CN109939245B - Paramagnetic nano material, preparation method thereof and application of paramagnetic nano material as nuclear magnetic resonance contrast agent - Google Patents
Paramagnetic nano material, preparation method thereof and application of paramagnetic nano material as nuclear magnetic resonance contrast agent Download PDFInfo
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Abstract
The invention discloses a paramagnetic nano material, a preparation method thereof and application as a nuclear magnetic resonance contrast agent, wherein the material is Gd6(OH)2(FluPO3)3(tBuCO2)10(H2O)6The Gd6-PSMA-PEG paramagnetic nano particle which is used as a core and takes amphiphilic block high molecular polystyrene-co-polymaleic acid-co-polyethylene glycol as a shell has uniform particle size, good dispersibility and water solubility and excellent magnetic property, can be used as a nuclear magnetic resonance contrast agent, and particularly can be used as a nuclear magnetic resonance T1The contrast agents are weighted. Compared with the traditional micromolecular nuclear magnetic resonance contrast agent, the solid tumor imaging contrast agent has obvious imaging contrast effect on the solid tumor by utilizing the high permeability and retention effect of the solid tumor; by utilizing the cluster compound of multiple gadolinium centers, the imaging effect is better when the same gadolinium amount is used, in addition, the using amount of the contrast agent can be reduced when the same imaging effect is achieved, and the toxicity of heavy metal gadolinium to a human body is reduced.
Description
Technical Field
The invention belongs to the field of medical materials, and particularly relates to Gd6(OH)2(FluPO3)3(tBuCO2)10(H2O)6(Gd 6 for short) as a core (wherein FluPO3Is 2, 7-di-tert-butyl-9- (9-methyl) fluorenylphosphonic acid, tBuCO22, 2-methylpropanoic acid), paramagnetic nanometer material taking amphiphilic block macromolecule polystyrene-co-polymaleic acid-co-polyethylene glycol (PSMA-PEG for short) as shell, preparation method and application as nuclear magnetic resonance contrast agent.
Background
Multi-centerThe metal cluster compound is a complex with a plurality of metal ion centers formed by coordinating a monodentate or multidentate organic ligand containing nitrogen, oxygen and the like with metal ions, and the polymetallic cluster compound is widely applied to the fields of optics, catalysis, biomedicine and the like because a single molecule contains a plurality of metal ion centers. The rare earth element gadolinium (Gd) has 7 unpaired electrons in its atom 4f electron orbit, which is the largest number of unpaired electrons in the rare earth element, so that gadolinium has a very large magnetic moment, and has special applications in many fields, such as gadolinium-potassium-garnet in magnetic refrigeration technology can be used as a medium material in a magnetic bubble memory device, and when it is subjected to a magnetic field in the vertical direction, a magnetic field disappearance phenomenon is generated soon after the magnetic field is strengthened, and the gadolinium-potassium-garnet can be used for information storage. In addition, Gd, which is paramagnetic3+Ions, which may also act as a Magnetic Resonance Imaging (MRI) contrast agent, however, naked Gd3+The ion toxicity is large, the Gd is not suitable for being directly injected into living animals, and the Gd is generally clinically used at present3+The Gd is wrapped in organic ligand, so that the metabolism speed of the Gd element in vivo is remarkably improved, and the toxicity of the Gd is reduced, for example, the nuclear magnetic resonance contrast agent which is most commonly used clinically is a gadolinium meglitic acid derivative.
The MRI contrast agent can increase the contrast between different tissues, so that the contrast between the pathological tissue and the surrounding environment is prominent to more conveniently judge the image brightness, because of the contrast mechanism of the nuclear magnetic resonance imaging, the MRI contrast agent has irreplaceable effect in the soft tissue contrast imaging, and as a non-radiation imaging mode, the nuclear magnetic resonance imaging has very little damage to a tested person and is considered as a safer clinical imaging means, because some focuses are difficult to clearly express in the nuclear magnetic resonance, the clinical nuclear magnetic resonance imaging can achieve good contrast effect only by the assistance of the contrast agent. Statistically, about 45% of clinical mri cases require contrast agents to achieve lesion detection.
Currently, the relaxation rate of the gadolinium meglumine derivative which is commercially used clinically is low, but the dose requirement of the gadolinium meglumine derivative is large, and the gadolinium complex which is used for the MRI contrast agent at present only contains one gadolinium atom and contains a plurality of gadolinium atomsGadolinium cluster compounds have better contrast effect and are not developed in large quantity at present. According to the Solomon-Breenbergen-Morgan Theory, T1The purpose of the weighted nuclear magnetic resonance contrast agent is to enable paramagnetic ions in the contrast agent to interact with water molecules in a contrast environment, so that the longitudinal relaxation time of the water molecules can be obviously shortened, and a higher contrast signal value can be achieved. T is1Weighting the effective part of the MRI contrast agent, i.e. the ion with high paramagnetism (here with Gd)3+For example), when there is a plurality of Gd3+Focusing on one molecule, i.e. forming clusters, it is possible to achieve a synergistic effect. This synergy makes it possible for some of the water molecules in the contrast agent solution to be both directly receptive to Gd3+The internal water molecule affected by the coordination of the ion with Gd3+Ion-influenced external water molecules of two or more Gd3+The combined action of the two components can effectively improve the longitudinal relaxation rate of the contrast agent, thereby achieving better contrast effect. Furthermore, the overall inversion time of the contrast agent units dispersed in water in solution will also have a significant impact on the performance of the contrast agent. Therefore, the gadolinium cluster compound molecules are bound in the macromolecule layer, namely, the gadolinium cluster compound nanoparticles coated by the macromolecule are formed, and the contrast capability of the contrast agent can be improved remarkably. The contrast agent with better contrast performance can reduce the poison of heavy metal in the contrast agent to the body while achieving satisfactory effect clinically by using less amount of the contrast agent, and on the other hand, the novel contrast agent can achieve better contrast effect when using the same amount of the heavy metal, thereby providing more reliable nuclear magnetic resonance images for clinical diagnosis.
Disclosure of Invention
In view of the above, the object of the present invention is to provide a pharmaceutical composition containing Gd6(OH)2(FluPO3)3(tBuCO2)10(H2O)6(abbreviated as Gd6) as a core, wherein FluPO3Is 2, 7-di-tert-butyl-9- (9-methyl) fluorenylphosphonic acid, tBuCO2Is 2, 2-methylpropanoic acid, and is prepared from amphiphilic block high-molecular polystyrene-co-polymaThe paramagnetic nanometer material with the shell of the alginic acid-co-polyethylene glycol (PSMA-PEG for short) has the advantages of uniform particle size, good dispersibility and water solubility and excellent magnetic property.
Another object of the present invention is to provide a method for preparing the above paramagnetic nano-material.
It is a further object of the present invention to provide the use of the paramagnetic nanomaterial as a contrast agent for nuclear magnetic resonance as T-nmr1The contrast agents are weighted.
The above object of the present invention can be achieved by the following technical solutions:
in a first aspect of the invention, the paramagnetic nanomaterial is Gd6(OH)2(FluPO3)3(tBuCO2)10(H2O)6Paramagnetic nanoparticles with a core and an amphiphilic block polymer polystyrene-co-polymaleic acid-co-polyethylene glycol as a shell; wherein the content of the first and second substances,
the hydrated particle size of the paramagnetic nano particle is 110nm, and the particle size of the particle obtained after drying is 85-86 nm;
the Zeta surface potential of the paramagnetic nano particle is-32 mV;
the particle size of the inner layer of the nano particle with the heavy element gadolinium in a dry state is 45-46 nm;
longitudinal relaxation rate of 59.02mM of the paramagnetic nanoparticle-1s-1；
The Gd6(OH)2(FluPO3)3(tBuCO2)10(H2O)6In, FluPO3Is 2, 7-di-tert-butyl-9- (9-methyl) fluorenylphosphonic acid, tBuCO22, 2-methyl propionic acid, 6 gadolinium atoms exist in one Gd6 cluster compound molecule in the crystal structure.
In a second aspect of the present invention, the method for preparing a paramagnetic nanomaterial specifically comprises the following steps:
(1) synthesis of Gd 6: weighing FluPO3H2(2, 7-di-tert-butyl-9- (9-methyl) fluorenylphosphonic acid, 0.1mmol, 0.0374g), [ Gd2(tBuCO2)6(tBuCO2H)6](gadolinium dodeca (2, 2-dimethylpropionate, 0.1mmol, 0.1532g) andtBuCO2h (2, 2-dimethyl propionic acid, 0.4mmol, 0.0408g), is respectively dissolved in 8mL acetonitrile and 8mL dichloromethane under slow stirring, stirred at normal temperature for reaction for 24 hours, filtered, kept stand and volatilized at room temperature to obtain colorless and transparent large diamond crystal Gd6 cluster;
(2) preparation of PSMA-PEG: dissolving 4mg of polystyrene-co-polymaleic anhydride copolymer (molecular weight 1600, 2.5 mu mol) and 2.5mg of amino polyethylene glycol (molecular weight 500, 5 mu mol) in a molar ratio of 1:2 in 4mL of tetrahydrofuran, and carrying out reflux reaction at 60 ℃ for 24 hours to obtain PSMA-PEG;
(3) preparing Gd6-PSMA-PEG paramagnetic nanoparticles: 1.625mg of the above PSMA-PEG (0.625. mu. mol) and 0.4mg of Gd6 (0.124. mu. mol) were dissolved in 5mL of tetrahydrofuran in a molar ratio of 5: 1, stirring for 5min, then carrying out ultrasonic treatment for 30 min, then quickly adding 10mL of pure water under the ultrasonic condition, and continuing ultrasonic treatment for 30 min; and putting the obtained mixed solution into a dialysis bag with the molecular weight cutoff of 8000-14000 daltons for dialysis to obtain the aqueous solution of the Gd6-PSMA-PEG paramagnetic nanoparticles.
In a third aspect of the invention, the Gd6-PSMA-PEG paramagnetic nanoparticle is used as a nuclear magnetic resonance contrast agent.
Further, the Gd6-PSMA-PEG paramagnetic nano particle is used as nuclear magnetic resonance T1The contrast agents are weighted.
Further, the amount of the Gd6-PSMA-PEG paramagnetic nanoparticles used is 0.01mmol Gd/kg body weight.
Compared with the prior art, the invention has the beneficial effects that:
1. the Gd6 cluster compound is prepared through volatilization crystallization, and then Gd6 is wrapped by PSMA-PEG through hydrophilic-hydrophobic interaction force, so that the Gd6-PSMA-PEG paramagnetic nano particle with a core-shell structure is obtained, the obtained nano particle is uniform in particle size and good in dispersity, and compared with a traditional small-molecule nuclear magnetic resonance contrast agent, the nuclear magnetic resonance contrast agent of the nano particle can utilize the high permeability and retention effect of a solid tumor, so that a more remarkable imaging contrast effect on the solid tumor is realized.
2. According to the invention, the cluster compound of multiple gadolinium centers is utilized, so that an excellent nuclear magnetic resonance imaging contrast effect can be achieved, on one hand, the imaging effect is better when the same gadolinium amount is used, on the other hand, the use amount of a contrast agent can be reduced when the same imaging effect is achieved, and the toxicity of heavy metal gadolinium to a human body is reduced.
Drawings
FIG. 1 is Gd of the present invention6(OH)2(FluPO3)3(tBuCO2)10(H2O)6The crystal structure of (1). According to the crystal structure, 6 gadolinium atoms exist in one Gd6 cluster compound molecule and are all concentrated in one molecule, and the explanation of the Solomon-Bulobiong-Morgan theory shows that the longitudinal relaxation rate of the material can be remarkably increased, so that a better contrast effect is achieved.
FIG. 2 is the hydration kinetic diameter of Gd6-PSMA-PEG paramagnetic nanoparticles of the present invention. As can be seen by water and kinetic characterization, the water and kinetic diameter of the Gd6-PSMA-PEG paramagnetic nanoparticle is 110 nanometers, which indicates that the Gd6-PSMA-PEG paramagnetic nanoparticle has better passive targeting tumor characteristics, and the metabolism of the Gd6-PSMA-PEG paramagnetic nanoparticle in a body cannot be influenced due to overlarge particle size.
FIG. 3 is a Zeta potential characterization plot of Gd6-PSMA-PEG paramagnetic nanoparticles of the present invention. The Zeta surface potential characterization shows that the Zeta surface potential of the Gd6-PSMA-PEG paramagnetic nanoparticles is-32 mV, which shows that the charge repulsion force between the Gd6-PSMA-PEG paramagnetic nanoparticles is strong, the Gd6-PSMA-PEG paramagnetic nanoparticles are not easy to agglomerate, and the stability of the material is good.
Fig. 4 is a scanning electron microscope image of Gd6-PSMA-PEG paramagnetic nanoparticles of the present invention. The particle size of the Gd6-PSMA-PEG paramagnetic nanoparticles in a dry state is about 85.6 nanometers as seen by an electron scanning microscope, and meanwhile, the Gd6-PSMA-PEG paramagnetic nanoparticles have good complete spherical morphology and good uniformity, so that the uniformity of the effect of the material in application is ensured.
FIG. 5 is a transmission electron microscope image of Gd6-PSMA-PEG paramagnetic nanoparticles of the present invention. The Gd6-PSMA-PEG paramagnetic nanoparticle has a particle size of about 45.2 nanometers in the inner layer of the nanoparticle with a heavy element gadolinium in a dry state as can be seen by an electron transmission microscope, and meanwhile, the Gd6-PSMA-PEG paramagnetic nanoparticle has a good complete spherical shape and good uniformity, so that the uniformity of the effect of the material in application is ensured.
Fig. 6 is a transverse and longitudinal relaxivity characterization of Gd6-PSMA-PEG paramagnetic nanoparticles of the present invention. The longitudinal relaxation rate (59.02 mM) of Gd6-PSMA-PEG paramagnetic nanoparticles was found by relaxation rate characterization-1s-1) Is the longitudinal relaxation rate (4.49 mM) of the clinically used gadopentetate dimeglumine-1s-1) About 13 times of that of the Gd6-PSMA-PEG paramagnetic nanoparticles, so that the Gd6-PSMA-PEG paramagnetic nanoparticles have good T1-weighting the effect of the magnetic resonance imaging.
FIG. 7 shows the T of Gd6-PSMA-PEG paramagnetic nanoparticles and commercial gadopentetate glucamine at different gadolinium concentrations in the present invention1And weighting the nuclear magnetic resonance imaging effect map. Through this T1The brightness value of the nuclear magnetic resonance image of the Gd6-PSMA-PEG paramagnetic nanoparticle solution is obviously higher than that of commercial gadopentetate meglumine under the same test condition and the same gadolinium concentration by using a weighted nuclear magnetic resonance imaging effect diagram, and the Gd6-PSMA-PEG paramagnetic nanoparticle contrast effect is proved to be excellent in the solution level.
FIG. 8 is an animal T of Gd6-PSMA-PEG paramagnetic nanoparticles of the present invention1And weighting the nuclear magnetic resonance imaging effect map. T by this animal1The effect graph of the weighted nuclear magnetic resonance imaging can show that the Gd6-PSMA-PEG paramagnetic nano particle has good nuclear magnetic contrast effect on the living body level.
FIG. 9 is an animal T of Gd6-PSMA-PEG paramagnetic nanoparticles of the present invention1Weighting a statistical table of brightness values at different time points of a tumor in a magnetic resonance imaging image. The Gd6-PSMA-PEG paramagnetic nano-particle has good effect on the magnetic resonance imaging contrast of animal tumors.
Detailed Description
The invention will now be further illustrated by reference to the following examples:
examples
The Gd6-PSMA-PEG paramagnetic nano particle is prepared by the following specific steps:
(1) weighing FluPO3H2(0.1mmol，0.0374g)，[Gd2(tBuCO2)6(tBuCO2H)6](0.1mmol, 0.1532g) andtBuCO2h (0.4mmol, 0.0408g) was dissolved in 8mL of acetonitrile and 8mL of dichloromethane with slow stirring, reacted for 24 hours with stirring at room temperature, filtered, allowed to stand, and volatilized at room temperature, and after about four days, colorless transparent large-sized diamond crystals Gd6 grew out.
(2) Taking 4mg of polystyrene-co-polymaleic anhydride copolymer (molecular weight 1600) and 2.5mg of aminopolyethylene glycol (molecular weight 500), wherein the molar ratio of the polystyrene-co-polymaleic anhydride copolymer to the aminopolyethylene glycol is 1:2, dissolving in 4mL tetrahydrofuran, and refluxing and reacting at 60 ℃ for 24 hours to obtain polymer PSMA-PEG.
(3) Dissolving 2.25mg PSMA-PEG and 0.4mg Gd6 in 5mL tetrahydrofuran, stirring for 5min, then carrying out ultrasonic treatment for 30 min, then rapidly adding 10mL pure water under the ultrasonic condition, and continuing the ultrasonic treatment for 30 min. And finally, putting the mixed solution into a dialysis bag with the molecular weight cutoff of 8000-14000 daltons, and dialyzing to obtain the aqueous solution of the Gd6-PSMA-PEG paramagnetic nanoparticles.
Referring to fig. 1, 2, 4 and 5, fig. 1 is a crystal structure of a colorless transparent bulk rhombohedral crystal Gd6 in step (1), 6 gadolinium atoms exist in one Gd6 cluster compound molecule and are all concentrated in one molecule, and through the explanation of solomon-bur-morgan theory, it can be found that the longitudinal relaxation rate of the material can be remarkably increased, so as to achieve a better contrast effect; as can be seen in fig. 2, the hydration kinetic diameter of Gd6-PSMA-PEG paramagnetic nanoparticle is 110 nm; fig. 4 is a scanning electron microscope image of Gd6-PSMA-PEG paramagnetic nanoparticles of the present invention. The particle size of the Gd6-PSMA-PEG paramagnetic nano particle in a dry state is about 85.6 nanometers as seen by an electron scanning microscope, and meanwhile, the Gd6-PSMA-PEG paramagnetic nano particle has good complete spherical morphology and good uniformity, so that the uniformity of the effect of the material in application is ensured; FIG. 5 is a transmission electron microscope image of Gd6-PSMA-PEG paramagnetic nanoparticles of the present invention. The Gd6-PSMA-PEG paramagnetic nanoparticle has a particle size of about 45.2 nanometers in the inner layer of the nanoparticle with a heavy element gadolinium in a dry state as can be seen by an electron transmission microscope, and meanwhile, the Gd6-PSMA-PEG paramagnetic nanoparticle has a good complete spherical shape and good uniformity, so that the uniformity of the effect of the material in application is ensured.
Examples of effects
Preparing Gd6-PSMA-PEG solution with the concentration of 0.2, 0.1, 0.05, 0.025 and 0mM gadolinium, characterizing the longitudinal relaxation rate and the nuclear magnetic resonance imaging of the solution under the magnetic field strength of 0.5T, preparing a commercial contrast agent gadolinium meglumine with the same concentration of Gd, and testing the longitudinal relaxation rate and the nuclear magnetic resonance imaging of the solution under the same condition; wherein, the recommended dosage of the clinical commercial nuclear magnetic resonance contrast agent gadolinium meglumine is 0.1mmol Gd/kg body weight, and the dosage of the Gd6-PSMA-PEG paramagnetic nano particle is 0.01mmol Gd/kg body weight.
Referring to FIG. 6, the longitudinal relaxation rate (r) of Gd6-PSMA-PEG paramagnetic nanoparticles was analyzed1) And transverse relaxation rate (r)2) By testing the relaxation time of Gd6-PSMA-PEG paramagnetic nanoparticle water solution with different gadolinium element concentrations under the magnetic field strength of 0.5T, the longitudinal relaxation rate of Gd6-PSMA-PEG paramagnetic nanoparticle can be measured to be 59.02s-1mM-1Transverse relaxation rate of 66.63s-1mM-1Under the same condition, the transverse relaxation rate of the clinically commercial nuclear magnetic resonance contrast agent gadopentetate meglumine injection under the same condition is 4.49s-1mM-1And a transverse relaxation rate of 5.06s-1mM-1. The higher relaxivity means that the Gd6-PSMA-PEG paramagnetic nanoparticles are more effective in shortening T1 and T1 of protons in tissues after entering the body than the clinically commercial gadopentetate dextran injection2The relaxation time can enhance the definition and contrast of the image, and provides better reliability for clinical diagnosis.
Referring to FIG. 7, the T of Gd6-PSMA-PEG paramagnetic nanoparticle solution at a field strength of 0.5T1Weighted magnetic resonance imaging with gadopentetate meglumine injection at equivalent Gd concentrationCompared under the same condition, the Gd6-PSMA-PEG paramagnetic nanoparticle solution has an image with brighter signal under the condition of the same gadolinium concentration as can be seen from a nuclear magnetic resonance image. The image shows that the Gd6-PSMA-PEG paramagnetic nano particle has better imaging effect when the same gadolinium content is used, is favorable for remarkably reducing the use amount of a contrast agent clinically and reduces the toxicity of heavy metal gadolinium to a human body.
Referring to fig. 8 and 9, mice bearing 4T1 transplantable tumors were injected caudal vein with Gd6-PSMA-PEG NPs material (in an amount of 1/10 for gadolinium meglumine gadolinium commercially available gadopentetate). The data map obtained by processing Matlab software with air and water as internal references, the processed image is shown in FIG. 8, the brightness of air is adjusted to 20, and the average brightness value of water is adjusted to 150. The images show that under the condition of using 1/10 dosage of gadopentetate dimeglumine gadolinium, Gd6-PSMA-PEG NPs can achieve good MRI contrast effect. By analyzing the intensity values at their tumors, fig. 9 was obtained, which can be seen to be maximal at 90min in the tumor, and to gradually decay thereafter, and to completely drain the tumor at about 300 min.
Claims (5)
1. Paramagnetic nano-material characterized by being Gd6(OH)2(FluPO3)3(tBuCO2)10(H2O)6Gd6-PSMA-PEG paramagnetic nano particle taking core and amphiphilic block high molecular polystyrene-co-polymaleic acid-co-polyethylene glycol as shell, the hydrated particle size of the Gd6-PSMA-PEG paramagnetic nano particle is 110nm, the particle size after drying is 85-86 nm, the Zeta surface potential is-32 mV, and the longitudinal relaxation rate is 59.02mM-1s-1The particle size of the inner layer of the nano particle with the heavy element gadolinium in a dry state is 45-46 nm; wherein the content of the first and second substances,
the Gd6(OH)2(FluPO3)3(tBuCO2)10(H2O)6In, FluPO3Is 2, 7-di-tert-butyl-9- (9-methyl) fluorenylphosphonate ion, tBuCO2Is 2, 2-methyl propionate ion, and 6 gadolinium atoms exist in one Gd6 cluster compound molecule in the crystal structure.
2. The method for preparing a paramagnetic nanomaterial according to claim 1, comprising the steps of:
(1) synthesis of Gd 6: 0.0374g FluPO was weighed3H2Namely 2, 7-di-tert-butyl-9- (9-methyl) fluorenylphosphonic acid, 0.1532g of [ Gd ]2(tBuCO2)6(tBuCO2H)6]Namely, didallagadolinum dodecapropionate (2, 2-dimethylpropionate) and 0.0408gtBuCO2H, namely 2, 2-dimethyl propionic acid is respectively dissolved in 8mL of acetonitrile and 8mL of dichloromethane under slow stirring, the mixture is stirred at normal temperature for reaction for 24 hours, then filtered and kept stand, and the mixture is volatilized at room temperature to obtain a colorless and transparent large diamond crystal Gd6 cluster compound;
(2) preparation of PSMA-PEG: dissolving 4mg of polystyrene-co-polymaleic anhydride copolymer with the molecular weight of 1600 and 2.5mg of amino polyethylene glycol with the molecular weight of 500 in a molar ratio of 1:2 in 4mL of tetrahydrofuran, and performing reflux reaction at 60 ℃ for 24 hours to obtain PSMA-PEG;
(3) preparing Gd6-PSMA-PEG paramagnetic nanoparticles: 1.625mg of the above PSMA-PEG and 0.4mg of Gd6 were dissolved in 5mL of tetrahydrofuran in a molar ratio of 5: 1, stirring for 5min, then performing ultrasonic treatment for 30 min, rapidly adding 10mL of pure water under the ultrasonic condition, and continuing ultrasonic treatment for 30 min; putting the obtained mixed solution into a dialysis bag with the molecular weight cutoff of 8000-14000 daltons for dialysis to obtain the aqueous solution of Gd6-PSMA-PEG paramagnetic nanoparticles.
3. Use of the Gd6-PSMA-PEG paramagnetic nanoparticle of claim 1 for the preparation of a nuclear magnetic resonance contrast agent.
4. Use according to claim 3, wherein the Gd6-PSMA-PEG paramagnetic nanoparticle is used as a nuclear magnetic resonance T1The contrast agents are weighted.
5. The use according to claim 3 or 4, wherein the Gd6-PSMA-PEG paramagnetic nanoparticle is used in an amount of 0.01 mmole Gd/kg body weight.
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