CN115317628B - Gadolinium-based magnetic resonance contrast agent synthesis method with high relaxation rate and long cycle time and application - Google Patents
Gadolinium-based magnetic resonance contrast agent synthesis method with high relaxation rate and long cycle time and application Download PDFInfo
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- CN115317628B CN115317628B CN202210252849.2A CN202210252849A CN115317628B CN 115317628 B CN115317628 B CN 115317628B CN 202210252849 A CN202210252849 A CN 202210252849A CN 115317628 B CN115317628 B CN 115317628B
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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
- A61K49/14—Peptides, e.g. proteins
- A61K49/143—Peptides, e.g. proteins the protein being an albumin, e.g. HSA, BSA, ovalbumin
Abstract
The invention discloses a gadolinium-based magnetic resonance contrast agent synthesis method with high relaxation rate and long cycle time and application thereof, belonging to the technical field of gadolinium-based magnetic resonance contrast agents, and comprising the following steps: s1: weighing gadolinium triflate or gadolinium chloride or gadolinium nitrate, dissolving in water, adding a pH9-12 Na2CO3/NaHCO3 buffer solution to precipitate, centrifuging, and re-suspending the precipitate with water to form a suspension, wherein S2: dissolving human serum albumin or bovine serum albumin in water, dropwise adding the water into S1 suspension in vibration, adding magnetons, heating at 25-45 ℃ for stirring reaction, centrifuging, and taking supernatant, and S3: the supernatant obtained in S2 was concentrated by ultrafiltration using a 100K ultrafiltration tube and filtered. Compared with the synthetic process of the gadolinium-based albumin compound contrast agent prepared by the simulated biomineralization method reported in the literature, the synthetic process is simpler and more reasonable, the relaxation rate of the contrast agent measured under the field intensity of 3T is up to 75mM-1S-1, which is 15 times that of Gd-DTPA, and the effective blood retention time is up to more than 150 minutes during living body imaging.
Description
Technical Field
The invention relates to the technical field of gadolinium-based magnetic resonance contrast agents, in particular to a synthesis method and application of a gadolinium-based magnetic resonance contrast agent with high relaxation rate and long cycle time.
Background
Depending on the purpose of use, magnetic resonance contrast agents can be divided into three categories: while the development of extracellular space contrast agent, blood pool contrast agent and hepatocyte specific contrast agent, but only 11 gadolinium-based contrast agents are approved by FDA for clinic, wherein Gd-DTPA, blood pool contrast agent gadolinium phosphorus three sodium and hepatocyte specific gadolinium sodium celecoxide are commonly used as extracellular space contrast agents, gd-DTPA can be distributed in the whole body tissue space within a few minutes as classical extracellular space contrast agents for inflammation and tumor imaging, but the process is non-specific and transient, often requires a large amount or repeated administration, and in addition, gd-DTPA can be simultaneously used for vascular imaging, but because the relaxation rate is too fast through renal metabolism and low, high scanning condition and injection dosage are required for obtaining good imaging effect, wherein the blood pool contrast agent can be divided into small molecular agents such as gadolinium phosphorus three sodium celecoxide and macromolecular agents, the gadolinium phosphorus three sodium is non-covalently combined in vivo and plasma albumin, so that the circulation time is prolonged, but the gadolinium phosphorus three sodium celecoxide is synthesized in a relatively complex manner, the relaxation rate is well compared with the contrast agent which is easy to prepare the contrast agent, the contrast agent has the advantages of improving the contrast ratio and the contrast ratio is well-established in clinical literature, the contrast agent has been easily and the contrast ratio is well-developed, and the contrast ratio is well-established in clinical literature.
Accordingly, one skilled in the art provides a synthesis method and application of gadolinium-based magnetic resonance contrast agent with high relaxation rate and long cycle time, so as to solve the problems set forth in the background art.
Disclosure of Invention
The invention aims to provide a synthesis method and application of a gadolinium-based magnetic resonance contrast agent with high relaxation rate and long cycle time, so as to solve the problems in the background technology.
In order to achieve the above purpose, the present invention provides the following technical solutions:
a gadolinium-based magnetic resonance contrast agent synthesis method with high relaxation rate and long cycle time and application thereof comprise the following steps:
s1: weighing gadolinium triflate or gadolinium chloride or gadolinium nitrate, dissolving in water, adding a pH9-12 Na2CO3/NaHCO3 buffer solution to precipitate, centrifuging, and re-suspending the precipitate with water to form a suspension;
s2: dissolving human serum albumin or bovine serum albumin in water, dropwise adding the water into S1 suspension in vibration, adding magnetons, heating at 25-45 ℃ for stirring reaction, and centrifuging to obtain supernatant;
s3: the supernatant obtained in S2 was concentrated by ultrafiltration using a 100K ultrafiltration tube and filtered.
As a further scheme of the invention: 18.5mg of gadolinium triflate or gadolinium chloride or gadolinium nitrate is adopted in the S1 and dissolved in 2ml of water, and the pH9-12 Na2CO3/NaHCO3 buffer solution added in the S1 is 2ml.
As still further aspects of the invention: the solution was centrifuged at 9000g for 3 minutes in S1, and the supernatant was discarded, while 4ml of water was taken for resuspension of the pellet and sufficiently blown down to form a suspension and transferred to a glass bottle.
As still further aspects of the invention: the albumin in S2 is human serum albumin or bovine serum albumin, the mass is 300m, BSA is dissolved in 6ml of water, and the stirring reaction time in S2 is 2 hours.
As still further aspects of the invention: the precipitate was removed in S2 by centrifugation at 9000g for 3 min.
As still further aspects of the invention: the ultrafiltration time in S3 was 12 minutes and the centrifugal force was 7200g.
As still further aspects of the invention: and (3) ultrafiltering the supernatant in the step (S3) to 3ml, and filtering with a 0.22um filter membrane to obtain BSA-Gd.
Compared with the prior art, the invention has the beneficial effects that:
compared with the synthetic process of the gadolinium-based albumin compound contrast agent prepared by the simulated biomineralization method reported in the literature, the synthetic process is simpler and more reasonable, the relaxation rate of the contrast agent measured under the field intensity of 3T is up to 75mM-1S-1, which is 15 times that of Gd-DTPA, and the effective blood retention time is up to more than 150 minutes during living body imaging.
Drawings
FIG. 1 is a graph of the hydrated particle size of BSA-Gd in accordance with the present invention;
FIG. 2 is a BSA-Gd electron microscope image of the present invention;
FIG. 3 is a graph of longitudinal relaxation rate of a commercial gadolinium-based contrast agent Gd-DTPA of the invention;
FIG. 4 is a graph of the longitudinal relaxation rate of BSA-Gd in accordance with the present invention;
FIG. 5 is a graph of incubation of BSA-Gd and Raw264.7 cells at different concentrations according to the invention;
FIG. 6 is a graph of liver and kidney function indicators according to the present invention;
FIG. 7 is a graph of staining data for tissue sections of mice in accordance with the present invention;
fig. 8 is a magnetic resonance imaging of a rat blood vessel in accordance with the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
As shown in fig. 1-4, example 1: a gadolinium-based magnetic resonance contrast agent synthesis method with high relaxation rate and long cycle time and application thereof comprise the following steps: s1: weighing gadolinium triflate or gadolinium chloride or gadolinium nitrate, dissolving in water, adding a pH9-12 Na2CO3/NaHCO3 buffer solution to precipitate, centrifuging, and re-suspending the precipitate with water to form a suspension, wherein S2: dissolving human serum albumin or bovine serum albumin in water, dropwise adding the water into S1 suspension in vibration, adding magneton, heating at 25-45 ℃ for stirring reaction, centrifuging to obtain supernatant, concentrating the supernatant obtained in S2 by ultrafiltration with a 100K ultrafiltration tube, filtering, dissolving 18.5mg gadolinium triflate or gadolinium chloride or gadolinium nitrate in 2ml of water in S1, adding pH9-12 Na2CO3/NaHCO3 buffer solution in S1 to 2ml, centrifuging for 3 min by 9000g in S1, discarding the supernatant, simultaneously taking 4ml of water to obtain heavy suspension precipitate, fully blowing to uniformly form suspension, transferring to a glass bottle, dissolving albumin in S2 into 6ml of water, stirring for 2 hours, centrifuging for 3 min by 9000g in S2, precipitating for 12 min in S3, centrifuging for 7200g, concentrating supernatant in S3 to 3ml, and ultrafiltering for 0.22 mu m to obtain the BSA-Gd filter membrane.
The particle size and appearance of BSA-Gd are characterized by a particle size meter and a transmission electron microscope, the particle size distribution is 1-10nm, a sample is imaged by a 3T Siemens magnetic resonance imaging system, a T1 value is obtained by exponential fitting, and the longitudinal relaxation rate is calculated.
As shown in fig. 5-7, example 2: a gadolinium-based magnetic resonance contrast agent synthesis method with high relaxation rate and long cycle time and application thereof comprise the following steps: s1: weighing gadolinium triflate or gadolinium chloride or gadolinium nitrate, dissolving in water, adding a pH9-12 Na2CO3/NaHCO3 buffer solution to precipitate, centrifuging, and re-suspending the precipitate with water to form a suspension, wherein S2: dissolving human serum albumin or bovine serum albumin in water, dropwise adding the water into S1 suspension in vibration, adding magneton, heating at 25-45 ℃ for stirring reaction, centrifuging to obtain supernatant, concentrating the supernatant obtained in S2 by ultrafiltration with a 100K ultrafiltration tube, filtering, dissolving 18.5mg gadolinium triflate or gadolinium chloride or gadolinium nitrate in 2ml of water in S1, adding pH9-12 Na2CO3/NaHCO3 buffer solution in S1 to 2ml, centrifuging for 3 min by 9000g in S1, discarding the supernatant, simultaneously taking 4ml of water to obtain heavy suspension precipitate, fully blowing to uniformly form suspension, transferring to a glass bottle, dissolving albumin in S2 into 6ml of water, stirring for 2 hours, centrifuging for 3 min by 9000g in S2, precipitating for 12 min in S3, centrifuging for 7200g, concentrating supernatant in S3 to 3ml, and ultrafiltering for 0.22 mu m to obtain the BSA-Gd filter membrane.
The CCK8 experiment is adopted to evaluate the proliferation influence of BSA-Gd and Raw264.7 cells with different concentrations after hatching for 24 hours, 250ug/ml Gd corresponds to the BSA concentration of about 100mg/ml, namely, tail intravenous injection concentration in a living experiment is adopted, the biochemical analysis is carried out on the blood of a mouse 24 hours after collecting the dose BSA-Gd and the equivalent PBS used for the tail intravenous injection experiment, compared with the PBS-injected mouse, the biochemical indexes of the reaction liver and kidney of the BSA-Gd-injected mouse are not obviously different, all the biochemical indexes are in a normal range, the tissue of the mouse is taken after taking the dose BSA-Gd and the equivalent PBS for 2 weeks for the tail intravenous injection experiment, the slice HE staining is carried out, and the slice result shows that the abnormal morphological change of the tissue of the BSA-Gd-injected mouse and the equivalent PBS is not seen, and the abnormal morphological manifestations of ischemia, edema, inflammation and the like are avoided.
As shown in fig. 8, example 3: a gadolinium-based magnetic resonance contrast agent synthesis method with high relaxation rate and long cycle time and application thereof comprise the following steps: s1: weighing gadolinium triflate or gadolinium chloride or gadolinium nitrate, dissolving in water, adding a pH9-12 Na2CO3/NaHCO3 buffer solution to precipitate, centrifuging, and re-suspending the precipitate with water to form a suspension, wherein S2: dissolving human serum albumin or bovine serum albumin in water, dropwise adding the water into S1 suspension in vibration, adding magneton, heating at 25-45 ℃ for stirring reaction, centrifuging to obtain supernatant, concentrating the supernatant obtained in S2 by ultrafiltration with a 100K ultrafiltration tube, filtering, dissolving 18.5mg gadolinium triflate or gadolinium chloride or gadolinium nitrate in 2ml of water in S1, adding pH9-12 Na2CO3/NaHCO3 buffer solution in S1 to 2ml, centrifuging for 3 min by 9000g in S1, discarding the supernatant, simultaneously taking 4ml of water to obtain heavy suspension precipitate, fully blowing to uniformly form suspension, transferring to a glass bottle, dissolving albumin in S2 into 6ml of water, stirring for 2 hours, centrifuging for 3 min by 9000g in S2, precipitating for 12 min in S3, centrifuging for 7200g, concentrating supernatant in S3 to 3ml, and ultrafiltering for 0.22 mu m to obtain the BSA-Gd filter membrane.
The arterial systems of heart, carotid artery, vertebral artery, etc. were visible within 30s after 3.5umol BSA-Gd injection, the heart developed more clearly and showed liver contours after 1 min, the jugular vein, subclavian vein, and axillary vein and finer vein branches all had obvious signals, the above vessels were still clearly discernable after imaging for 2 hours, and the liver signals were gradually enhanced, and the heart and jugular vein, subclavian vein contours were still discernable after 150 min.
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should make equivalent substitutions or modifications according to the technical scheme of the present invention and the inventive concept thereof, and should be covered by the scope of the present invention.
Claims (6)
1. A method for synthesizing a gadolinium-based magnetic resonance contrast agent with high relaxation rate and long cycle time, which is characterized by comprising the following steps:
s1: 18.5mg of trifluormet powder was weighed outDissolving gadolinium sulfonate or gadolinium chloride or gadolinium nitrate in 2ml water, adding Na with pH of 9-12 2 CO 3 /NaHCO 3 Precipitating with buffer solution 2ml, centrifuging, and re-suspending the precipitate with water to form suspension;
s2: dissolving human serum albumin or bovine serum albumin in water, dropwise adding the water-soluble bovine serum albumin or bovine serum albumin into the suspension formed in the step S1 in vibration, adding magnetons, heating at 25-45 ℃ for stirring reaction, and centrifuging to obtain supernatant;
s3: and (3) ultrafiltering, concentrating and filtering the supernatant obtained in the step (S2) by using a 100K ultrafiltration tube to obtain the gadolinium-based magnetic resonance contrast agent BSA-Gd.
2. A method of synthesizing a gadolinium-based magnetic resonance contrast agent having a high relaxation rate and a long cycle time according to claim 1, wherein:
the solution was centrifuged at 9000g for 3 minutes in S1, and the supernatant was discarded, while 4ml of water was taken for resuspension of the pellet and sufficiently blown down to form a suspension and transferred to a glass bottle.
3. A method of synthesizing a gadolinium-based magnetic resonance contrast agent having a high relaxation rate and a long cycle time according to claim 1, wherein:
the albumin in S2 is human serum albumin or bovine serum albumin, the mass is 300m, BSA is dissolved in 6ml of water, and the stirring reaction time in S2 is 2 hours.
4. A method of synthesizing a gadolinium-based magnetic resonance contrast agent having a high relaxation rate and a long cycle time according to claim 1, wherein:
the precipitate was removed in S2 by centrifugation at 9000g for 3 min.
5. A method of synthesizing a gadolinium-based magnetic resonance contrast agent having a high relaxation rate and a long cycle time according to claim 1, wherein:
the ultrafiltration time in S3 was 12 minutes and the centrifugal force was 7200g.
6. A method of synthesizing a gadolinium-based magnetic resonance contrast agent having a high relaxation rate and a long cycle time according to claim 1, wherein:
and (3) ultrafiltering the supernatant in the step (S3) to 3ml, and filtering with a 0.22um filter membrane to obtain BSA-Gd.
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| WO2016097963A1 (en) * | 2014-12-16 | 2016-06-23 | Fondazione Istituto Italiano Di Tecnologia | Albumin nanoparticles encapsulating gadolinium and method of synthesis thereof |
| CN107551279A (en) * | 2017-09-14 | 2018-01-09 | 苏州大学 | Extra small albumen composite nano-granule near infrared light fuel factor and multi-modality imaging function and its preparation method and application |
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