CN102167813A - Fluorescent tracing nanometer magnetic resonance imaging contrast agent - Google Patents

Fluorescent tracing nanometer magnetic resonance imaging contrast agent Download PDF

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CN102167813A
CN102167813A CN 201110024488 CN201110024488A CN102167813A CN 102167813 A CN102167813 A CN 102167813A CN 201110024488 CN201110024488 CN 201110024488 CN 201110024488 A CN201110024488 A CN 201110024488A CN 102167813 A CN102167813 A CN 102167813A
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peg
dtpaa
qdtpagd
sherwood oil
compound
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CN102167813B (en
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杨正银
汪宝堆
李勇
刘增臣
李天荣
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Lanzhou University
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Lanzhou University
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Abstract

The invention discloses a compound and a preparation method and application thereof. The expression of the compound is F3O4-PEG-QDTPAGd and the structure of the compound is shown in the specification. The compound can be used in the magnetic resonance imaging detection, the fluorescent tracing of fluorescer, the nanometer magnetic resonance imaging and the contrast agent with liver targeting.

Description

A kind of fluorescent tracing nano magnetic resonance imaging contrast agent
Technical field
The present invention relates to a kind of compound that can be used as contrast medium, particularly a kind ofly be used for that nuclear magnetic resonance detects, have the fluorescent tracing nano magnetic resonance imaging contrast agent of fluorescent agent.
Background technology
Nuclear magnetic resonance (MRI) technology is to tumour, and the early diagnosis of malignant changes such as cardiovascular and cerebrovascular diseases is very effective, so be widely used in medical science and high-new scientific research field.Because the instrumental resolution that the MRI technology is used is always limited, so need to be used contrast medium in many cases to increase image definition.But the development of contrast medium can not be satisfied the required of clinical diagnosis far away.Still micro-clinically now at the horse root that uses, a kind of many carboxyls polyamines base Gd (III) title complex, or the German product of the eighties in last century.The micro-no target of existing horse root, its imaging effect still remains to be improved under some use occasion.Seek that new than existing contrast medium the target MRI compound of better effect to be arranged be the focus of association area worker research.
Summary of the invention
The invention provides the preparation method of a kind of compound and this compound, this compound can be used as the contrast medium that nuclear magnetic resonance detects, and this contrast medium has a better effect than existing horse root is micro-, and have target fluorescent tracing group, Gd (III) title complex is by δ-amino polyoxamide methyl-3, and the 4-dihydroxy-benzene is bonded on the nano ferriferrous oxide carrier.
Compound of the present invention, its expression formula are F 3O 4-PEG-QDTPAGd, structure is as shown in the formula showing:
Figure BSA00000424098400011
Formula 1
PEG is δ-amino polyoxamide methyl-3 in the expression formula, and 4-dihydroxy-benzene, QDTPAGd are that diethylenetriamine-acetyl (8 '-quinoline) amine-ethanoyl-nitrilotriacetic closes gadolinium (III).F is existing fluorophor in the structural formula, and for example fluorophor F can be ready-made flavones fluorophor, and preferred F is a 8-quinolylamine fluorophor.
The preparation method of the preferred compound of the present invention is: with ferriferrous oxide nano-particle and δ-amino polyoxamide methyl-3,4-dihydroxy-benzene (PEG) is a raw material, earlier with 60mg δ-amino polyoxamide methyl-3, the 4-dihydroxy-benzene is scattered in the chloroform, the 150mg ferriferrous oxide nano-particle is dissolved in the solution of chloroform, fully stirs the back under the mixture room temperature and makes product Fe by adding sherwood oil at adorned nanoparticle 3O 4-PEG-NH 2Be precipitated out, centrifugation goes out product, with a spot of trichloromethane dissolving, adds sherwood oil more therein and produces precipitation and recentrifuge separation, carries out purifying three times so repeatedly, will be dispersed among the DMF by the decorated nanometer particle then, uses in order to next step reaction; Weighing 239mg diethylene triamine pentacetic acid (DTPA) dianhydride (DTPAA), it is dissolved in dry DMF, stir moments later, add the 0.8mL anhydrous triethylamine, DTPAA is dissolved in DMF fully, then gets the 8-quinolylamine that 69mg is dissolved in the 10mL dry DMF, in 2 hours, it is slowly joined in the DTPAA solution again, after fully stirring under the room temperature, the mixed solution rotary evaporation is removed unnecessary solvent, obtain saturated 8-AQ-DTPAA DMF solution; Get DMF liquid and the Fe of the saturated 8-AQ-DTPAA of equimolar amount 3O 4-PEG-NH 2Mix and stir diel, add sherwood oil more therein and make by the decorated nanometer particle precipitation, centrifugation goes out post precipitation again with a spot of trichloromethane dissolving, continues to add sherwood oil and produces precipitation, centrifugation so obtains by decorated nanometer particle Fe behind the triplicate purifying 3O 4-PEG-DTPA-8-AQ is dispersed in the water it stand-by; Get equimolar Gadolinium trinitrate and join the Fe that has prepared 3O 4In-PEG-DTPA-8-AQ the dispersion liquid, the stirring at room diel behind the filtering reacting liquid, adds sherwood oil more therein and makes F 3O 4-PEG-QDTPAGd is precipitated out, and dissolves with a spot of trichloromethane through the centrifugation after product, continues to add sherwood oil and makes F 3O 4-PEG-QDTPAGd is precipitated out, and centrifugation again is so repeatedly after the purification process three times, with last products therefrom nanometer F 3O 4-PEG-QDTPAGd is dispersed in the water.
This compound of the present invention can be used as the fluorescent tracing nano magnetic resonance imaging contrast agent and uses.Show that according to relevant test compound of the present invention has the liver target, it is micro-that its longitudinal relaxation efficient is better than existing MRI contrast medium horse root, and compound of the present invention also has the advantage that fluorescence shows simultaneously.
Description of drawings
Accompanying drawing 1 is δ-amino polyoxamide methyl-3, the IR spectrogram of 4-dihydroxy-benzene.
Accompanying drawing 2 is Fe 3O 4-PEG-NH 2The IR spectrogram.
Accompanying drawing 3 is the IR spectrogram of 8-AQ-DTPAA.
Accompanying drawing 4 is Fe 3O 4The IR spectrogram of-PEG-DTPA-8-AQ.
Accompanying drawing 5 is the UV-vis spectrogram of 8-AQ-DTPAA.
Accompanying drawing 6 is Fe 3O 4The UV-vis spectrogram of-PEG-DTPA-8-AQ.
Accompanying drawing 7 is .Fe 3O 4-PEG-DTPA-8-AQ (peak 1) and Fe 3O 4-PEG-NH 2The fluorescence spectrum figure at (peak 2).
Accompanying drawing 8 is Fe 3O 4The transmission electron microscope picture of-PEG-QDTPAGd.
Accompanying drawing 9 is the mouse liver MRI figure (contrast) that does not use contrast medium.
Accompanying drawing 10 is the mouse liver MRI figure of contrast medium for adopting compound of the present invention.
Embodiment
Below provide the preparation and the corresponding test situation of compound of the present invention.
One, the preparation of compound and sign
1. buy or prepare a certain amount of ferriferrous oxide nano-particle raw material.
2. buy or preparation δ-amino polyoxamide methyl-3 the 4-dihydroxy-benzene.
3.PEG the magnetic nano-particle of modifying preparation
Weighing 60mg δ-amino polyoxamide methyl-3, the 4-dihydroxy-benzene is scattered in it in chloroform, and the solution that then ferriferrous oxide nano-particle is dissolved in chloroform adds above-mentioned reaction system.Stir diel under the mixture room temperature, then, adorned nanoparticle is separated out precipitation by adding sherwood oil, and centrifugation gets product (Fe 3O 4-PEG-NH 2), with a spot of trichloromethane dissolving, continue to add sherwood oil and separate out precipitation again, centrifugation, it is inferior to give a baby a bath on the third day after its birth so repeatedly, will be dispersed among the DMF by the decorated nanometer particle at last, uses in order to next step reaction, and synthetic route is as follows:
Figure BSA00000424098400031
Formula 2
4. the preparation that has the nanoparticle of fluorescence
Weighing 239mg diethylene triamine pentacetic acid (DTPA) dianhydride (DTPAA), it is dissolved in dry DMF, stir moments later, add the 0.8mL anhydrous triethylamine, DTPAA is dissolved in DMF fully, then get the 8-quinolylamine (8-AQ) that 69mg is dissolved in the 10mL dry DMF, in 2h, slowly join in the DTPAA solution by constant pressure funnel, stir under the room temperature 1 round the clock after, with the mixed solution rotary evaporation, obtain small amount of liquid, its note is 8-AQ-DTPAA.The take a morsel DMF liquid of 8-AQ-DTPAA is with Fe 3O 4-PEG-NH 2Mix and stir diel.Last adorned nanoparticle is separated out post precipitation by adding sherwood oil, centrifugation, and product dissolves with a spot of trichloromethane, and continue to add sherwood oil and separate out precipitation again, centrifugation, repetitive scrubbing is three times like this, then will be by decorated nanometer particle Fe 3O 4-PEG-DTPA-8-AQ is dispersed in the water stand-by, and synthetic route is as follows:
Figure BSA00000424098400041
Formula 3
5. the preparation of targeted contrast agent
With Gadolinium trinitrate add prepared by decorated nanometer Fe 3O 4In-PEG-DTPA-8-AQ the dispersion liquid, the stirring at room diel.After using the cotton filtering reacting liquid then, and then adorned nanoparticle is separated out precipitation by adding sherwood oil, back centrifugation, product dissolves with a spot of trichloromethane, continue to add sherwood oil and separate out precipitation again, centrifugation, repetitive scrubbing is three times like this, at last adorned nanoparticle is dispersed in the water, its expression formula is F 3O 4-PEG-QDTPAGd, structure is suc as formula showing that as 1 wherein: F is a 8-quinolylamine fluorophor; F 3O 4Be nano ferriferrous oxide; PEG is δ-amino polyoxamide methyl-3, the 4-dihydroxy-benzene; QDTPAGd is that diethylenetriamine-acetyl (8 '-quinoline) amine-ethanoyl-nitrilotriacetic closes gadolinium (III).
Two, sample is formed sign:
1. sample appearance: brown oily solid is dispersed in the water and did not precipitate in 6 months.
2.Fe 3O 4Each integral part feature of-PEG-QDTPAGd
Figure BSA00000424098400051
3. compound characterizes
Accompanying drawing 1 is δ-amino polyoxamide methyl-3, the IR spectrum of 4-dihydroxy-benzene, 3435cm -1Be the v (N-H) of amino and the v (O-H) of phenolic hydroxyl group, 1640cm -1Be the skeletal vibration peak of phenyl ring, these peaks are δ-amino polyoxamide methyl-3, the feature IR absorption peak of 4-dihydroxy-benzene.
Accompanying drawing 2 is Fe 3O 4-PEG-NH 2IR spectrum, 3433cm -1Be amino v (N-H), 1636cm -1Be the skeletal vibration peak of phenyl ring, 601cm -1Be that pyrocatechol closes Fe 3O 4V (Fe-O), prove δ-amino polyoxamide methyl-3, the 4-dihydroxy-benzene has been bonded in nanometer Fe 3O 4On.
Accompanying drawing 3 is the IR spectrogram of 8-AQ-DTPAA, 3425cm -1Be amino v (N-H), 1725cm -1Be the v (C=O) of DTPAA, 1634cm -1It is quinoline ring skeletal vibration peak.This shows that the 8-quinolylamine is connected on the DTPAA.
Accompanying drawing 4 is Fe 3O 4The IR spectrogram of-PEG-DTPA-8-AQ, 3424cm -1Be amino v (N-H), 1731cm -1Be the v (C=O) of DTPAA, 1634cm -1Be the skeletal vibration peak of quinoline ring and phenyl ring, 616cm -1Be that pyrocatechol closes Fe 3O 4V (Fe-O), above characteristic peak is consistent with precursor I R characteristic peak, proves that made sample is correct.
Accompanying drawing 5,6 is respectively 8-AQ-DTPAA and Fe 3O 4The UV-vis spectrogram of-PEG-DTPA-8-AQ, the UV maximum absorption band of 8-AQ-DTPAA is at 280nm and 350nm, Fe 3O 4The UV maximum absorption band of-PEG-DTPA-8-AQ has proved further that at 280nm and 300nm the conclusion of IR (accompanying drawing 2,3) is correct.
Accompanying drawing 7 is Fe 3O 4The fluorescence spectrum figure of-PEG-DTPA-8-AQ, 358nm place cutting edge of a knife or a sword 1 is Fe among the figure 3O 4The fluorescence emission peak of-PEG-DTPA-8-AQ (connecting F), the peak 2 at 450nm place is Fe 3O 4-PEG-NH 2The fluorescence emission peak of (not connecting F), the former fluorescent emission intensity is stronger about 60 times than the latter, and the latter does not have fluorescence substantially.Fluorescent emission intensity significantly strengthens after proving compound introducing F of the present invention.
Accompanying drawing 8 is Fe 3O 4The transmission electron microscope picture of-PEG-QDTPAGd, target product remains finely dispersed nanoparticle as seen from the figure, and the about 10nm of particle diameter, icp analysis show that the mol ratio of Fe in the product: Gd is 1.82: 1.
Three, mouse living imaging contrast experiment
Accompanying drawing 9 is schemed (being control group) for the mouse liver MRI with contrast medium not.Accompanying drawing 10 is the mouse liver MRI figure of contrast medium for adopting compound of the present invention, and wherein the same position of same reference numeral is used the MRI figure of the micro-medicine of existing horse root and used compound F 17-hydroxy-corticosterone of the present invention among Fig. 9 and 10 3O 4-PEG-QDTPAGd MRI figure.Accompanying drawing 9 and 10 imaging picture all are to finish on MiniMR-60 animal magnetic resonance imager, and the imaging sequence that makes is the multilayer spin-echo sequence.Compound of the present invention adopts and is tried the mouse subcutaneous administration in the test, and the result shows and uses the mouse of being tried of compound of the present invention only to look like to have clear improvement at the liver station diagram.Comparison diagram 9,10 uses F as can be known 3O 4The mouse liver image definition is obviously improved behind-the PEG-QDTPAGd, and this proves that compound of the present invention is the MRI contrast medium that liver is had target, and its effect to be better than existing MRI contrast medium horse root micro-, this point can be by the R of The compounds of this invention 1Proved (seeing the following form) for micro-high 7.69 times than horse root.
The sample title T 1(ms) C(mmol/L) R 1(Mm -1s -1)
Horse root micro-(control group) 104.11 1.10 8.14
Fe 3O 4-PEG-QDTPAGd 30.2 0.531 62.58
H 2O 3771.84
It is the Fe of 0.531mmol/L that last tabular has gone out concentration 3O 4Micro-and the neat solvent (H of the horse root of-PEG-QDTPAGd and 1.10mmol/L 2O) longitudinal relaxation time (T 1) measured value, according to T 1Calculate Fe 3O 4The relaxation efficient R of-PEG-QDTPAGd 1=62.58Mm -1s -1, the R that the horse root is micro- 1=8.14Mm -1s -1As seen the R of The compounds of this invention 1Micro-higher 7.69 times than horse root, it is micro-to prove that its imaging effect is better than existing MRI contrast medium horse root.

Claims (4)

1. compound, its expression formula is F 3O 4-PEG-QDTPAGd, structure is as shown in the formula showing:
Figure FSA00000424098300011
PEG is amino polyoxamide methyl-3 in the expression formula, and 4-dihydroxy-benzene, QDTPAGd are that diethylenetriamine-acetyl (8 '-quinoline) amine-ethanoyl-nitrilotriacetic closes gadolinium (III).F is a fluorophor in the structural formula.
2. the described compound of claim 1 is characterized in that F is a 8-quinolylamine fluorophor.
3. the preparation method of the compound of claim 2, it is characterized in that: with ferriferrous oxide nano-particle and δ-amino polyoxamide methyl-3, the 4-dihydroxy-benzene is a raw material, earlier with 60mg δ-amino polyoxamide methyl-3, the 4-dihydroxy-benzene is scattered in the chloroform, the 150mg ferriferrous oxide nano-particle is dissolved in the solution of chloroform, fully stirs the back under the mixture room temperature and makes product Fe by adding sherwood oil at adorned nanoparticle 3O 4-PEG-NH 2Be precipitated out, centrifugation goes out product, with a spot of trichloromethane dissolving, adds sherwood oil more therein and produces precipitation and recentrifuge separation, carries out purifying three times so repeatedly, will be dispersed among the DMF by the decorated nanometer particle then, uses in order to next step reaction; Weighing 239mg diethylene triamine pentacetic acid (DTPA) dianhydride (DTPAA), it is dissolved in dry DMF, stir moments later, add the 0.8mL anhydrous triethylamine, DTPAA is dissolved in DMF fully, then gets the 8-quinolylamine that 69mg is dissolved in the 10mL dry DMF, in 2 hours, it is slowly joined in the DTPAA solution again, after fully stirring under the room temperature, the mixed solution rotary evaporation is removed unnecessary solvent, obtain the DMF solution of the 8-AQ-DTPAA of saturated solution; Get DMF liquid and the Fe of the saturated 8-AQ-DTPAA of equimolar amount 3O 4-PEG-NH 2Mix and stir diel, add sherwood oil more therein and make by the decorated nanometer particle precipitation, centrifugation goes out post precipitation again with a spot of trichloromethane dissolving, continue to add sherwood oil and produce precipitation, centrifugation, behind the triplicate purifying like this, will be by decorated nanometer particle Fe 3O 4-PEG-DTPA-8-AQ is dispersed in the water stand-by; Equimolar Gadolinium trinitrate is joined the Fe that has prepared 3O 4-PEG-DTPA-8-AQ is by in the decorated nanometer particle dispersion, and the stirring at room diel behind the filtering reacting liquid, adds sherwood oil more therein and makes F 3O 4-PEG-QDTPAGd is precipitated out, and dissolves with a spot of trichloromethane through the centrifugation after product, continues to add sherwood oil and makes F 3O 4-PEG-QDTPAGd is precipitated out, and centrifugation again is so repeatedly after the purification process three times, at last with adorned nanoparticle F 3O 4-PEG-QDTPAGd is dispersed in the water.
4. claim 1 or the 2 described compounds application that is to prepare the fluorescent tracing nano magnetic resonance imaging contrast agent.
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CN102516822A (en) * 2011-11-04 2012-06-27 昆明理工大学 Surface-functionalized Fe3O4 nanoparticles as well as preparation method and application thereof
CN103980297A (en) * 2014-04-15 2014-08-13 大连大学 Multi-functional imaging probe for mercury ion detection
CN107007843A (en) * 2017-03-03 2017-08-04 广州军区广州总医院 PET/MRI bimodal developer SPIO NOTA68Ga and preparation method thereof and purposes
CN109568666A (en) * 2018-12-10 2019-04-05 济宁医学院 Gd:Fe3O4Reparation and MRI angiographic method of the@RA composite Nano molecule for neurologic defict

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Publication number Priority date Publication date Assignee Title
CN102516822A (en) * 2011-11-04 2012-06-27 昆明理工大学 Surface-functionalized Fe3O4 nanoparticles as well as preparation method and application thereof
CN102516822B (en) * 2011-11-04 2014-08-06 昆明理工大学 Surface-functionalized Fe3O4 nanoparticles as well as preparation method and application thereof
CN103980297A (en) * 2014-04-15 2014-08-13 大连大学 Multi-functional imaging probe for mercury ion detection
CN107007843A (en) * 2017-03-03 2017-08-04 广州军区广州总医院 PET/MRI bimodal developer SPIO NOTA68Ga and preparation method thereof and purposes
CN109568666A (en) * 2018-12-10 2019-04-05 济宁医学院 Gd:Fe3O4Reparation and MRI angiographic method of the@RA composite Nano molecule for neurologic defict
CN109568666B (en) * 2018-12-10 2021-02-02 锦州医科大学附属第一医院 Gd:Fe3O4Method for repairing spinal nerve injury by using @ RA composite nano molecule and MRI (magnetic resonance imaging) contrast method

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