RARE EARTH-BASED NANOPARTICLE MAGNETIC RESONANCE CONTRAST AGENT AND PREPARATION METHOD THEREOF

Abstract

A rare earth-based nanoparticle magnetic resonance contrast agent and a preparation method thereof are provided. The rare earth-based nanoparticle magnetic resonance contrast agent is rare earth-based inorganic nanoparticles having the surfaces coated with hydrophilic ligands. The rare earth-based nanoparticles are first obtained by a high-temperature oil phase reaction, and then the surfaces thereof are coated with hydrophilic molecules to obtain the rare earth-based nanoparticle magnetic resonance contrast agent. Compared with the existing clinical contrast agent, the magnetic resonance contrast agent of the present invention has a greatly improved relaxivity, a good imaging effect, a low required injection dose, and long in vivo residence time. In addition, the rigid structure of the inorganic nanoparticles can effectively reduce the leakage possibility of gadolinium ions.

Claims

1. A rare earth-based nanoparticle magnetic resonance contrast agent, characterized in being rare earth-based inorganic nanoparticles coated with hydrophilic ligands.

2. The rare earth-based nanoparticle magnetic resonance contrast agent as described in claim 1, characterized in that the composition of the rare earth-based nanoparticles is M.sub.aREO.sub.bX.sub.c, wherein RE represents a rare earth element, M represents an alkali or alkaline earth metal, X represents a fluorine or chlorine, 0a1, 0b1.5, and 0c4; or the rare earth-based inorganic nanoparticles are an inorganic compound doped by using the M.sub.aREO.sub.bX.sub.c as a substrate.

3. The rare earth-based nanoparticle magnetic resonance contrast agent as described in claim 1, characterized in that the rare earth element comprises one or more of lanthanum, cerium, praseodymium, neodymium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, lutetium, scandium, and yttrium.

4. The rare earth-based nanoparticle magnetic resonance contrast agent as described in claim 1, characterized in that the surface coating ligands of the rare earth-based nanoparticles are one or more of the following: citric acid, cysteine, polyvinyl alcohol, polyethyleneimine, polyvinyl pyrrolidone, and polyacrylic acid.

5. A preparation method of the rare earth-based nanoparticle magnetic resonance contrast agent as described in claim 1, characterized by comprising the following steps: 1) adding a certain amount of a rare earth precursor or a mixture of a rare earth precursor and a non-rare earth precursor into a high-boiling organic solvent to obtain a solution A; 2) performing vacuum pumping on the solution A to remove moisture, then heating up to 250-340 C. under the protection of an inert gas, maintaining for 15 min-24 h, and then cooling to room temperature to obtain a sol B; 3) performing centrifugal separation on the sol B, washing the obtained precipitate, and then coating the surface of the precipitate with hydrophilic ligands; and 4) dispersing the coated particles into a solvent to obtain the contrast agent.

6. The method as described in claim 5, characterized in that the high-boiling organic solvent refers to a mixed solvent composed of one or more of oleic acid, linoleic acid, oleylamine, octadecene, hexadecylamine and octadecylamine.

7. The method as described in claim 5, characterized in that the rare earth precursor is a mixture of one or more of the following: rare-earth hydroxides, oxalates, acetates, trifluoroacetates, trichloroacetates, acetylacetonates, and phenyl acetylacetonates; and the non-rare earth precursor is a mixture of one or more of the following: alkali-metal and alkaline earth-metal fluorides, hydroxides, oxalates, acetates, trifluoroacetates, trichloroacetates, acetylacetonates, and phenyl acetylacetonates.

8. The method as described in claim 5, characterized in that the molar ratio of the precursor to the solvent is 1:20-1:200 in step 1); vacuum pumping is performed at 100-140 C. in step 2); and a large amount of ethanol is employed to wash in step 3).

9. The method as described in claim 5, characterized in that a washing manner employed in step 3) is centrifugal washing, and washing is performed for 2 to 6 times.

10. The method as described in claim 5, characterized in that the solvent is water or physiological saline in step 4).

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIG. 1 shows a contrast of magnetic resonance images obtained by using a rare earth-based nanoparticle magnetic resonance contrast agent and five clinically commonly-used contrast agents under different concentrations, wherein the used scanning sequence is a T.sub.1 weighted sequence, and the used magnetic field strength is 3 T.

[0029] FIG. 2 shows a contrast of magnetic resonance images obtained by using a rare earth-based nanoparticle magnetic resonance contrast agent and five clinically commonly-used contrast agents under different concentrations, wherein the used scanning sequence is a T.sub.2 weighted sequence, and the used magnetic field strength is 3 T.

[0030] FIG. 3 shows a contrast of magnetic resonance images obtained by using a rare earth-based nanoparticle magnetic resonance contrast agent and five clinically commonly-used contrast agents under different concentrations, wherein the used scanning sequence is a ceMRA sequence, and the used magnetic field strength is 3 T.

[0031] FIG. 4 shows a contrast of magnetic resonance images obtained by using a rare earth-based nanoparticle magnetic resonance contrast agent and five clinically commonly-used contrast agents under different concentrations, wherein the used scanning sequence is a LAVA sequence, and the used magnetic field strength is 3 T.

[0032] FIG. 5 is a diagram showing a contrast of relaxivities obtained by using a rare earth-based nanoparticle magnetic resonance contrast agent and five clinically commonly-used contrast agents, wherein the used magnetic field strength is 3 T.

[0033] FIG. 6 shows a contrast of relaxivities obtained by using a rare earth-based nanoparticle magnetic resonance contrast agent at different magnetic field strengths.

DETAILED DESCRIPTION OF THE INVENTION

[0034] The following describes the rare earth-based nanoparticle magnetic resonance contrast agent and the preparation method thereof of the present invention in connection with specific embodiments, so as to make the public better understand the technical contents, rather than to limit the technical contents. Actually, the improvements which are made for the composite material and the preparation method thereof with same or similar principles all fall within the protection scope of the present application. The following only takes a 50 ml capacity reaction system as an example to exemplify the embodiments, and the present invention can be implemented in a mode of same proportional amplification of each material in actual preparations.

Embodiment 1

[0035] Synthesis of Gd.sub.2O.sub.3 nanoparticles: adding 0.5 mmol of gadolinium acetylacetonate into a mixed solvent of oleic acid (4 mL) and oleylamine (12 mL), heating up to 340 C. under the protection of an inert gas, maintaining the temperature for 15 min, cooling the reaction solution to room temperature, adding a large amount of ethanol thereinto, and performing centrifugal washing twice to obtain the Gd.sub.2O.sub.3 nanoparticles.

Embodiment 2

[0036] Synthesis of Pr.sub.2O.sub.3 nanoparticles: adding 0.5 mmol of praseodymium acetate into a mixed solvent of oleic acid (6 mL) and oleylamine (12 mL), heating up to 340 C. under the protection of an inert gas, maintaining the temperature for 2 h, cooling the reaction solution to room temperature, adding a large amount of ethanol thereinto, and performing centrifugal washing twice to obtain the Pr.sub.2O.sub.3 nanoparticles.

Embodiment 3

[0037] Synthesis of Er.sub.2O.sub.3 nanoparticles: adding 0.5 mmol of phenyl erbium acetylacetonate into a mixed solvent of oleic acid (6 mL) and oleylamine (8 mL), heating up to 310 C. under the protection of an inert gas, maintaining the temperature for 1 h, cooling the reaction solution to room temperature, adding a large amount of ethanol thereinto, and performing centrifugal washing twice to obtain the Er.sub.2O.sub.3 nanoparticles.

Embodiment 4

[0038] Synthesis of Y.sub.2O.sub.3 nanoparticles: adding 0.5 mmol of yttrium hydroxide into a mixed solvent of oleic acid (2 mL), oleylamine (3 mL), and octadecene (5 mL), heating up to 310 C. under the protection of an inert gas, maintaining the temperature for 1 h, cooling the reaction solution to room temperature, adding a large amount of ethanol thereinto, and performing centrifugal washing twice to obtain the Y.sub.2O.sub.3 nanoparticles.

Embodiment 5

[0039] Synthesis of LaF.sub.3 nanoparticles: adding 1 mmol of lanthanum trifluoroacetate and 0.5 mmol of lithium fluoride into a mixed solvent of oleic acid (20 mmol) and octadecene (20 mmol), heating up to 260 C. under the protection of an inert gas, maintaining the temperature for 4 h, cooling the reaction solution to room temperature, adding a large amount of ethanol thereinto, and performing centrifugal washing twice to obtain the LaF.sub.3 nanoparticles.

Embodiment 6

[0040] Synthesis of CeOF nanoparticles: adding 1 mmol of cerium oxalate into a mixed solvent of oleic acid (5 mmol) and hexadecylamine (35 mmol), heating up to 320 C. under the protection of an inert gas, maintaining the temperature for 1 h, cooling the reaction solution to room temperature, adding a large amount of ethanol thereinto, and performing centrifugal washing twice to obtain the CeOF nanoparticles.

Embodiment 7

[0041] Synthesis of EuOCl nanoparticles: adding 1 mmol of europium trichloroacetate into a mixed solvent of oleic acid (20 mmol) and octadecene (20 mmol), heating up to 330 C. under the protection of an inert gas, maintaining the temperature for 1 h, cooling the reaction solution to room temperature, adding a large amount of ethanol thereinto, and performing centrifugal washing twice to obtain the EuOCl nanoparticles.

Embodiment 8

[0042] Synthesis of NaDyF.sub.4:Yb,Er nanoparticles: adding 0.78 mmol of dysprosium trifluoroacetate, 0.20 mmol of yttrium trifluoroacetate, 0.02 mmol of erbium trifluoroacetate, and 1 mmol of sodium trifluoroacetate into a mixed solvent of oleic acid (10 mmol), octadecylamine (10 mmol), and octadecene (20 mmol), heating up to 250 C. under the protection of an inert gas, maintaining the temperature for 0.5 h, cooling the reaction solution to room temperature, adding a large amount of ethanol thereinto, and performing centrifugal washing four times to obtain the NaDyF.sub.4:Yb,Er nanoparticles.

Embodiment 9

[0043] Synthesis of LiTmF.sub.4 nanoparticles: adding 1 mmol of lithium trifluoroacetate and 1 mmol of thulium trifluoroacetate into a mixed solvent of oleic acid (20 mmol) and octadecene (20 mmol), heating up to 320 C. under the protection of an inert gas, maintaining the temperature for 15 h, cooling the reaction solution to room temperature, adding a large amount of ethanol thereinto, and performing centrifugal washing six times to obtain the LiTmF.sub.4 nanoparticles.

Embodiment 10

[0044] Synthesis of KYb.sub.2F.sub.7 nanoparticles: adding 1 mmol of potassium trifluoroacetate and 1 mmol of ytterbium trifluoroacetate into a mixed solvent of oleic acid (20 mmol) and octadecene (20 mmol), heating up to 310 C. under the protection of an inert gas, maintaining the temperature for 2 h, cooling the reaction solution to room temperature, adding a large amount of ethanol thereinto, and performing centrifugal washing six times to obtain the KYb.sub.2F.sub.7 nanoparticles.

Embodiment 11

[0045] Synthesis of BaYF.sub.5 nanoparticles: adding 1 mmol of barium oxalate and 1 mmol of yttrium trifluoroacetate into a mixed solvent of linoleic acid (10 mmol), oleic acid (10 mmol) and octadecylamine (20 mmol), heating up to 340 C. under the protection of an inert gas, maintaining the temperature for 24 h, cooling the reaction solution to room temperature, adding a large amount of ethanol thereinto, and performing centrifugal washing six times to obtain the BaYF.sub.5 nanoparticles.

Embodiment 12

[0046] Coating citric acid on particle surfaces: dispersing Gd.sub.2O.sub.3 nanoparticles (0.1 mmol) obtained in Embodiment 1 into 5 ml of chloroform, adding a citric acid aqueous solution (n/n=20), and vigorously stirring at room temperature for at least 6 h; taking the upper suspension liquid, adding a large amount of ethanol and centrifuging, and dispersing the obtained precipitate into pure water to obtain the nanoparticle magnetic resonance contrast agent.

Embodiment 13

[0047] Coating cysteine on particle surfaces: dispersing Y.sub.2O.sub.3 nanoparticles (0.1 mmol) obtained in Embodiment 4 into 5 ml of chloroform, adding a cysteine aqueous solution (n/n=30), and vigorously stirring at room temperature for at least 6 h; taking the upper layer suspension liquid, adding a large amount of ethanol and centrifuging, and dispersing the obtained precipitate into pure water to obtain the nanoparticle magnetic resonance contrast agent.

Embodiment 14

[0048] Coating polyvinyl alcohol on particle surfaces: dispersing CeOF nanoparticles (0.1 mmol) obtained in Embodiment 6 into 10 ml of cyclohexane, adding 10 mL of N,N-dimethyl formamide and 50 mg of nitrosonium tetrafluoroborate, and vigorously stirring at room temperature for no less than 1 h; taking the lower layer liquid, adding a large amount of toluene and centrifuging, dissolving the obtained precipitate into 10 mL of N,N-dimethyl formamide again, adding 50 mg of polyvinyl alcohol, and stirring for no less than 4 h; then adding a large amount of acetone into the solution, centrifuging, and dispersing the obtained precipitate into pure water to obtain the nanoparticle magnetic resonance contrast agent.

Embodiment 15

[0049] Coating polyethylene imine on particle surfaces: dispersing LaF.sub.3 nanoparticles (0.2 mmol) obtained in Embodiment 5 into 10 ml of cyclohexane, adding 10 mL of N,N-dimethyl formamide and 50 mg of nitrosonium tetrafluoroborate, and vigorously stirring for no less than 1 h; taking the lower layer liquid, adding a large amount of toluene and centrifuging, dissolving the obtained precipitate into 10 mL of N,N-dimethyl formamide again, adding 50 mg of polyethylene imine, and stirring for no less than 4 h; then adding a large amount of acetone into the solution, centrifuging, and dispersing the obtained precipitate into pure water to obtain the nanoparticle magnetic resonance contrast agent.

Embodiment 16

[0050] Coating polyethylene pyrrolidinone on particle surfaces: dispersing NaDyF.sub.4:Yb,Er nanoparticles (0.2 mmol) obtained in Embodiment 8 into 10 ml of cyclohexane, adding 10 mL of N,N-dimethyl formamide and 50 mg of nitrosonium tetrafluoroborate, and vigorously stirring for no less than 1 h; taking the lower layer liquid, adding a large amount of toluene and centrifuging, dissolving the obtained precipitate into 10 mL of N,N-dimethyl formamide again, adding 50 mg of polyethylene pyrrolidinone, and stirring for no less than 4 h; then adding a large amount of acetone into the solution, centrifuging, and dispersing the obtained precipitate into pure water to obtain the nanoparticle magnetic resonance contrast agent.

[0051] FIG. 1 to FIG. 4 show contrasts of magnetic resonance images obtained by using the rare earth-based nanoparticle magnetic resonance contrast agent obtained from Embodiment 12 and five clinically commonly-used contrast agents under different concentrations, wherein the used magnetic field strengths are 3 T. The used scanning sequence in FIG. 1 is a T.sub.1 weighted sequence; the used scanning sequence in FIG. 2 is a T.sub.2 weighted sequence; the used scanning sequence in FIG. 3 is a ceMRA sequence; and the used scanning sequence in FIG. 4 is a LAVA sequence. It can be seen from FIG. 1 to FIG. 4 that the imaging effect of the rare earth-based nanoparticle magnetic resonance contrast agent obtained in Embodiment 12 is superior to that obtained by using the clinically commonly-used contrast agents under the same concentration, and the contrasting effect is remarkably improved with the increase of the concentration (the brighter images in FIG. 1, FIG. 3, and FIG. 4 indicate a better contrasting effect, and the darker image in FIG. 2 indicates a better contrasting effect). It should be noted that, in FIG. 1 the images of the rare earth-based nanoparticle magnetic resonance contrast agent becomes darkened under a relatively high concentration due to the existence of saturation effect, that is, at this time the T.sub.1 contrasting effect has reached the limit, and the T.sub.2 contrasting effect will be improved and partially offset the T.sub.1 contrasting effect under a high concentration, which shows that the rare earth-based nanoparticle magnetic resonance contrast agent can achieve the same contrasting effect under a concentration lower than that of the clinically commonly-used contrast agent.

[0052] FIG. 5 is a diagram showing a contrast of relaxivities obtained by using the rare earth-based nanoparticle magnetic resonance contrast agent obtained in Embodiment 12 and five clinically commonly-used contrast agents, wherein the used magnetic field strength is 3 T. It can be seen from FIG. 5 that the longitudinal and transverse relaxivities of the rare earth-based nanoparticle magnetic resonance contrast agent obtained in Embodiment 12 are higher than those of the clinically commonly-used contrast agents.

[0053] FIG. 6 shows a contrast of a relaxivity obtained by using the rare earth-based nanoparticle magnetic resonance contrast agent obtained in Embodiment 12 at different magnetic field strengths. It can be seen from FIG. 6 that the rare earth-based nanoparticle magnetic resonance contrast agent obtained in Embodiment 12 exhibits high longitudinal and transverse relaxivities at both high magnetic field strength and low magnetic field strength.

[0054] The rare earth-based nanoparticle magnetic resonance contrast agent of the present invention can significantly reduce the relaxation time of surrounding protons, thereby greatly increasing the contrast ratio of local tissues. The rare earth-based nanoparticle magnetic resonance contrast agent of the present application has such advantages as high relaxivity, long in vivo residence time, low injection dose, and small leakage possibility of the rare earth ions and the like, and can effectively increase the diagnostic accuracy and the safety of the contrast agent.

[0055] The foregoing described embodiments of the present invention are not intended to limit the present invention. Those skilled in the art can make some changes and modifications without departing from the spirit and scope of the invention. Therefore the protective scope of the present invention is defined only by the claims.