF

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WO2018153349A1
WO2018153349A1 PCT/CN2018/076992 CN2018076992W WO2018153349A1 WO 2018153349 A1 WO2018153349 A1 WO 2018153349A1 CN 2018076992 W CN2018076992 W CN 2018076992W WO 2018153349 A1 WO2018153349 A1 WO 2018153349A1
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mmt
dtpa
solution
complex
composite
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PCT/CN2018/076992
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French (fr)
Chinese (zh)
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陆杨
闫旭
潘晓锋
董良
徐运军
苏杨
凌代舜
徐维平
李飞
宋永红
钱海生
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合肥工业大学
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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
    • 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

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  • the invention belongs to the technical field of chemical preparation and drug research and development, and particularly relates to an MMT-Gd-DTPA complex and a synthesis method thereof and the application as a T1 contrast agent in the diagnosis of digestive tract magnetic resonance.
  • T1-weighted magnetic resonance imaging is widely used in clinical practice, and the contrast agent used for magnetic resonance imaging develops rapidly, but the development of MR oral contrast agent is slow, which limits the use of magnetic resonance imaging technology in the diagnosis of gastrointestinal diseases.
  • the existing MR oral contrast agents still have shortcomings in many aspects, such as causing discomfort, inducing other diseases, or causing unnecessary side effects, posing a potential threat to human health;
  • Most of the MR contrast agents available for oral administration are costly and expensive, and are not conducive to popularization and application.
  • the present invention provides an MMT-Gd-DTPA composite and a synthesis method thereof and the application in the diagnosis of digestive tract magnetic resonance, and the technical problem to be solved is the existing MR.
  • Oral contrast agents have the disadvantages of poor biocompatibility, low synthetic yield, and high cost.
  • the invention first discloses a method for synthesizing the MMT-Gd-DTPA complex, comprising the following steps:
  • the solution B is transferred to a high temperature reaction kettle, placed in an oven, reacted at 150 ° C ⁇ 180 ° C for 12 to 24 hours, to obtain a reaction solution C;
  • reaction solution C was centrifuged, and the obtained product was freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd composite powder;
  • reaction liquid F a reaction liquid F
  • reaction solution F was centrifuged, and the obtained product was freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd-DTPA composite powder.
  • the invention further discloses the MMT-Gd-DTPA composite synthesized by the above synthetic method, which has a diameter of 9-10 ⁇ m, good biocompatibility and high longitudinal relaxation rate r 1 , and the r 1 value is 5.1. -5.563 mM -1 S -1 .
  • the invention also discloses the application of the above MMT-Gd-DTPA complex in the diagnosis of digestive tract magnetic resonance, that is, as a T1 magnetic resonance molecular imaging contrast agent (MR oral contrast agent), for diagnosis of digestive tract diseases.
  • MR oral contrast agent magnetic resonance molecular imaging contrast agent
  • the MMT-Gd-DTPA composite prepared by using the montmorillonite (MMT) as a carrier of the invention exhibits a good longitudinal relaxation rate r 1 and good biocompatibility.
  • MMT montmorillonite
  • the use of montmorillonite as a carrier is not only safe, but also the high adsorption property of montmorillonite itself makes it evenly distributed on the inner wall of the gastrointestinal tract, so that the MMT-Gd-DTPA complex acts as a digestive tract contrast agent. Has a good imaging effect. Therefore, the MMT-Gd-DTPA complex prepared by the present invention has important significance as a MR oral contrast agent for the diagnosis of digestive tract diseases.
  • the invention adopts the relatively mature hydrothermal reaction method as the basic experimental method, and the experimental process is simple and the operability is strong.
  • the MMT-Gd-DTPA complex prepared by the invention has low cost and high synthetic yield and is suitable for popularization as a commercial clinical MR oral contrast agent.
  • the invention can obtain MMT-Gd-DTPA composite by simple hydrothermal synthesis, centrifugal separation and freeze-drying, and the method is simple, easy to implement, high in synthesis yield, low in cost, and can be mass-produced;
  • the material not only has a good longitudinal relaxation rate r 1 and good biocompatibility, but also has a good adhesion effect on the digestive tract wall. It is a good T1 magnetic resonance molecular imaging oral contrast agent in the digestive tract.
  • the MMT-Gd-DTPA composite obtained by the invention is low in toxicity and free from other polluting impurities.
  • Example 1 is a scanning electron microscope (SEM) photograph of the MMT-Gd-DTPA composite of Example 1 dispersed in water;
  • Example 2 is a result of in vitro cytotoxicity test of the MMT-Gd-DTPA complex of Example 1;
  • Figure 3 is a view showing the leakage of strontium ions in the simulated intestinal fluid by the MMT-Gd-DTPA composite of Example 1;
  • Figure 4 is a view showing the leakage of strontium ions in the simulated gastric juice of the MMT-Gd-DTPA complex of Example 1;
  • Figure 5 is a longitudinal relaxation rate r 1 of the MMT-Gd-DTPA composite of Example 1 .
  • the solution B was transferred to a high temperature reaction kettle, placed in an oven, placed at 150 ° C for 12 hours to obtain a reaction solution C;
  • reaction solution C was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd composite;
  • reaction liquid F a reaction liquid F
  • reaction solution F was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd-DTPA complex.
  • Fig. 1 is a scanning electron micrograph of the MMT-Gd-DTPA composite prepared in the present example, and it can be seen from the figure that the product has a diameter of about 9.5 ⁇ m.
  • the specific test method is: planting human umbilical vein endothelial cells at a concentration of 1 ⁇ 10 4 in a 96-well plate at a concentration of 1 ⁇ 10 4 cells per well were incubated for 24 hours, and then co-cultured with human umbilical vein endothelial cells by adding aqueous solutions of different concentrations of MMT, MMT-Gd and MMT-Gd-DTPA. After 24 hours, the matrix was removed, and human umbilical vein endothelial cells were washed 3 times with PBS solution, and MTT at a concentration of 5 mg/mL was added and incubated for 4 hours.
  • the survival rate of human umbilical vein endothelial cells was determined by measuring the absorbance of the product at a wavelength of 490 nm using an ELx800 Absorbance plate reader.
  • the activity of human umbilical vein endothelial cells to which MMT was added was substantially unchanged as compared with the control group (concentration: 0 ⁇ g/mL).
  • concentrations of 100 ⁇ g/mL and 150 ⁇ g/mL the activity of human umbilical vein endothelial cells added with MMT-Gd decreased significantly. Compared with the control group, the cell activity decreased by about 20%.
  • Fig. 3 and Fig. 4 respectively show the precipitation of strontium ions in the simulated intestinal fluid and the simulated gastric juice prepared by the MMT-Gd-DTPA composite prepared in the present embodiment, and the specific test method is: 1 mg of MMT-Gd and MMT-Gd-, respectively.
  • DTPA was added to 5 mL of simulated intestinal fluid or simulated gastric fluid, and then simulated gastrointestinal fluid containing MMT-Gd and MMT-Gd-DTPA was separately added to a dialysis bag having a molecular weight of 500-1000.
  • the dialysis bag was placed in a beaker containing 100 mL of deionized water, and the beaker was placed in a shaker (the shaking speed of the shaker was set to 150 rpm, the temperature was set to 37 ° C, and the time was set to 72 hours).
  • Deionized water in the beaker was taken at 24h, 48h and 72h, and the content of strontium ions in deionized water was determined by ICP-AES to determine the precipitation of strontium ions.
  • 10 ⁇ g/mL and 1 ⁇ g/mL of Gd aqueous solution and DIW (deionized water) were used as a reference.
  • the total mass ratio of strontium ions to total ion mass of MMT-Gd in simulated gastric juice and simulated intestinal fluid within 72 hours is about 97% and 95%, respectively.
  • MMT-Gd-DTPA in the simulated gastric juice and simulated intestinal fluid within 72h of the amount of strontium ions and the total mass ratio of strontium ions were about 0.9% and 0.7%, respectively, far lower than MMT-Gd in simulated gastric juice and Simulating the precipitation of strontium ions in intestinal fluid, indicating that DTPA and MMT-Gd chelate effectively prevent the leakage of strontium ions, greatly improving the biosafety of MMT-Gd-DTPA.
  • Figure 5 is the longitudinal relaxation rate r 1 of the MMT-Gd-DTPA composite prepared in the present example. It can be seen from the figure that the longitudinal relaxation rate r 1 of the product reaches 5.563 mM -1 S -1 , which is very good. Prospects for clinical application.
  • the solution B was transferred to a high temperature reaction kettle, placed in an oven, placed at 180 ° C for 24 hours to obtain a reaction solution C;
  • reaction solution C was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd composite;
  • reaction solution F was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain an MMT-Gd-DTPA complex.
  • the sample was characterized by a scanning electron microscope (ZEISS MERLIN Compact), and it was found that the MMT-Gd-DTPA composite obtained in this example had a diameter of about 9.4 ⁇ m.
  • the MTT-Gd-DTPA composite prepared in this example has good cytotoxicity test results and good biosafety.
  • the MMT-Gd-DTPA complex prepared in this example showed substantially no precipitation of strontium ions in the simulated gastrointestinal solution.
  • the in vitro longitudinal relaxation rate r 1 of the MMT-Gd-DTPA complex prepared in this example reached 5.1 mM -1 S -1 .
  • the solution B was transferred to a high temperature reaction kettle, placed in an oven, placed at 180 ° C for 16 hours to obtain a reaction solution C;
  • reaction solution C was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd composite;
  • reaction solution F was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd-DTPA complex.
  • the sample was characterized by a scanning electron microscope (ZEISS MERLIN Compact), and it was found that the MMT-Gd-DTPA composite obtained in this example had a diameter of about 9.7 ⁇ m.
  • the MTT-Gd-DTPA composite prepared in this example has good cytotoxicity test results and good biosafety.
  • the MMT-Gd-DTPA complex prepared in this example showed substantially no precipitation of strontium ions in the simulated gastrointestinal solution.
  • the in vitro longitudinal relaxation rate r 1 of the MMT-Gd-DTPA complex prepared in this example reached 5.4 mM -1 S -1 .
  • the solution B was transferred to a high temperature reaction kettle, placed in an oven, placed at 170 ° C for 24 hours to obtain a reaction solution C;
  • reaction solution C was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd composite;
  • reaction solution F was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd-DTPA complex.
  • the sample was characterized by scanning electron microscopy (ZEISS MERLIN Compact), and it was found that the MMT-Gd-DTPA composite selected for this example had a diameter of about 9.2 ⁇ m.
  • the MTT-Gd-DTPA composite prepared in this example has good cytotoxicity test results and good biosafety.
  • the MMT-Gd-DTPA complex prepared in this example showed substantially no precipitation of strontium ions in the simulated gastrointestinal solution.
  • the in vitro longitudinal relaxation rate r 1 of the MMT-Gd-DTPA complex prepared in this example reached 5.1 mM -1 S -1 .
  • the solution B was transferred to a high temperature reaction kettle, placed in an oven, placed at 170 ° C for 24 hours to obtain a reaction solution C;
  • reaction solution C was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd composite;
  • reaction solution F was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain an MMT-Gd-DTPA complex.
  • the sample was characterized by scanning electron microscopy (ZEISS MERLIN Compact), and the MMT-Gd-DTPA composite obtained in this example had a diameter of about 9.1 ⁇ m.
  • the MTT-Gd-DTPA composite prepared in this example has good cytotoxicity test results and good biosafety.
  • the MMT-Gd-DTPA complex prepared in this example showed substantially no precipitation of strontium ions in the simulated gastrointestinal solution.
  • the in vitro longitudinal relaxation rate r 1 of the MMT-Gd-DTPA complex prepared in this example reached 5.33 mM -1 S -1 .

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Abstract

Provided are a MMT-Gd-DTPA complex and a synthetic method and the use thereof in the magnetic resonance diagnosis of the digestive tract. The synthetic method is characterized in that: MMT powder and GdCl3 are mixed in water and react to obtain an MMT-Gd complex powder, and the MMT-Gd complex powder reacts with DTPA in water, thus obtaining the MMT-Gd-DTPA complex. The MMT-Gd-DTPA complex is obtained through hydro-thermal synthesis, and the method is simple and easy to implement, and the obtained complex not only has a good longitudinal relaxation rate r1 and a good biocompatibility, but also has a good effect in terms of adhesion to the digestive tract wall, is a better T1 magnetic resonance molecular imaging oral contrast agent, and has great clinical application potential.

Description

一种MMT-Gd-DTPA复合物及其合成方法和在消化道磁共振诊断中的应用MMT-Gd-DTPA complex and its synthesis method and application in diagnosis of digestive tract magnetic resonance 技术领域Technical field
本发明属于化学制备和药物研发技术领域，具体涉及一种MMT-Gd-DTPA复合物及其合成方法和作为T1造影剂在消化道磁共振诊断中的应用。The invention belongs to the technical field of chemical preparation and drug research and development, and particularly relates to an MMT-Gd-DTPA complex and a synthesis method thereof and the application as a T1 contrast agent in the diagnosis of digestive tract magnetic resonance.
背景技术Background technique
目前T1加权磁共振成像在临床上应用较为广泛，用于磁共振成像的造影剂发展迅速，但是MR口服造影剂的发展缓慢，限制了磁共振成像技术在胃肠道疾病诊断方面的使用。At present, T1-weighted magnetic resonance imaging is widely used in clinical practice, and the contrast agent used for magnetic resonance imaging develops rapidly, but the development of MR oral contrast agent is slow, which limits the use of magnetic resonance imaging technology in the diagnosis of gastrointestinal diseases.
美国《物理化学学报》(J.Phys.Chem，1996年，第100卷，第16429–16434页)，报道了通过对膨润土进行钆离子插层，得到的膨润土-钆离子的复合物，实验证明了这种复合物的混悬剂具有良好的T1造影效果，可以作为MR口服造影剂用于消化道疾病的诊断。但是这种复合物在酸性环境下易发生钆离子的泄露，大大降低了材料本身作为MR口服造影剂的安全性，造成了对人体健康的潜在威胁。故而膨润土-钆离子的复合物因生物相容性和安全性欠佳而不适于推广使用。American Journal of Physical Chemistry (J. Phys. Chem, 1996, Vol. 100, pp. 16429–16434), reported a composite of bentonite-strontium ions obtained by intercalating cesium ions with bentonite. The suspension of this complex has a good T1 contrast effect and can be used as a MR oral contrast agent for the diagnosis of digestive tract diseases. However, this complex is prone to leakage of strontium ions in an acidic environment, which greatly reduces the safety of the material itself as a MR oral contrast agent, and poses a potential threat to human health. Therefore, the bentonite-germanium complex is not suitable for popularization due to poor biocompatibility and safety.
英国《生物医学核磁共振》(NMR IN BIOMEDICINE.，2016，第29卷，第475-482页)报道了将商用临床血管造影剂马根维显(Magnevist)和钆贝葡胺(MultiHance)作为口服造影剂进行动物的体内实验。结果显示部分马根维显和钆贝葡胺会经肾脏代谢后通过尿液被排出体外。但是由于钆具有肾毒性，这种代谢途径可能会对患有肾脏疾病的患者的健康造成潜在的威胁，而且这类商用临床造影剂造价较高，不宜于被广泛推广。British "Biomedical Nuclear Magnetic Resonance" (NMR IN BIOMEDICINE., 2016, Vol. 29, pp. 475-482) reports the commercial clinical angiographic agents Magnevist and MultiHance as oral contrast agents. In vivo experiments with animals were performed. The results showed that some of Magnevist and Muscarine were excreted in the urine through the kidneys. However, due to nephrotoxicity, this metabolic pathway may pose a potential threat to the health of patients with kidney disease, and such commercial clinical contrast agents are relatively expensive and should not be widely promoted.
综上所述，现有的MR口服造影剂在许多方面仍存在着不足，比如会引起患者的不适、诱发其他疾病、或者产生不必要的副作用，对人体健康造成潜在的威胁；而且现有的可供口服的MR造影剂大多生产成本较高、价格昂贵、不利于推广应用。In summary, the existing MR oral contrast agents still have shortcomings in many aspects, such as causing discomfort, inducing other diseases, or causing unnecessary side effects, posing a potential threat to human health; Most of the MR contrast agents available for oral administration are costly and expensive, and are not conducive to popularization and application.
发明内容Summary of the invention
本发明为避免上述现有技术所存在的不足之处，提供了一种MMT-Gd-DTPA复合物及其合成方法和在消化道磁共振诊断中的应用，所要解决的技术问题是现有MR口服造影剂生物相容性欠佳、合成产率较低、价格昂贵等缺点。In order to avoid the deficiencies of the prior art mentioned above, the present invention provides an MMT-Gd-DTPA composite and a synthesis method thereof and the application in the diagnosis of digestive tract magnetic resonance, and the technical problem to be solved is the existing MR. Oral contrast agents have the disadvantages of poor biocompatibility, low synthetic yield, and high cost.
本发明为解决技术问题，采用如下技术方案：The present invention solves the technical problem and adopts the following technical solutions:
本发明首先公开了MMT-Gd-DTPA复合物的合成方法，包括如下步骤：The invention first discloses a method for synthesizing the MMT-Gd-DTPA complex, comprising the following steps:
a、称取1～3g的MMT(蒙脱土)粉末于烧杯中，加入20～40mL去离子水，分散均匀，得到溶液A；a, weigh 1 ~ 3g of MMT (montmorillonite) powder in a beaker, add 20 ~ 40mL of deionized water, dispersed evenly, to obtain a solution A;
b、向所述溶液A中加入0.5～3g的GdCl 3分散均匀，得到溶液B； b, adding 0.5 to 3 g of GdCl 3 to the solution A to be uniformly dispersed to obtain a solution B;
c、将所述溶液B转入高温反应釜后放入烘箱，在150℃～180℃下反应12～24小时，得到反应液C；c, the solution B is transferred to a high temperature reaction kettle, placed in an oven, reacted at 150 ° C ~ 180 ° C for 12 to 24 hours, to obtain a reaction solution C;
d、将所述反应液C离心分离，所得产物冷冻干燥24小时后取出，获得MMT-Gd复合物粉末；d, the reaction solution C was centrifuged, and the obtained product was freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd composite powder;
e、称取0.5～2.5g的MMT-Gd复合物于烧杯中，加入20～40mL去离子水，分散均匀，得到溶液D；e, weigh 0.5 ~ 2.5g of MMT-Gd complex in a beaker, add 20 ~ 40mL of deionized water, dispersed evenly, to obtain a solution D;
f、将0.5～2.5g的DTPA(二乙基三胺五乙酸)加入到溶液D中，经搅拌超声分散均匀后，得到溶液E；f, 0.5 ~ 2.5g of DTPA (diethyltriamine pentaacetic acid) was added to the solution D, after ultrasonic dispersion by stirring, to obtain a solution E;
g、在60～80℃下，将所述溶液E油浴搅拌6～8h，得到反应液F；g, at 60 ~ 80 ° C, the solution E oil bath is stirred for 6 ~ 8h, to obtain a reaction liquid F;
h、将所述反应液F离心分离，所得产物冷冻干燥24小时后取出，即获得MMT-Gd-DTPA复合物粉末。h, the reaction solution F was centrifuged, and the obtained product was freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd-DTPA composite powder.
本发明进一步公开了上述合成方法所合成的MMT-Gd-DTPA复合物，其直径为9～10μm，具有较好的生物相容性和较高的纵向弛豫率r 1，r 1值为5.1-5.563mM -1S -1。 The invention further discloses the MMT-Gd-DTPA composite synthesized by the above synthetic method, which has a diameter of 9-10 μm, good biocompatibility and high longitudinal relaxation rate r 1 , and the r 1 value is 5.1. -5.563 mM -1 S -1 .
本发明还公开了上述MMT-Gd-DTPA复合物在消化道磁共振诊断中的应用，即作为T1磁共振分子影像造影剂(MR口服造影剂)，用于消化道疾病的诊断。The invention also discloses the application of the above MMT-Gd-DTPA complex in the diagnosis of digestive tract magnetic resonance, that is, as a T1 magnetic resonance molecular imaging contrast agent (MR oral contrast agent), for diagnosis of digestive tract diseases.
本发明采用蒙脱土(MMT)作为载体制备的MMT-Gd-DTPA复合物表现出良好的纵向弛豫率r 1和较好的生物相容性。另外，以蒙脱土作为载体不仅安全性高，而且蒙脱土本身所具有的高吸附性能使它均匀的分布在胃肠道内壁上，从而使MMT-Gd-DTPA复合物作为消化道造影剂具有良好的成像效果。所以，本发明制备的MMT-Gd-DTPA复合物作为MR口服造影剂运用于消化道疾病的诊断具有重要的意义。同时，本发明以目前比较成熟的水热反应法为基本实验方法，实验过程简单、可操作性强。本发明制备的MMT-Gd-DTPA复合物所需成本较低，合成产率高，适于作为商业化的临床MR口服造影剂推广使用。 The MMT-Gd-DTPA composite prepared by using the montmorillonite (MMT) as a carrier of the invention exhibits a good longitudinal relaxation rate r 1 and good biocompatibility. In addition, the use of montmorillonite as a carrier is not only safe, but also the high adsorption property of montmorillonite itself makes it evenly distributed on the inner wall of the gastrointestinal tract, so that the MMT-Gd-DTPA complex acts as a digestive tract contrast agent. Has a good imaging effect. Therefore, the MMT-Gd-DTPA complex prepared by the present invention has important significance as a MR oral contrast agent for the diagnosis of digestive tract diseases. At the same time, the invention adopts the relatively mature hydrothermal reaction method as the basic experimental method, and the experimental process is simple and the operability is strong. The MMT-Gd-DTPA complex prepared by the invention has low cost and high synthetic yield and is suitable for popularization as a commercial clinical MR oral contrast agent.
与已有技术相比，本发明的有益效果体现在：Compared with the prior art, the beneficial effects of the present invention are embodied in:
1、本发明通过简单的水热合成、离心分离、冷冻干燥即可获得MMT-Gd-DTPA复合物，方法简单、易于实现、合成产率高、成本较低，可进行大规模生产；所得复合物不仅具有良好的纵向弛豫率r 1和很好的生物相容性，且在消化道壁上有很好的粘覆效果，是较好的T1磁共振分子影像口服造影剂，在消化道疾病诊断等领域具有很多重要的应用，具有较大的临床应用潜力。 1. The invention can obtain MMT-Gd-DTPA composite by simple hydrothermal synthesis, centrifugal separation and freeze-drying, and the method is simple, easy to implement, high in synthesis yield, low in cost, and can be mass-produced; The material not only has a good longitudinal relaxation rate r 1 and good biocompatibility, but also has a good adhesion effect on the digestive tract wall. It is a good T1 magnetic resonance molecular imaging oral contrast agent in the digestive tract. There are many important applications in the field of disease diagnosis and have great potential for clinical application.
2、本发明所获得的MMT-Gd-DTPA复合物，低毒且无其它污染性杂质产生。2. The MMT-Gd-DTPA composite obtained by the invention is low in toxicity and free from other polluting impurities.
附图说明DRAWINGS
图1为实施例1的MMT-Gd-DTPA复合物分散在水中的扫描电镜(SEM)照片；1 is a scanning electron microscope (SEM) photograph of the MMT-Gd-DTPA composite of Example 1 dispersed in water;
图2为实施例1的MMT-Gd-DTPA复合物的体外细胞毒性试验结果；2 is a result of in vitro cytotoxicity test of the MMT-Gd-DTPA complex of Example 1;
图3为实施例1的MMT-Gd-DTPA复合物在模拟肠液中钆离子的泄露情况；Figure 3 is a view showing the leakage of strontium ions in the simulated intestinal fluid by the MMT-Gd-DTPA composite of Example 1;
图4为实施例1的MMT-Gd-DTPA复合物在模拟胃液中钆离子的泄露情况；Figure 4 is a view showing the leakage of strontium ions in the simulated gastric juice of the MMT-Gd-DTPA complex of Example 1;
图5为实施例1的MMT-Gd-DTPA复合物的纵向弛豫率r 1。 Figure 5 is a longitudinal relaxation rate r 1 of the MMT-Gd-DTPA composite of Example 1 .
具体实施方式detailed description
下面对本发明的实施例作详细说明，下述实施例在以本发明技术方案为前提下进行实施，给出了详细的实施方式和具体的操作过程，但本发明的保护范围不限于下述的实施例。The embodiments of the present invention are described in detail below. The following embodiments are implemented on the premise of the technical solution of the present invention, and detailed implementation manners and specific operation procedures are given, but the scope of protection of the present invention is not limited to the following. Example.
实施例1Example 1
本实施例按如下步骤进行MMT-Gd-DTPA复合物的制备：In this example, the preparation of the MMT-Gd-DTPA composite was carried out as follows:
a、称取1g的MMT粉末于烧杯中，加入20mL的去离子水，分散均匀，得到溶液A；a, weigh 1g of MMT powder in a beaker, add 20mL of deionized water, and disperse evenly to obtain a solution A;
b、向溶液A中加入0.5g的GdCl 3分散均匀，得到溶液B； b, adding 0.5 g of GdCl 3 to solution A to disperse uniformly, to obtain solution B;
c、将溶液B转入高温反应釜后放入烘箱，在150℃下放置12小时，得到反应液C；c, the solution B was transferred to a high temperature reaction kettle, placed in an oven, placed at 150 ° C for 12 hours to obtain a reaction solution C;
d、将反应液C离心分离，所得产物转入冷冻干燥机中冷冻干燥24小时后取出，获得MMT-Gd复合物；d, the reaction solution C was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd composite;
e、称取0.5g的MMT-Gd复合物于烧杯中，加入20mL的去离子水，分散均匀，得到溶液D；e, weigh 0.5g of MMT-Gd complex in a beaker, add 20mL of deionized water, disperse evenly, to obtain a solution D;
f、将0.5g的DTPA加入到溶液D中，经搅拌超声分散均匀后，得到溶液E；f, 0.5g of DTPA is added to the solution D, after ultrasonic dispersion by stirring, the solution E is obtained;
g、在60℃下，将步骤f制备的溶液E油浴搅拌6h，得到反应液F；g, at 60 ° C, the solution E prepared in step f oil bath was stirred for 6h, to obtain a reaction liquid F;
h、将反应液F离心分离，所得产物转入冷冻干燥机中冷冻干燥24小时后取出，获得MMT-Gd-DTPA复合物。h. The reaction solution F was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd-DTPA complex.
图1为本实施例所制备的MMT-Gd-DTPA复合物的扫描电子显微镜照片，从图中可以看出本产物直径约为9.5μm。Fig. 1 is a scanning electron micrograph of the MMT-Gd-DTPA composite prepared in the present example, and it can be seen from the figure that the product has a diameter of about 9.5 μm.
图2为本实施例所制备的MMT-Gd-DTPA复合物的体外细胞毒性试验结果，具体试验方法是：将浓度为1×10 4的人脐静脉内皮细胞种植在96孔板中，浓度为每孔1×10 4个细胞，孵育24小时，然后加入不同浓度MMT、MMT-Gd、MMT-Gd-DTPA的水溶液与人脐静脉内皮细胞共培养。24小时后将基质去除，并将人脐静脉内皮细胞用PBS溶液洗涤3遍，再加入浓度为5mg/mL的MTT并孵育4小时。将最终产物加入到120mL的DMSO中摇晃10分钟后，通过使用ELx800Absorbance酶标仪测量产物在490nm波长处的吸光度来确定人脐静脉内皮细胞的存活率。从图2中可以看出，与对照组(浓度为0μg/mL)相比，加入MMT的人脐静脉内皮细胞的活性基本上没有变化。在MMT-Gd浓度为100μg/mL和150μg/mL时，加入MMT-Gd的人脐静脉内皮细胞的活性出现明显下降，与对照组相比，细胞活性下降了约20％， 这可能是因为钆离子的泄露而造成的。与之相比，即使在MMT-Gd-DTPA浓度为100μg/mL和150μg/mL时，加入MMT-Gd-DTPA的细胞仍然能够保持较高的细胞活性(细胞活性约98％)，与对照组基本无差异，说明DTPA与MMT-Gd螯合之后有效的阻止了钆离子的泄露有关。由此可知MMT-Gd-DTPA复合物具有极低的细胞毒性，生物安全性良好，具有很大的临床应用潜力。 2 is a result of in vitro cytotoxicity test of the MMT-Gd-DTPA complex prepared in the present embodiment, and the specific test method is: planting human umbilical vein endothelial cells at a concentration of 1×10 4 in a 96-well plate at a concentration of 1×10 4 cells per well were incubated for 24 hours, and then co-cultured with human umbilical vein endothelial cells by adding aqueous solutions of different concentrations of MMT, MMT-Gd and MMT-Gd-DTPA. After 24 hours, the matrix was removed, and human umbilical vein endothelial cells were washed 3 times with PBS solution, and MTT at a concentration of 5 mg/mL was added and incubated for 4 hours. After the final product was shaken in 120 mL of DMSO for 10 minutes, the survival rate of human umbilical vein endothelial cells was determined by measuring the absorbance of the product at a wavelength of 490 nm using an ELx800 Absorbance plate reader. As can be seen from Fig. 2, the activity of human umbilical vein endothelial cells to which MMT was added was substantially unchanged as compared with the control group (concentration: 0 μg/mL). At the MMT-Gd concentrations of 100 μg/mL and 150 μg/mL, the activity of human umbilical vein endothelial cells added with MMT-Gd decreased significantly. Compared with the control group, the cell activity decreased by about 20%. This may be because 钆Caused by the leakage of ions. In contrast, even at MMT-Gd-DTPA concentrations of 100 μg/mL and 150 μg/mL, cells supplemented with MMT-Gd-DTPA were able to maintain high cell viability (cell activity of approximately 98%), compared with the control group. There is basically no difference, indicating that DTPA and MMT-Gd chelate effectively prevent the leakage of strontium ions. It can be seen that the MMT-Gd-DTPA complex has extremely low cytotoxicity, good biosafety and great potential for clinical application.
图3和图4分别为本实施例所制备的MMT-Gd-DTPA复合物在模拟肠液和模拟胃液中的钆离子析出情况，具体试验方法是：分别将1mg的MMT-Gd和MMT-Gd-DTPA加入到5mL的模拟肠液或模拟胃液中，然后将含有MMT-Gd和MMT-Gd-DTPA的模拟胃肠道液分别加入到分子量为500-1000的透析袋中。将透析袋放入含有100mL去离子水的烧杯中，并将烧杯放入摇床(摇床的摇动速度设定为150转/分钟，温度设定为37℃，时间设置为72小时)。分别于24h、48h和72h取烧杯中的去离子水，通过ICP-AES检测去离子水中钆离子的含量来确定钆离子的析出情况。图中以10μg/mL和1μg/mL的Gd水溶液及DIW(去离子水)作为参照。可以看出，MMT-Gd在模拟胃液和模拟肠液中72h内的钆离子析出量与钆离子总质量比分别约为97％和95％。与之相比，MMT-Gd-DTPA在模拟胃液和模拟肠液中72h内的钆离子析出量与钆离子总质量比分别约为0.9％和0.7％，远远低于MMT-Gd在模拟胃液和模拟肠液中钆离子的析出量，说明DTPA与MMT-Gd螯合之后有效的阻止了钆离子的泄露，大大提高了MMT-Gd-DTPA的生物安全性。Fig. 3 and Fig. 4 respectively show the precipitation of strontium ions in the simulated intestinal fluid and the simulated gastric juice prepared by the MMT-Gd-DTPA composite prepared in the present embodiment, and the specific test method is: 1 mg of MMT-Gd and MMT-Gd-, respectively. DTPA was added to 5 mL of simulated intestinal fluid or simulated gastric fluid, and then simulated gastrointestinal fluid containing MMT-Gd and MMT-Gd-DTPA was separately added to a dialysis bag having a molecular weight of 500-1000. The dialysis bag was placed in a beaker containing 100 mL of deionized water, and the beaker was placed in a shaker (the shaking speed of the shaker was set to 150 rpm, the temperature was set to 37 ° C, and the time was set to 72 hours). Deionized water in the beaker was taken at 24h, 48h and 72h, and the content of strontium ions in deionized water was determined by ICP-AES to determine the precipitation of strontium ions. In the figure, 10 μg/mL and 1 μg/mL of Gd aqueous solution and DIW (deionized water) were used as a reference. It can be seen that the total mass ratio of strontium ions to total ion mass of MMT-Gd in simulated gastric juice and simulated intestinal fluid within 72 hours is about 97% and 95%, respectively. In contrast, MMT-Gd-DTPA in the simulated gastric juice and simulated intestinal fluid within 72h of the amount of strontium ions and the total mass ratio of strontium ions were about 0.9% and 0.7%, respectively, far lower than MMT-Gd in simulated gastric juice and Simulating the precipitation of strontium ions in intestinal fluid, indicating that DTPA and MMT-Gd chelate effectively prevent the leakage of strontium ions, greatly improving the biosafety of MMT-Gd-DTPA.
图5为本实施例所制备的MMT-Gd-DTPA复合物的纵向弛豫率r 1，从图中可以看出产物的纵向弛豫率r 1达到5.563mM -1S -1，有很好的临床应用前景。 Figure 5 is the longitudinal relaxation rate r 1 of the MMT-Gd-DTPA composite prepared in the present example. It can be seen from the figure that the longitudinal relaxation rate r 1 of the product reaches 5.563 mM -1 S -1 , which is very good. Prospects for clinical application.
实施例2Example 2
本实施例按如下步骤进行MMT-Gd-DTPA复合物的制备：In this example, the preparation of the MMT-Gd-DTPA composite was carried out as follows:
a、称取3g的MMT粉末于烧杯中，加入40mL的去离子水，分散均匀，得到溶液A；a, weigh 3g of MMT powder in a beaker, add 40mL of deionized water, disperse evenly, to obtain a solution A;
b、向溶液A中加入3g的GdCl 3分散均匀，得到溶液B； b, adding 3 g of GdCl 3 to solution A to disperse uniformly, to obtain solution B;
c、将溶液B转入高温反应釜后放入烘箱，在180℃下放置24小时，得到反应液C；c, the solution B was transferred to a high temperature reaction kettle, placed in an oven, placed at 180 ° C for 24 hours to obtain a reaction solution C;
d、将反应液C离心分离，所得产物转入冷冻干燥机中冷冻干燥24小时后取出，获得MMT-Gd复合物；d, the reaction solution C was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd composite;
e、称取2.5g的MMT-Gd复合物于烧杯中，加入40mL的去离子水，分散均匀，得到溶液D；e, weigh 2.5g of MMT-Gd complex in a beaker, add 40mL of deionized water, disperse evenly, to obtain a solution D;
f、将2.5g的DTPA加入到溶液D中，经搅拌超声分散均匀后，得到溶液E；f, 2.5g of DTPA was added to the solution D, after ultrasonic dispersion by stirring, the solution E was obtained;
g、在75℃下，将步骤f制备的溶液E油浴搅拌8h，得到反应液F；g, at 75 ° C, the solution E prepared in step f oil bath was stirred for 8h, to obtain a reaction solution F;
h、将反应液F离心分离，所得产物转入冷冻干燥机中冷冻干燥24小时后取出，获得 MMT-Gd-DTPA复合物。h, the reaction solution F was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain an MMT-Gd-DTPA complex.
经扫描电子显微镜对样品进行表征(ZEISS MERLIN Compact)，可知本实施例所获得的MMT-Gd-DTPA复合物直径约为9.4μm。本实施例所制备的MMT-Gd-DTPA复合物体外细胞毒性试验结果良好，生物安全性良好。本实施例所制备的MMT-Gd-DTPA复合物在模拟的胃肠道溶液中基本上没有出现钆离子的析出。本实施例所制备的MMT-Gd-DTPA复合物的体外纵向弛豫率r 1达到5.1mM -1S -1。 The sample was characterized by a scanning electron microscope (ZEISS MERLIN Compact), and it was found that the MMT-Gd-DTPA composite obtained in this example had a diameter of about 9.4 μm. The MTT-Gd-DTPA composite prepared in this example has good cytotoxicity test results and good biosafety. The MMT-Gd-DTPA complex prepared in this example showed substantially no precipitation of strontium ions in the simulated gastrointestinal solution. The in vitro longitudinal relaxation rate r 1 of the MMT-Gd-DTPA complex prepared in this example reached 5.1 mM -1 S -1 .
实施例3Example 3
本实施例按如下步骤进行MMT-Gd-DTPA复合物的制备：In this example, the preparation of the MMT-Gd-DTPA composite was carried out as follows:
a、称取1.5g的MMT粉末于烧杯中，加入40mL的去离子水，分散均匀，得到溶液A；a, weigh 1.5g of MMT powder in a beaker, add 40mL of deionized water, disperse evenly, to obtain a solution A;
b、向溶液A中加入1.5g的GdCl 3分散均匀，得到溶液B； b, adding 1.5 g of GdCl 3 to solution A to disperse uniformly, to obtain solution B;
c、将溶液B转入高温反应釜后放入烘箱，在180℃下放置16小时，得到反应液C；c, the solution B was transferred to a high temperature reaction kettle, placed in an oven, placed at 180 ° C for 16 hours to obtain a reaction solution C;
d、将反应液C离心分离，所得产物转入冷冻干燥机中冷冻干燥24小时后取出，获得MMT-Gd复合物；d, the reaction solution C was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd composite;
e、称取1g的MMT-Gd复合物于烧杯中，加入40mL的去离子水，分散均匀，得到溶液D；e, weigh 1g of MMT-Gd complex in a beaker, add 40mL of deionized water, disperse evenly, to obtain a solution D;
f、将1g的DTPA加入到溶液D中，经搅拌超声分散均匀后，得到溶液E；f, 1g of DTPA is added to the solution D, after ultrasonic dispersion by stirring, to obtain a solution E;
g、在70℃下，将步骤f制备的溶液E油浴搅拌8h，得到反应液F；g, at 70 ° C, the solution E prepared in step f oil bath was stirred for 8h, to obtain a reaction solution F;
h、将反应液F离心分离，所得产物转入冷冻干燥机中冷冻干燥24小时后取出，获得MMT-Gd-DTPA复合物。h. The reaction solution F was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd-DTPA complex.
经扫描电子显微镜对样品进行表征(ZEISS MERLIN Compact)，可知本实施例所获得的MMT-Gd-DTPA复合物直径约为9.7μm。本实施例所制备的MMT-Gd-DTPA复合物体外细胞毒性试验结果良好，生物安全性良好。本实施例所制备的MMT-Gd-DTPA复合物在模拟的胃肠道溶液中基本上没有出现钆离子的析出。本实施例所制备的MMT-Gd-DTPA复合物的体外纵向弛豫率r 1达到5.4mM -1S -1。 The sample was characterized by a scanning electron microscope (ZEISS MERLIN Compact), and it was found that the MMT-Gd-DTPA composite obtained in this example had a diameter of about 9.7 μm. The MTT-Gd-DTPA composite prepared in this example has good cytotoxicity test results and good biosafety. The MMT-Gd-DTPA complex prepared in this example showed substantially no precipitation of strontium ions in the simulated gastrointestinal solution. The in vitro longitudinal relaxation rate r 1 of the MMT-Gd-DTPA complex prepared in this example reached 5.4 mM -1 S -1 .
实施例4Example 4
本实施例按如下步骤进行MMT-Gd-DTPA复合物的制备：In this example, the preparation of the MMT-Gd-DTPA composite was carried out as follows:
a、称取2g的MMT粉末于烧杯中，加入30mL的去离子水，分散均匀，得到溶液A；a, weigh 2g of MMT powder in a beaker, add 30mL of deionized water, disperse evenly, to obtain a solution A;
b、向溶液A中加入溶液加入2g的GdCl 3分散均匀，得到溶液B； b, adding solution to solution A, adding 2g of GdCl 3 to disperse evenly, to obtain solution B;
c、将溶液B转入高温反应釜后放入烘箱，在170℃下放置24小时，得到反应液C；c, the solution B was transferred to a high temperature reaction kettle, placed in an oven, placed at 170 ° C for 24 hours to obtain a reaction solution C;
d、将反应液C离心分离，所得产物转入冷冻干燥机中冷冻干燥24小时后取出，获得MMT-Gd复合物；d, the reaction solution C was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd composite;
e、称取1.5g的MMT-Gd复合物于烧杯中，加入30mL的去离子水，分散均匀，得到溶液D；e, weigh 1.5g of MMT-Gd complex in a beaker, add 30mL of deionized water, disperse evenly, to obtain a solution D;
f、将1.5g的DTPA加入到溶液D中，经搅拌超声分散均匀后，得到溶液E；f, 1.5g of DTPA was added to the solution D, after ultrasonic dispersion by stirring, to obtain a solution E;
g、在70℃下，将步骤f制备的溶液E油浴搅拌7h，得到反应液F；g, at 70 ° C, the solution E prepared in step f oil bath was stirred for 7h, to obtain a reaction solution F;
h、将反应液F离心分离，所得产物转入冷冻干燥机中冷冻干燥24小时后取出，获得MMT-Gd-DTPA复合物。h. The reaction solution F was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd-DTPA complex.
经扫描电子显微镜对样品进行表征(ZEISS MERLIN Compact)，可知本实施例所选用的MMT-Gd-DTPA复合物直径约为9.2μm。本实施例所制备的MMT-Gd-DTPA复合物体外细胞毒性试验结果良好，生物安全性良好。本实施例所制备的MMT-Gd-DTPA复合物在模拟的胃肠道溶液中基本上没有出现钆离子的析出。本实施例所制备的MMT-Gd-DTPA复合物的体外纵向弛豫率r 1达到5.1mM -1S -1。 The sample was characterized by scanning electron microscopy (ZEISS MERLIN Compact), and it was found that the MMT-Gd-DTPA composite selected for this example had a diameter of about 9.2 μm. The MTT-Gd-DTPA composite prepared in this example has good cytotoxicity test results and good biosafety. The MMT-Gd-DTPA complex prepared in this example showed substantially no precipitation of strontium ions in the simulated gastrointestinal solution. The in vitro longitudinal relaxation rate r 1 of the MMT-Gd-DTPA complex prepared in this example reached 5.1 mM -1 S -1 .
实施例5Example 5
本实施例按如下步骤进行MMT-Gd-DTPA复合物的制备：In this example, the preparation of the MMT-Gd-DTPA composite was carried out as follows:
a、称取2.5g的MMT粉末于烧杯中，加入30mL的去离子水，分散均匀，得到溶液A；a, weigh 2.5g of MMT powder in a beaker, add 30mL of deionized water, disperse evenly, to obtain a solution A;
b、向溶液A中加入2.5g的GdCl 3分散均匀，得到溶液B； b, adding 2.5 g of GdCl 3 to solution A to disperse uniformly, to obtain solution B;
c、将所述溶液B转入高温反应釜后放入烘箱，在170℃下放置24小时，得到反应液C；c, the solution B was transferred to a high temperature reaction kettle, placed in an oven, placed at 170 ° C for 24 hours to obtain a reaction solution C;
d、将反应液C离心分离，所得产物转入冷冻干燥机中冷冻干燥24小时后取出，获得MMT-Gd复合物；d, the reaction solution C was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd composite;
e、称取2g的MMT-Gd复合物于烧杯中，加入30mL的去离子水，分散均匀，得到溶液D；e, weigh 2g of MMT-Gd complex in a beaker, add 30mL of deionized water, disperse evenly, to obtain a solution D;
f、将2g的DTPA加入到溶液D中，经搅拌超声分散均匀后，得到溶液E；f, 2g of DTPA is added to the solution D, after ultrasonic dispersion by stirring, the solution E is obtained;
g、在70℃下，将步骤f制备的溶液E油浴搅拌7h，得到反应液F；g, at 70 ° C, the solution E prepared in step f oil bath was stirred for 7h, to obtain a reaction solution F;
h、将反应液F离心分离，所得产物转入冷冻干燥机中冷冻干燥24小时后取出，获得MMT-Gd-DTPA复合物h, the reaction solution F was centrifuged, and the obtained product was transferred to a freeze dryer and freeze-dried for 24 hours, and then taken out to obtain an MMT-Gd-DTPA complex.
经扫描电子显微镜对样品进行表征(ZEISS MERLIN Compact)，本实施例所获得的MMT-Gd-DTPA复合物直径约为9.1μm。本实施例所制备的MMT-Gd-DTPA复合物体外细胞毒性试验结果良好，生物安全性良好。本实施例所制备的MMT-Gd-DTPA复合物在模拟的胃肠道溶液中基本上没有出现钆离子的析出。本实施例所制备的MMT-Gd-DTPA复合物的体外纵向弛豫率r 1达到5.33mM -1S -1。 The sample was characterized by scanning electron microscopy (ZEISS MERLIN Compact), and the MMT-Gd-DTPA composite obtained in this example had a diameter of about 9.1 μm. The MTT-Gd-DTPA composite prepared in this example has good cytotoxicity test results and good biosafety. The MMT-Gd-DTPA complex prepared in this example showed substantially no precipitation of strontium ions in the simulated gastrointestinal solution. The in vitro longitudinal relaxation rate r 1 of the MMT-Gd-DTPA complex prepared in this example reached 5.33 mM -1 S -1 .
以上所述仅为本发明的示例性实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。The above description is only exemplary embodiments of the present invention, and is not intended to limit the present invention. Any modifications, equivalents, and improvements made within the spirit and principles of the present invention should be included in the protection of the present invention. Within the scope.

Claims (5)

  1. 一种MMT-Gd-DTPA复合物的合成方法，其特征在于包括如下步骤：A method for synthesizing MMT-Gd-DTPA composites, comprising the steps of:
    a、称取1～3g的MMT粉末于烧杯中，加入20～40mL去离子水，分散均匀，得到溶液A；a, weigh 1 ~ 3g of MMT powder in a beaker, add 20 ~ 40mL of deionized water, dispersed evenly, to obtain a solution A;
    b、向所述溶液A中加入0.5～3g的GdCl3分散均匀，得到溶液B；b, adding 0.5 to 3 g of GdCl3 to the solution A to disperse uniformly, to obtain a solution B;
    c、将所述溶液B转入高温反应釜后放入烘箱，在150℃～180℃下反应12～24小时，得到反应液C；c, the solution B is transferred to a high temperature reaction kettle, placed in an oven, reacted at 150 ° C ~ 180 ° C for 12 to 24 hours, to obtain a reaction solution C;
    d、将所述反应液C离心分离，所得产物冷冻干燥24小时后取出，获得MMT-Gd复合物；d, the reaction solution C was centrifuged, and the obtained product was freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd complex;
    e、称取0.5～2.5g的MMT-Gd复合物于烧杯中，加入20～40mL去离子水，分散均匀，得到溶液D；e, weigh 0.5 ~ 2.5g of MMT-Gd complex in a beaker, add 20 ~ 40mL of deionized water, dispersed evenly, to obtain a solution D;
    f、将0.5～2.5g的DTPA加入到溶液D中，经搅拌超声分散均匀后，得到溶液E；f, 0.5 ~ 2.5g of DTPA is added to the solution D, after ultrasonic dispersion by stirring, to obtain a solution E;
    g、在60～80℃下，将所述溶液E油浴搅拌6～8h，得到反应液F；g, at 60 ~ 80 ° C, the solution E oil bath is stirred for 6 ~ 8h, to obtain a reaction liquid F;
    h、将所述反应液F离心分离，所得产物冷冻干燥24小时后取出，即获得MMT-Gd-DTPA复合物粉末。h, the reaction solution F was centrifuged, and the obtained product was freeze-dried for 24 hours, and then taken out to obtain a MMT-Gd-DTPA composite powder.
  2. 一种权利要求1所述的合成方法所合成的MMT-Gd-DTPA复合物。A MMT-Gd-DTPA composite synthesized by the synthesis method of claim 1.
  3. 根据权利要求2所述的MMT-Gd-DTPA复合物，其特征在于：所述MMT-Gd-DTPA复合物的直径为9～10μm。The MMT-Gd-DTPA composite according to claim 2, wherein the MMT-Gd-DTPA composite has a diameter of 9 to 10 μm.
  4. 根据权利要求2所述的MMT-Gd-DTPA复合物，其特征也在于：所述MMT-Gd-DTPA复合物的纵向弛豫率r 1值为5.1-5.563mM -1S -1。 The MMT-Gd-DTPA composite according to claim 2, wherein the MMT-Gd-DTPA complex has a longitudinal relaxation rate r 1 of 5.1-5.563 mM -1 S -1 .
  5. 一种权利要求2～4中任意一项所述MMT-Gd-DTPA复合物在消化道磁共振诊断中的应用，其特征在于：用于作为T1磁共振分子影像口服造影剂。Use of the MMT-Gd-DTPA complex according to any one of claims 2 to 4 for the diagnosis of digestive tract magnetic resonance, characterized in that it is used as an oral contrast agent for T1 magnetic resonance molecular imaging.
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