CN104258421A - Noble metal/paramagnetic metal composite nanoparticles and application thereof - Google Patents
Noble metal/paramagnetic metal composite nanoparticles and application thereof Download PDFInfo
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Abstract
The invention discloses noble metal/paramagnetic metal composite nanoparticles and an application thereof. The noble metal/paramagnetic metal composite nanoparticles have the characteristics of good chemical stability, good contrast effect and good biocompatibility, and can be used as MRI and CT enhanced contrast agents.
Description
Technical field
The present invention relates to a kind of nanosecond medical science technical field, specifically a kind of Synthesis and applications of organometallic polymer composite nanoparticle.
Technical background
Gold prepared by the scholar of home and abroad/gadolinium composite nanoparticle mainly comprises: D.P.Cormode etc. prepare in the liquid phase with Jin Weihe, phospholipid and be the high density lipoprotein nanoparticle of shell containing gadolinium part, particle diameter is about 9.7nm, can be used as fluorescence, CT and MRI multimode contrast agent; Carbamide and the GdCl such as K.W.Hu
36H
2o mol ratio be 4:1 reflux in 91 DEG C of aqueous solutions 4 hours preparation mean diameter be the Gd of 441nm
2o (CO
3)
2h
2o granule, then be polymerized with tetraethoxysilane and generate the coated Gd of silicon
2o (CO
3)
2h
2o/Si, through silane coupler modification of surfaces generation-NH
2be combined with electrostatic interaction with electronegative nanometer gold after functional group, then introduce formaldehyde reduction gold chloride system and promote golden shell to grow finally to prepare with gold to be the Gd of shell
2o (CO
3)
2h
2o/Si compound particle; D.Gerion etc. adopt Citrate Buffer first to prepare Jenner's rice glue that particle diameter is 5nm and 10nm, adding phosphatization hydrogen meter surface-active agent makes colloid-stabilised, then carry out Silanization reaction and make its external sheath silicon dioxide through subsequent treatment, then generating covalent bond with Gd-DOTA and be prepared into the Gd-DOTA-SiO that particle diameter is no more than 18nm
2-Au compound particle; Y.Chen etc. to utilize Gd-Si-DTPA grafting containing the mesopore silicon oxide enriching specific surface area to Au@mSiO
2gd-Si-DTPA-Au@mSiO is prepared in the hole of Nano capsule
2the meso-porous nano capsule of core/shell structure, can be applicable to biological bimodal imaging and comprises dark ground light scattering cell and T
1weighting MR imaging; Multilamellar organic mass shell clad nano gold such as C.Alric prepares nanoparticle, and its MRI potentiation stems from the gadolinium ion had in casing, and the gold be wrapped by is checked X-ray and had stronger absorption, and result shows that this particle is applicable to dual form imaging; The citrate ion that S.M.Nasiruzzaman etc. replace nanometer gold surface by gadolinium ion part (GdL) prepares the compound particle GdL@Au that particle diameter is about 12nm, and one of them compound particle comprises 1.4 × 10
3individual GdL, can be used as MRI and CT contrast agent; Moriggi etc. as protective agent, prepare the gold nanoclusters that Dt is coated with the smaller ligand DTTA (Dt) of sulfydryl modification, then with Gd
3+be obtained by reacting gold/gadolinium composite nanoparticle for MRI contrast agent.
Summary of the invention
First object of the present invention is to provide that a kind of chemical stability is good, the noble metal/paramagnetic metal composite nanoparticle of contrasting effects and good biocompatibility.
Second object of the present invention is to provide described noble metal/paramagnetic metal composite nanoparticle strengthens contrast medium application as MRI and CT.
For achieving the above object, the present invention adopts following technical scheme:
Noble metal involved in the present invention/paramagnetic metal composite nanoparticle is made up of noble metal nano particles, organic bonding units and paramagnetic metal, and its preparation method comprises the following steps:
(1) polysuccinimide is dissolved in N, in dinethylformamide (DMF), be warming up to 30 ~ 65 DEG C under nitrogen protection and stirring, then add compd A, stop heating after 24-48 hour, reactant mixture obtains product I after dialysing, revolving steaming, drying; Described compd A is 1-alkyl azide amine, and wherein the carbon atom number of alkyl is at 2 ~ 6;
(2) product I is dissolved in N, in dinethylformamide, nitrogen protection and dropping compd B and catalyst n under stirring, N-diisopropylethylamine, stop heating in 30 ~ 80 DEG C of reactions after 24-48 hour, reactant mixture through dialysis, revolve steaming, drying obtains product II; Described compd B is p-aminophenyl thiophenol or L-cysteine hydrochloride or Mercaptamine;
(3) by the N shown in product II and formula (I)
2-(4-alkynyl)-diethylenetriamines-four tert-butyl ester is dissolved in oxolane, add the sodium ascorbate of brand-new and the aqueous solution of copper sulphate pentahydrate again, under room temperature, react extract and separate organic layer after 2-4 hour, then through dialysis, revolve steaming, drying obtains product III;
(4) product III is dissolved in dichloromethane, under stirring, slowly drips trifluoroacetic acid, stop after finishing room temperature reaction 24-48 hour, revolve and steam removing dichloromethane and trifluoroacetic acid, add ether ultrasonic disperse, obtain product IV through separation, washing, drying;
(5) be dissolved in ultra-pure water by product IV, drip the aqueous solution of Compound C, drip complete adjust ph to 8-9, then stir 1-2 hour, reactant mixture obtains product V through dialysis, drying; Described Compound C is selected from paramagnetic lanthanide series metal chloride;
(6) preparation gold or Nano silver grain;
(7) product V is dissolved in dimethyl sulfoxine (DMSO), and add step (6) freshly prepd gold or Nano silver grain, after reacting 12-24 hour under room temperature, reactant mixture through dialysis, revolve steaming, drying obtains end product noble metal/paramagnetic metal composite nanoparticle.
Further, in step (1), the molar ratio of polysuccinimide and compd A is 1:0.2 ~ 0.5.
Further, the molar ratio of product I, compd B, DIPEA is 1:0.8 ~ 0.5:0.8 ~ 0.5.
Further, in step (3), product II and N
2the molar ratio of-(4-alkynyl)-diethylenetriamines-four tert-butyl ester, sodium ascorbate, copper sulfate is 1:0.2 ~ 0.5:0.2 ~ 0.5:0.2 ~ 0.5.
Further, in step (4), the molar ratio of product III and trifluoroacetic acid is 1:4 ~ 8.
Further, in step (5), the molar ratio of product IV and Compound C is 1:1 ~ 2.
Further, in step (6), the preparation method of gold or Nano silver grain is conventional reduction method, those skilled in the art can complete preparation according to prior art, such as can be prepared as follows: appropriate precious metal chemical complex (auric chloride, perchloric acid gold, silver nitrate etc.) is dissolved in ultra-pure water, proper amount of sodium citrate or sodium borohydride is added rapidly after being heated to boiling, react and be cooled to room temperature after 5-10 minute, continue to stir after 0.5-1 hour and stop, obtaining noble metal nano colloid solution.Wherein the mol ratio of precious metal chemical complex and sodium citrate or sodium borohydride is 1:4 ~ 8.
Further, in step (7), the molar ratio of the nano noble metal particles in product V and nano-noble metal colloid solution is 1:8 ~ 32.
Present invention also offers described noble metal/paramagnetic metal composite nanoparticle strengthens contrast medium application as MRI and CT.
In the present invention, the molecular weight of macromolecular compound is all the mean molecule quantity adopting gel chromatography to record.
Compared with prior art, the present invention is successively reacted with polysuccinimide by compd A and compd B, obtain the copolymer containing multiple nitrine functional group and multiple mercapto functional group, and paramagnetic metal ion is introduced in this copolymer, obtain macromole paramagnetic metal coordination compound, and utilize Au-S key or Ag-S key by this coordination compound and Precious Metals-Gold or nano grain of silver sublink, thus prepare a kind of chemically stable noble metal/paramagnetic metal composite nanoparticle.This compound particle has following advantage: (1) is bonding units with macromolecular chain, adds the number of sites of gadolinium ion chelating, contributes to improving Relaxivity; (2) macromolecular chain exists multiple sulfydryl, stable chemical bond can be formed with noble metal nano particles, contribute to improving chemical stability; (3) noble metal nano particles not only can as the assembly platform of bonding units, simultaneously because its special permanent magnetism also can be used as signal amplification unit, the use of polysuccinimide makes this compound particle have good biocompatibility in addition, is expected to agent as a comparison and is applied to medical imaging field.
Accompanying drawing explanation
Fig. 1 is the structural representation of gold/gadolinium composite nanoparticle that embodiment 1 obtains.
Fig. 2 is transmission electron microscope (TEM) image of gold/gadolinium composite nanoparticle that embodiment 1 obtains.
Fig. 3 is the MRI image of gold/gadolinium composite nanoparticle that embodiment 1 obtains, from left to right be followed successively by gold/gadolinium composite nanoparticle, not containing tester (the product V namely in embodiment 1), the Magnevist Solution injection (Beilu Pharmaceutical Industry Co., Ltd., Beijing) of gold, concentration is followed successively by 1.00,0.50,0.25,0.125,0.0625,0.0 × 10 from top to bottom
-3mmolL
-1.
Fig. 4 is the CT image of gold/gadolinium composite nanoparticle that embodiment 1 obtains, and 1-6 concentration is followed successively by 1.00,0.50,0.25,0.125,0.0625,0.0 × 10
-3mmolL
-1.
Detailed description of the invention
Following instance is provided in order to set forth spy of the present invention further.Obvious embodiments of the present invention are not limited to following embodiment.
Embodiment 1
Step a; polysuccinimide (molecular weight 20000) 1.0g is dissolved in 5mL N; in dinethylformamide (DMF) solvent; and drop in 100ml there-necked flask; stir; logical nitrogen protection, adds 0.4g1-nitrine propylamine after being warming up to 60 DEG C, react after 24 hours and stop heating.Reactant mixture is transferred to molecular cut off be 3500 bag filter dialyse in DMF 48 hours, rotary evaporation is removed DMF and is obtained darkorange thick liquid, after drying under reduced pressure product I.
Step b, is dissolved in 1.25g product I in 5mL DMF, and logical nitrogen protection, stirs and add 1.13g Mercaptamine, 1.32g DIPEA, and 60 DEG C of reactions stopped heating after 24 hours.Mixture after reaction being transferred to molecular cut off is dialyse 48 hours in ultra-pure water in 3500 bag filters, and rotary evaporation is removed most of water postlyophilization and obtained pale pink solid product II.
Step c, gets 1.25g product II and 3.90g N
2-(4-alkynyl)-diethylenetriamines-four tert-butyl ester is dissolved in 5mL oxolane, then adds freshly prepared 1molL
-1sodium ascorbate and each 1mL of copper sulphate pentahydrate aqueous solution, react under room temperature after 2 hours and add 10mL water, 10mL dichloromethane, stir and be transferred to separatory funnel after 2 minutes, retain organic layer, after dialysing 24 hours in dichloromethane, rotary evaporation removing dichloromethane, obtains product III after drying under reduced pressure.
Steps d, 3.0g product III is dissolved in 5mL dichloromethane, stir, slowly drip 2mL trifluoroacetic acid under room temperature, room temperature reaction stopped after 24 hours, revolved after steaming removing dichloromethane and trifluoroacetic acid, add 10mL ether ultrasonic disperse 10 minutes, obtain white solid powder, then wash three times with absolute ether, after drying under reduced pressure, obtain product IV.
Step e, is dissolved in 2.5g product IV in 5mL ultra-pure water, by 0.7g GdCl
3soluble in water, and point three droppings, dropwise rear saturated solution of sodium bicarbonate adjust ph is 8-9 at every turn.Stir, after 1 hour, reactant mixture is moved into bag filter, after dialysing 48 hours in water, lyophilization obtains product V.
Step f, is dissolved in 0.42g gold chloride in 20mL ultra-pure water, is heated to boiling, adds rapidly 1.00g sodium citrate, react and be cooled to room temperature after 5 minutes, continues stirring and stops after 0.5 hour, obtain nano gold sol product VI.
Step g, 0.2g product V is dissolved in 2mL DMSO, and drip 10mL concentration 0.001mol/L product VI, reacting under room temperature moved in 3500Da bag filter after 12 hours, dialyse 24 hours in ultra-pure water, revolve steaming and to remove after most of water under 3000 revs/min of revolutions centrifugalize 30 minutes, get upper solution and concentrate postlyophilization and obtain end product.
End product is configured to variable concentrations aqueous solution (1.00,0.50,0.25,0.125,0.0625,0.0mmolL
-1).Then be placed in small test tube, test imaging effect respectively in nuclear magnetic resonance imaging instrument and computed tomographic scanner.Result shows, in embodiment 1, composite nanoparticle possesses MRI reinforced effects (as Fig. 3), and CT imaging effect (as Fig. 4).Its MRI relaxation rate is 47.6mM
-1s
-1, the CT value of 1mM is 59.5/0.8.
Embodiment 2
Step a; polysuccinimide (molecular weight 20000) 1.0g is dissolved in 5mL N; in dinethylformamide (DMF) solvent; and drop in 100ml there-necked flask; stir; logical nitrogen protection, adds 0.4g1-nitrine propylamine after being warming up to 60 DEG C, react after 24 hours and stop heating.Reactant mixture is transferred to molecular cut off be 3500 bag filter dialyse in DMF 48 hours, rotary evaporation is removed DMF and is obtained darkorange thick liquid, after drying under reduced pressure product I.
Step b, is dissolved in 1.25g product I in 5mL DMF, and logical nitrogen protection, stirs and add 1.13g Mercaptamine, 1.32g DIPEA, and 60 DEG C of reactions stopped heating after 24 hours.Mixture after reaction being transferred to molecular cut off is dialyse 48 hours in ultra-pure water in 3500 bag filters, and rotary evaporation is removed most of water postlyophilization and obtained pale pink solid product II.
Step c, gets 1.25g product II and 3.90g N
2-(4-alkynyl)-diethylenetriamines-four tert-butyl ester is dissolved in 5mL oxolane, then adds freshly prepared 1molL
-1sodium ascorbate and each 1mL of copper sulphate pentahydrate aqueous solution, react under room temperature after 2 hours and add 10mL water, 10mL dichloromethane, stir and be transferred to separatory funnel after 2 minutes, retain organic layer, after dialysing 24 hours in dichloromethane, rotary evaporation removing dichloromethane, obtains product III after drying under reduced pressure.
Steps d, 3.0g product III is dissolved in 5mL dichloromethane, stir, slowly drip 2mL trifluoroacetic acid under room temperature, room temperature reaction stopped after 24 hours, revolved after steaming removing dichloromethane and trifluoroacetic acid, add 10mL ether ultrasonic disperse 10 minutes, obtain white solid powder, then wash three times with absolute ether, after drying under reduced pressure, obtain product IV.
Step e, is dissolved in 2.5g product IV in 5mL ultra-pure water, by 0.7g GdCl
3soluble in water, and point three droppings, dropwise rear saturated solution of sodium bicarbonate adjust ph is 8-9 at every turn.Stir, after 1 hour, reactant mixture is moved into bag filter, after dialysing 48 hours in water, lyophilization obtains product V.
25mL concentration is 2 × 10 by step f with vigorous stirring in cryosel bath
-3molL
-1 silver nitrate solutionbeing added drop-wise to 25mL concentration is 8 × 10
-3molL
-1in sodium borohydride aqueous solution, react and obtain Nano silver grain hydrosol product VI after 30 minutes.
Step g, 0.2g product V is dissolved in 2mL DMSO, and drip 10mL concentration 0.001mol/L product VI, reacting under room temperature moved in 3500Da bag filter after 12 hours, dialyse 24 hours in ultra-pure water, revolve steaming and to remove after most of water under 3000 revs/min of revolutions centrifugalize 30 minutes, get upper solution and concentrate postlyophilization and obtain end product.
Embodiment 3
Step a, is dissolved in polysuccinimide 1.0g in 5mLDMF solvent, and drops in 100ml there-necked flask, stirs, and logical nitrogen protection, adds 0.4g1-nitrine propylamine after being warming up to 60 DEG C, reacts after 24 hours and stops heating.Reactant mixture is transferred to molecular cut off be 3500 bag filter dialyse in DMF 48 hours, rotary evaporation is removed DMF and is obtained darkorange thick liquid, after drying under reduced pressure product I.
Step b, is dissolved in 5mL DMF solvent by 1.25g product I, logical nitrogen protection, stirring adds
2.5g is to amino phenylmercaptan., 1.32g DIPEA, reactant mixture to be transferred to molecular cut off by 60 DEG C of reactions after 24 hours be dialyse 48 hours in ultra-pure water in 3500 bag filters, and rotary evaporation is removed most of water postlyophilization and obtained product II.
Step c, gets 1.0g product II and 3.90g N
2-(4-alkynyl)-diethylenetriamines-four tert-butyl ester is dissolved in 5mL oxolane, then adds freshly prepared 1molL
-1sodium ascorbate and each 1mL of copper sulphate pentahydrate aqueous solution, react under room temperature after 2 hours and add 10mL water, 10mL dichloromethane, stir and be transferred to separatory funnel after 2 minutes, retain organic layer, after dialysing 24 hours in dichloromethane, rotary evaporation removing dichloromethane, obtains product III after drying under reduced pressure.
Steps d, 3.0g product III is dissolved in 5mL dichloromethane, stir, slowly drip 2mL trifluoroacetic acid under room temperature, room temperature reaction stopped after 24 hours, revolved after steaming removing dichloromethane and trifluoroacetic acid, add 10mL ether ultrasonic disperse 10 minutes, obtain white solid powder, then wash three times with absolute ether, after drying under reduced pressure, obtain product IV.
Step e, is dissolved in 2.5g product IV in 5mL ultra-pure water, by 0.7g GdCl
3soluble in water, and point three droppings, dropwise rear saturated solution of sodium bicarbonate adjust ph is 8-9 at every turn.Stir, after 1 hour, reactant mixture is moved into bag filter, after dialysing 48 hours in water, lyophilization obtains product V.
Step f, is dissolved in 0.42g gold chloride in 20mL ultra-pure water, is heated to boiling, adds rapidly 1.00g sodium citrate, react and be cooled to room temperature after 5 minutes, continues stirring and stops after 0.5 hour, obtain nano gold sol product VI.
Step g, 0.2g product V is dissolved in 2mL DMSO, and drip 10mL concentration 0.001mol/L product VI, reacting under room temperature moved in 3500Da bag filter after 12 hours, dialyse 24 hours in ultra-pure water, revolve steaming and to remove after most of water under 3000 revs/min of revolutions centrifugalize 30 minutes, get upper solution and concentrate postlyophilization and obtain end product.
Embodiment 4
Step a, is dissolved in polysuccinimide 1.0g in 5mL DMF solvent, and drops in 100ml there-necked flask, stirs, and logical nitrogen protection, adds 0.2g1-nitrine propylamine after being warming up to 60 DEG C, reacts after 24 hours and stops heating.Reactant mixture is transferred to molecular cut off be 3500 bag filter dialyse in DMF 48 hours, rotary evaporation is removed DMF and is obtained darkorange thick liquid, after drying under reduced pressure product I.
Step b, is dissolved in 5mL DMF solvent by 1.25g product I, logical nitrogen protection, stirring adds
1.25g to amino phenylmercaptan., 1.32g DIPEA, reactant mixture to be transferred to molecular cut off by 60 DEG C of reactions after 24 hours be dialyse 48 hours in ultra-pure water in 3500 bag filters, and rotary evaporation is removed most of water postlyophilization and obtained product II.
Step c, gets 1.0g product II and 3.90g N
2-(4-alkynyl)-diethylenetriamines-four tert-butyl ester is dissolved in 5mL oxolane, then adds freshly prepared 1molL
-1sodium ascorbate and each 1mL of copper sulphate pentahydrate aqueous solution, react under room temperature after 2 hours and add 10mL water, 10mL dichloromethane, stir and be transferred to separatory funnel after 2 minutes, retain organic layer, after dialysing 24 hours in dichloromethane, rotary evaporation removing dichloromethane, obtains product III after drying under reduced pressure.
Steps d, 3.0g product III is dissolved in 5mL dichloromethane, stir, slowly drip 2mL trifluoroacetic acid under room temperature, room temperature reaction stopped after 24 hours, revolved after steaming removing dichloromethane and trifluoroacetic acid, add 10mL ether ultrasonic disperse 10 minutes, obtain white solid powder, then wash three times with absolute ether, after drying under reduced pressure, obtain product IV.
Step e, is dissolved in 2.5g product IV in 5mL ultra-pure water, by 0.7g GdCl
3soluble in water, and point three droppings, dropwise rear saturated solution of sodium bicarbonate adjust ph is 8-9 at every turn.Stir, after 1 hour, reactant mixture is moved into bag filter, after dialysing 48 hours in water, lyophilization obtains product V.
25mL concentration is 2 × 10 by step f with vigorous stirring in cryosel bath
-3molL
-1 silver nitrate solutionbeing added drop-wise to 25mL concentration is 8 × 10
-3molL
-1in sodium borohydride aqueous solution, react and obtain Nano silver grain hydrosol product VI after 30 minutes.
Step g, 0.2g product V is dissolved in 2mL DMSO, and drip 10mL concentration 0.001mol/L product VI, reacting under room temperature moved in 3500Da bag filter after 12 hours, dialyse 24 hours in ultra-pure water, revolve steaming and to remove after most of water under 3000 revs/min of revolutions centrifugalize 30 minutes, get upper solution and concentrate postlyophilization and obtain end product.
Claims (9)
1. noble metal/paramagnetic metal composite nanoparticle, be made up of noble metal nano particles, organic bonding units and paramagnetic metal, its preparation method comprises the following steps:
(1) polysuccinimide is dissolved in N, in dinethylformamide (DMF), be warming up to 30 ~ 65 DEG C under nitrogen protection and stirring, then add compd A, stop heating after 24-48 hour, reactant mixture obtains product I after dialysing, revolving steaming, drying; Described compd A is 1-alkyl azide amine, and wherein the carbon atom number of alkyl is at 2 ~ 6;
(2) product I is dissolved in N, in dinethylformamide, nitrogen protection and dropping compd B and catalyst n under stirring, N-diisopropylethylamine, stop heating in 30 ~ 80 DEG C of reactions after 24-48 hour, reactant mixture through dialysis, revolve steaming, drying obtains product II; Described compd B is p-aminophenyl thiophenol or L-cysteine hydrochloride or Mercaptamine;
(3) by the N shown in product II and formula (I)
2-(4-alkynyl)-diethylenetriamines-four tert-butyl ester is dissolved in oxolane, add the sodium ascorbate of brand-new and the aqueous solution of copper sulphate pentahydrate again, under room temperature, react extract and separate organic layer after 2-4 hour, then through dialysis, revolve steaming, drying obtains product III;
(4) product III is dissolved in dichloromethane, under stirring, slowly drips trifluoroacetic acid, stop after finishing room temperature reaction 24-48 hour, revolve and steam removing dichloromethane and trifluoroacetic acid, add ether ultrasonic disperse, obtain product IV through separation, washing, drying;
(5) be dissolved in ultra-pure water by product IV, drip the aqueous solution of Compound C, drip complete adjust ph to 8-9, then stir 1-2 hour, reactant mixture obtains product V through dialysis, drying; Described Compound C is selected from paramagnetic lanthanide series metal chloride;
(6) preparation gold or Nano silver grain;
(7) product V is dissolved in dimethyl sulfoxine (DMSO), and add step (6) freshly prepd gold or Nano silver grain, after reacting 12-24 hour under room temperature, reactant mixture through dialysis, revolve steaming, drying obtains end product noble metal/paramagnetic metal composite nanoparticle.
2. noble metal/paramagnetic metal composite nanoparticle as claimed in claim 1, it is characterized in that: in step (1), the molar ratio of polysuccinimide and compd A is 1:0.2 ~ 0.5.
3. noble metal/paramagnetic metal composite nanoparticle as claimed in claim 1, it is characterized in that: in step (2), the molar ratio of product I, compd B, DIPEA is 1:0.8 ~ 0.5:0.8 ~ 0.5.
4. noble metal/paramagnetic metal composite nanoparticle as claimed in claim 1, is characterized in that: in step (3), product II and N
2the molar ratio of-(4-alkynyl)-diethylenetriamines-four tert-butyl ester, sodium ascorbate, copper sulfate is 1:0.2 ~ 0.5:0.2 ~ 0.5:0.2 ~ 0.5.
5. noble metal/paramagnetic metal composite nanoparticle as claimed in claim 1, it is characterized in that: in step (4), the molar ratio of product III and trifluoroacetic acid is 1:4 ~ 8.
6. noble metal/paramagnetic metal composite nanoparticle as claimed in claim 1, it is characterized in that: in step (5), the molar ratio of product IV and Compound C is 1:1 ~ 2.
7. noble metal/paramagnetic metal composite nanoparticle as claimed in claim 1, is characterized in that: in step (7), and the molar ratio of the nano noble metal particles in product V and nano-noble metal colloid solution is 1:8 ~ 32.
8. noble metal/paramagnetic metal composite nanoparticle as claimed in claim 1 strengthens the application of contrast medium as MRI.
9. noble metal/paramagnetic metal composite nanoparticle as claimed in claim 1 strengthens the application of contrast medium as CT.
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