CN106924762A - A kind of magnetic nanoparticle compound for T1, T2 bimodal magnetic resonance contrast agent and preparation method thereof - Google Patents

A kind of magnetic nanoparticle compound for T1, T2 bimodal magnetic resonance contrast agent and preparation method thereof Download PDF

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CN106924762A
CN106924762A CN201710167283.2A CN201710167283A CN106924762A CN 106924762 A CN106924762 A CN 106924762A CN 201710167283 A CN201710167283 A CN 201710167283A CN 106924762 A CN106924762 A CN 106924762A
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CN106924762B (en
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周欣
黄曦
陈世桢
孙献平
刘买利
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Wuhan Institute of Physics and Mathematics of CAS
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    • A61K49/00—Preparations for testing in vivo
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    • A61K49/1833—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with a small organic molecule
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Abstract

It is used for T the invention discloses one kind1、T2Magnetic nanoparticle compound of bimodal magnetic resonance contrast agent and preparation method thereof, the magnetic nanoparticle compound is three-layer nuclear shell structure, and described core is Fe3O4Nano particle, intermediate layer is the silicon dioxide layer of manganoporphyrin hydrochloride, and outermost layer is the acrylic acid polymer layer of the cyclic peptide group cRGD of targeted integration element acceptor.Its preparation method is：1、OA@Fe3O4@nSiO2@mSiO2Preparation；2、OA@Fe3O4@nSiO2@mSiO2The preparation of@PAA cRGD；3rd, the preparation of manganoporphyrin hydrochloride；4th, the preparation of Mn IOSP.The magnetic nanoparticle compound is used to prepare that relaxation rate of new generation is high, and toxicity is low, circulation time T long1/T2Bimodal magnetic resonance imaging contrast, its performance that can improve imaging and the degree of accuracy, and with good biocompatibility.

Description

One kind is used for T1、T2The magnetic nanoparticle compound of bimodal magnetic resonance contrast agent and Its preparation method
Technical field
Preparation and tumour diagnosis and treatment technical field of imaging the invention belongs to nucleus magnetic resonance contrast agent, and in particular to a kind of For T1、T2Magnetic nanoparticle compound of bimodal magnetic resonance contrast agent and preparation method thereof.
Background technology
Magnetic resonance imaging (MRI) is with Inherent advantages such as Noninvasive, biological safety and spatial resolutions high It is considered as one of most effective means of medical diagnosis on disease.In mri, proton density is different with flip-flop transition can influence relaxation speed Rate, the MRI for causing different biological tissues and organ to show feature is contrasted.However, when target organ and surrounding position contrast effect When fruit is not obvious, accurate detection target area has difficulties.MRI contrast agent can accelerate the T of target site1Or T2Relaxation rate, So as to strengthen the contrast of lesions position and normal structure, increase sensitivity and figure by strengthening contrast in clinical practice As quality, so that diagnosis is more accurate.
Common MRI contrast agent is divided into two classes：One class is the Paramagnetic compounds such as gadolinium (Gd) or manganese (Mn), such radiography Agent can cause proton relaxation around to change and mainly change T1In the relaxation time, apply in T1T faster is obtained in weighted imaging1 Relaxation rate (R1,1/T1), cause T1Weighted image brightens；Another kind is superparamagnetism material, and major part is based on iron oxide Nano particle, can shorten T2In the relaxation time, cause T faster2Relaxation rate (R2,1/T2) make T2Weighted imaging is dimmed.But T1Weighted imaging and T2Weighted imaging contrast agent has their own merits and demerits.Such as T based on gadolinium1Weighted mri radiography Agent has outstanding contrasting effects, but is also threatened with bio-toxicity simultaneously, and some clinic gadolinium class contrast agent have makes kidney There is the potential threat of kidney source sexual system fibrosis (NSF) in the patient after disease or kidney transplant；Based on T2Weighted imaging SPIO nano particle has hypotoxicity, but then, because Susceptibility effect and its negative contrasting effects, with The adjacent tissues such as bone, vascular system of the surrounding with low MR signals can not distinguish well, ferric oxide nano particles contrast agent Using being restricted.The micromolecular compound of manganese is used for T1Imaging can reduce the poison that free manganese ion is directly used in imaging Property, and typically there is relaxation rate higher compared with the nano particle of manganese, and the imaging effect of pH responses can be improved further The performance of imaging.
Environmental response diagnosing image can effectively improve the imaging performance of contrast agent so that being imaged and detecting more accurate.By In the change of malignant tumour metabolic pathway, tumor microenvironment has obvious difference compared with normal structure.Acidic cancer microenvironment Formation to raise glycolysis metabolism, lactic acid largely production cause pH value decline it is related.Development is to the special pH sensitives Hypersensitive detection, imaging and the treatment that nano-particle is used as tumour have certain potentiality.
Traditional MRI contrast agent mainly influences T1、T2One of which imaging pattern, by T1And T2The bimodulus that contrast agent is combined State contrast agent brings new breakthrough for contrast agent.However, the design of such contrast agent realizes there is challenge.The imaging that pH is responded And T1、T2Bimodal imaging pattern new imaging unit designed in conjunction, this kind of contrast agent can provide differentiation diseased region and just The more accurate magnetic resonance imaging information in normal position, has great application potential in the application of molecular imaging.
The content of the invention
It is used for T the invention provides one kind1、T2The magnetic nanoparticle compound and its system of bimodal magnetic resonance contrast agent Preparation Method, the magnetic nanoparticle is used to prepare that relaxation rate of new generation is high, and toxicity is low, circulation time T long1/T2Bimodal magnetic is total to Shake image-forming contrast medium, by T1And T2Two kinds of imaging patterns are combined, and in combination with the environmental response performance of contrast agent, are released at a low ph Put the T that mangano-porphyrin realizes pH responses1Imaging, the final performance for improving imaging and the degree of accuracy, and contrast agent has good life Thing compatibility.
In the preparation method of the magnetic nanoparticle compound, the mild condition needed for each step reaction, it is easy to operate.
Realize technical scheme that above-mentioned purpose of the present invention used for：
One kind is used for T1、T2The magnetic nanoparticle compound of bimodal magnetic resonance contrast agent, described magnetic nanoparticle Compound is three layers of nucleocapsid structure, and described core is Fe3O4Nano particle, intermediate layer is 5,10,15,20-2- ([4- benzene of load Formamido group] urethanes) mangano-porphyrin hydrochloride silicon dioxide layer, outermost layer be targeted integration element acceptor cyclic peptide The acrylic acid polymer layer of group-cRGD.
One kind is used for T1、T2The preparation method of the magnetic nanoparticle compound of bimodal magnetic resonance contrast agent, its feature exists In comprising the following steps：
1、OA@Fe3O4@nSiO2@mSiO2Preparation：
1.1st, the Fe for first wrapping up oleic acid3O4Nano particle OA@Fe3O4It is dispersed in hexamethylene, obtains OA@Fe3O4Dispersion Liquid；
1.2nd, in hexamethylene andIn CO-520, OA@Fe are added3O4Dispersion liquid, is well mixed, and is subsequently adding ammonia Water and tetraethyl orthosilicate, OA@Fe3O4, tetraethyl orthosilicate, ammoniacal liquor andThe mass ratio of CO-520 is 1:9-11:17.5- 18.5:120-140, room temperature and it is closed under conditions of stirring reaction 4-8 hours, obtain one layer of solid silica of parcel OA@Fe3O4, it is designated as OA@Fe3O4@nSiO2；
1.3rd, in the mixed aqueous solution of hexadecyltrimethylammonium chloride and organic base triethanolamine, OA@Fe are added3O4@ nSiO2Aqueous dispersions and tetraethyl orthosilicate, now the pH of system is 9-10, OA@Fe3O4@nSiO2, tetraethyl orthosilicate and hexadecane The mass ratio of base trimethyl ammonium chloride is 1：15-25：300-400, reacts 0.5-1.5 hours at 60-100 DEG C, is wrapped up One layer of OA@Fe of mesoporous silicon oxide3O4@nSiO2, it is designated as OA@Fe3O4@nSiO2@mSiO2；
2、OA@Fe3O4@nSiO2@mSiO2The preparation of@PAA-cRGD：
2.1st, polyacrylic acid is dispersed in the cushioning liquid of pH5.0-6.0, adds 1- (3- dimethylamino-propyls) -3- second Base carbodiimide hydrochloride, N-hydroxy-succinamide and cyclic peptide c (RGDyK), polyacrylic acid, 1- (3- dimethylamino-propyls)- 3- ethyl-carbodiimide hydrochlorides, N-hydroxy-succinamide, the mol ratio of cyclic peptide c (RGDyK) are 1-3:0.5-1.5:1-3: 0.1-1, adjusts the pH to 7.0-7.5 of system, reacts 10-12 hours at room temperature, and the mix products dialysis of gained falls remnants not After the small molecule of reaction, PAA-cRGD solution is obtained；
2.2nd, by OA@Fe3O4@nSiO2@mSiO2Dispersion in deionized water, adds PAA-cRGD solution and ammoniacal liquor, now The pH of system is 8-10, OA@Fe3O4@nSiO2@mSiO2It is 1 with the mass ratio of PAA-cRGD:1.5-2.5, ultrasonic mixing is uniform, Isopropanol is added dropwise while stirring so that PAA-cRGD is deposited on OA@Fe3O4@nSiO2@mSiO2On surface, OA@Fe are obtained3O4@ nSiO2@mSiO2@PAA-cRGD；
3rd, the preparation of 5,10,15,20-2- ([4- benzamidos] urethanes) mangano-porphyrin hydrochloride：
3.1st, in methyl alcohol, 5,10,15,20-2- ([the 4- tert-butyl groups-benzamido] urethanes) porphyrins and four Acetate hydrate manganese reacts, and 5,10,15,20-2- ([the 4- tert-butyl groups-benzamido] urethanes) porphyrins and four are hydrated second The mol ratio of sour manganese is 1：5-6, flows back 10-14 hours at 60-80 DEG C, obtains 5,10,15,20-2- ([4- benzamidos] Urethanes) mangano-porphyrin；
3.2nd, in dichloromethane, 5,10,15,20-2- ([4- benzamidos] urethanes) mangano-porphyrins and chlorine Change the Isosorbide-5-Nitrae-dioxane solution reaction of hydrogen, 5,10,15,20-2- ([4- benzamidos] urethanes) mangano-porphyrins with The mol ratio of hydrogen chloride is 1：90-110, at room temperature reaction sloughs N-boc blocking groups in 10-14 hours, obtains 5,10,15,20- 2- ([4- benzamidos] urethanes) mangano-porphyrin hydrochloride；
4th, the preparation of Mn-IOSP：
By OA@Fe3O4@nSiO2@mSiO2@PAA-cRGD are scattered in the mixed solution equipped with deionized water and isopropanol In reaction vessel, 5,10,15,20-2- ([4- benzamidos] urethanes) mangano-porphyrin HCI solutions, OA@are added Fe3O4@nSiO2@mSiO2@PAA-cRGD and 5,10,15,20-2- ([4- benzamidos] urethanes) mangano-porphyrin salt The mass ratio of hydrochlorate is 1：1-2, container is placed in shaking table, is mixed 22-26 hours at 30-40 DEG C, is obtained for T1、T2It is double The magnetic nanoparticle of mode magnetic resonance contrast agent, is designated as Mn-IOSP.
Further, in step 2.1.2, the mass fraction for adding ammoniacal liquor is 25-30%；In step 2.2.2, ammoniacal liquor is added Concentration is 2mol/L.
Further, in step 2.2.1,1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides and N- are first added HOSu NHS, stirs 2h at room temperature, adds cyclic peptide c (RGDyK).
Further, in step 2.2.2, isopropanol was added dropwise to complete with 0.5-1.5 hours, final system reclaimed water and isopropanol Volume ratio is 1:8-10.
Further, in step 2.2.1, the mix products of gained are carried out with the bag filter that molecular cut off is 1000Da Analysis.
Further, described cushioning liquid is MES cushioning liquid, and the concentration of MES is 50mM.
Further, the weight average molecular weight of described polyacrylic acid is 2000.
Further, the concentration of the Isosorbide-5-Nitrae-dioxane solution of described hydrogen chloride is 3-4M.
Further, the rotating speed of the shaking table is 100rpm.
Compared with prior art, advantages and advantages of the invention are：
1st, magnetic nanoparticle compound of the invention is used to prepare T1/T2Bimodal magnetic resonance imaging contrast, gained is made Shadow agent is smaller to cell and tissue toxicity, with biocompatibility higher, has better T for tumor locus1、T2Into Image intensifying effect.
2nd, it is with passive target and active target after magnetic nanoparticle compound outermost layer of the invention is connected to-cRGD To the nano-particle complex of ability, its targeting to tumor locus is enhanced.
3rd, magnetic nanoparticle compound of the invention is used to prepare T1/T2Bimodal magnetic resonance imaging contrast, gained Contrast agent r in the PBS of pH 7.4 and pH 5.02/r1Ratio be respectively 20.6 and 7.7, it was demonstrated that it has under weak acid environment There is enhanced T1Imaging effect.
Brief description of the drawings
Fig. 1 is OA@Fe prepared by embodiment 13O4(A)、OA@Fe3O4@nSiO2(B)、OA@Fe3O4@nSiO2@mSiO2(C) With OA@Fe3O4@nSiO2@mSiO2The transmission electron microscope picture of@PAA-cRGD (D).
Fig. 2 is the uv absorption spectra of PAA-cRGD, PAA and c (RGDyK) prepared by embodiment 1.
Fig. 3 is OA@Fe prepared by embodiment 13O4@nSiO2@mSiO2Nitrogen adsorption-the desorption curve of@PAA-cRGD.
Fig. 4 is OA@Fe prepared by embodiment 13O4@nSiO2、OA@Fe3O4@nSiO2@mSiO2With OA@Fe3O4@nSiO2@ mSiO2The hysteresis curve of@PAA-cRGD.
Fig. 5 be embodiment 1 prepare Mn-IOSP in various concentrations, the PBS cushioning liquid of pH T1、T2Relaxation rate.
Fig. 6 is the T after Mn-IOSP prepared by embodiment 1 is incubated jointly with Non-small Cell Lung Cancer A 5491、T2MR is imaged Figure.
Fig. 7 is that Mn-IOSP prepared by embodiment 1 is used for T of the contrast agent to nude mouse tumor position1、T2MR weighted imaging figures.
Fig. 8 is that Mn-IOSP prepared by embodiment 1 is used for MTT experiment figure of the contrast agent to A549 cells.
Fig. 9 is that Mn-IOSP prepared by embodiment 1 is used for contrast agent after the nude mice tail vein injection 2 days of tumour transplatation H＆E staining tissue slides figures.
Specific embodiment
With reference to specific embodiment, the present invention is described in detail.
Embodiment 1
1st, the Fe of oleic acid parcel3O4The preparation of nano particle：
1.1st, by 1.08g FeCl3·6H2O, 3.65g enuatrol are dissolved in 8ml ethanol, 6ml distilled water and 14ml hexanes In mixed solvent, mixed liquor is obtained, mixed liquor is heated to 70 DEG C and the 4h that flows back, after backflow terminates, be cooled to room temperature, be layered, Separate to obtain top organic layer, by organic layer with water washing is distilled 3 times, dry, obtain iron oleate；
1.2nd, weigh in 1.8g iron oleates and 0.62g oleic acid addition conical flask, 10g trioctylamines are subsequently adding, under stirring Conical flask is heated to 340 DEG C, and insulated and stirred 1h with the speed of 25 DEG C/min, triangle is flowed through with stream of nitrogen gas again under stirring Mix products in conical flask are cooled to room temperature by flask, and mix products ethanol-hexane mixed solvent precipitate-is divided again (purification every time uses ethanol 100mL, hexane 10mL) purification three times is dissipated, ethanol precipitation is finally used again, obtain oleic acid parcel Fe3O4Nano particle, is designated as OA@Fe3O4, by OA@Fe3O4It is dispersed in hexamethylene, is configured to the OA@Fe of 7.5mg/mL3O4Dispersion Liquid.
2、OA@Fe3O4@nSiO2@mSiO2Preparation：
2.1st, 1mL is pipettedCO-520 and 20mL hexamethylenes, stirring mixing 30 minutes, are subsequently adding 1mLOA@ Fe3O4Dispersion liquid, after stirring mixing 2h, (ammoniacal liquor plays catalysis TEOS hydrolysis to be subsequently added into 150 μ L ammoniacal liquor (28wt%) Effect) and stirring 1h is sealed, then 70 μ LTEOS (tetraethyl orthosilicate) are added at twice, (25 DEG C) are anti-at room temperature after resealing After answering 6h, reaction to terminate, add methyl alcohol and be centrifuged, solid methyl alcohol, the deionized water for obtaining wash centrifugation successively, dry, and obtain To one layer of OA@Fe of solid silica of parcel3O4, it is designated as OA@Fe3O4@nSiO2.By 12mgOA@Fe3O4@nSiO2It is scattered in In 20mL deionized waters, OA@Fe are obtained3O4@nSiO2Aqueous dispersions are standby；
2.2nd, 2.0g CTAC (hexadecyltrimethylammonium chloride) and 0.2g TEA (triethylamine) are dissolved in 20mL and are gone In ionized water, 10mLOA@Fe are subsequently adding3O4@nSiO2Aqueous dispersions, stir 1h, then add at 80 DEG C after ultrasonic mixing is uniform Enter 120 μ L TEOS (tetraethyl orthosilicate), now the pH of system is 9-10, continue stirring reaction 1h, reaction is cooled to room after terminating Temperature, centrifugation, the solid methyl alcohol and deionized water of gained are washed successively, the operation of repeated washing 3 times, and the solid of gained is used Methanol solution (1wt%, each usage amount the be 20mL) dispersion of NaCl, centrifugation after 3 hours repeats the dispersion-be centrifuged Journey 3 times, to remove the CTAC of residual, then with deionized water (each usage amount is 20mL) dispersion gained solid, centrifugation, Repeat the dispersion-centrifugal process 3 times, 45 DEG C of vacuum drying obtain wrapping up one layer of OA@Fe of mesoporous silicon oxide3O4@nSiO2, It is designated as OA@Fe3O4@nSiO2@mSiO2, it is standby.
3、OA@Fe3O4@nSiO2@mSiO2The preparation of@PAA-cRGD：
3.1st, 400mg polyacrylic acid (Mw molecular weight=2000) is dispersed in the MES cushioning liquid (50mM) of pH5.5, (N- hydroxysuccinimidyls acyl is sub- to be subsequently added into 20mg EDC (1- (3- dimethylamino-propyls) -3- ethyl carbodiimides) and 12mg NHS Amine), 2h is stirred, 10mg cyclic peptide c (RGDyK) is subsequently adding, the pH value of system is adjusted to 7.4 with 0.1M sodium hydroxide solutions, React 12h under room temperature (25 DEG C), after reaction terminates, gained mix products molecular cut off be 1000Da bag filter go from In sub- water dialyse, remove residual EDC, NHS and c (RGDyK), dialysis change a deionized water for every eight hours, every time using go from Sub- water 2L, changes altogether 5 times and goes to collect solution in bag filter after water, obtains the PAA-cRGD solution of 2mg/mL；
3.2nd, by 0.01g OA@Fe3O4@nSiO2@mSiO2Add in 10mL deionized waters, ultrasonic 10min disperses, then The ammoniacal liquor (2mol/L) of 10mL PAA-cRGD solution and 150 μ L is added, continues ultrasonic mixing 1h, now the pH value of system is 8- 10,180mL isopropanols are dropwise added dropwise under stirring with dropping funel again, it is added dropwise to complete within about 1 hour, it is centrifuged, the solid second of gained Alcohol, deionized water (ethanol and each usage amount of deionized water are 20mL) wash centrifugation, the process weight of washing centrifugation successively Multiple 3 times, 45 DEG C of vacuum drying 12h obtain OA@Fe3O4@nSiO2@mSiO2@PAA-cRGD nano particles.
4th, the preparation of 5,10,15,20-2- ([4- benzamidos] urethanes) mangano-porphyrin hydrochloride：
4.1 will dissolve after 94mg 5,10,15,20- tetra- (4- carboxyl phenyls) porphyrin, 143mg EDC and 90mg NHS mixing In 4mL DMF (DMF), 1 hour activated carboxyl, Ran Houjia are reacted under nitrogen protection and room temperature (25 DEG C) Enter 151mg N-Boc- ethylenediamines and 118mg DMAP (DMAP), (25 DEG C) are continued magnetic agitation reaction at room temperature 24h, after reaction terminates, the mix products of gained is poured into 100mL saturation NaCl solutions, is filtered using sand core funnel, with full The filter residue rinsed on funnel with NaCl solution, the filter residue for then being rinsed on funnel with methyl alcohol collects filtrate, filtrate rotary evaporation Instrument is evaporated methyl alcohol and obtains residue, and residue over silica gel post is further purified, the solvent for using be methylene chloride/methanol= 90:10, collect product and dry, obtain 5,10,15,20-2- ([the 4- tert-butyl groups-benzamido] urethanes) porphins Quinoline；
4.2nd, by 15,20-2- ([the 4- tert-butyl groups-benzamido] urethanes) porphyrin (50mg) and four of gained Acetate hydrate manganese (50mg) is added in methyl alcohol, is heated to reflux in 70 DEG C of oil baths 12 hours, is filtered after the completion of reaction, the filter of gained (solvent is methylene chloride/methanol=90 to slag silica gel column separating purification:10), collect product and dry, obtain 5,10,15, 20-2- ([4- benzamidos] urethanes) mangano-porphyrin, (MALDI MS) Calculated (M) 1411.5712； Observed(M)1411.5767.
The structural formula of 5,10,15,20-2- ([4- benzamidos] urethanes) mangano-porphyrin is：
4.3rd, in 0 DEG C of ice bath, by the 5 of gained, 10,15,20-2- ([4- benzamidos] urethanes) manganese- The Isosorbide-5-Nitrae of porphyrin (30mg) and 0.5mL4M hydrogen chloride-dioxane solution is added in dichloromethane, then directly at room temperature (25 DEG C) react and slough N-boc blocking groups in 12 hours, obtain 5,10,15,20-2- ([4- benzamidos] urethanes) Mangano-porphyrin hydrochloride, (MALDI MS) Calculated (M) 1155.2682, (M-4HCl) 1011.3615；Observed(M- 4HCl)1011.3632.
The structural formula of 5,10,15,20-2- ([4- benzamidos] urethanes) mangano-porphyrin hydrochloride is：
5th, the preparation of Mn-IOSP：
5,10,15,20-2- ([4- benzamidos] urethanes) mangano-porphyrin hydrochloride of gained is added into water In be made into the solution A of 10mg/mL, by 5mg OA@Fe3O4@nSiO2@mSiO2@PAA-cRGD nano particles are scattered in water (5mL) In the mixed solution of isopropanol (45mL), dispersion liquid B is obtained, by 1mL solution As and dispersion liquid B addition reaction vessels, incite somebody to action anti- Container is answered to be placed in shaking table (shaking table temperature is 37 DEG C, rotating speed 100rpm) mixing 24h, after mixing terminates, centrifugation, the solid of gained Washed-be centrifuged 3 times with the PBS solution (10mL) of pH 7.4, obtained for T1、T2The magnetic Nano of bimodal magnetic resonance contrast agent Particle composites, are designated as Mn-IOSP.
By Mn-IOSP obtained in the present embodiment disperse again in the solution, for detect Mn-IOSP every property and into As performance.
By OA@Fe obtained in the present embodiment3O4、OA@Fe3O4@nSiO2、OA@Fe3O4@nSiO2@mSiO2With OA@Fe3O4@ nSiO2@mSiO2@PAA-cRGD are scanned with transmission electron microscope, and the transmission electron microscope picture of gained by Fig. 1 as shown in figure 1, can be seen Go out, OA@Fe3O4、OA@Fe3O4@nSiO2、OA@Fe3O4@nSiO2@mSiO2With OA@Fe3O4@nSiO2@mSiO2@PAA-cRGD etc. Nano particle favorable dispersibility, uniform particle diameter, OA@Fe3O4@nSiO2@mSiO2The particle size of@PAA-cRGD nano particles is about It is 100nm.
PAA-cRGD solution obtained in the present embodiment is detected with ultraviolet absorption spectroscopy, the ultra-violet absorption spectrum of gained Figure is as shown in Fig. 2 figure it is seen that the absworption peak at 274nm proves that cyclic peptide c (RGDyK) has been successfully connected on PAA.
By OA@Fe obtained in the present embodiment3O4@nSiO2@mSiO2@PAA-cRGD nano particles carry out nitrogen adsorption-desorption Isothermal experiment, the nitrogen adsorption-desorption curve for obtaining are as shown in figure 3, from the figure 3, it may be seen that the specific surface area of the nano particle is 349m2/ g, pore-size distribution reaches peak value at 3.5nm, it was demonstrated that the nano particle has meso-hole structure.
By OA@Fe obtained in the present embodiment3O4@nSiO2、OA@Fe3O4@nSiO2@mSiO2With OA@Fe3O4@nSiO2@ mSiO2@PAA-cRGD carry out hysteresis curve sign, and the hysteresis curve of gained is as shown in figure 4, from fig. 4, it can be seen that these three are received Rice grain all has superparamagnetism.
Mn-IOSP obtained in the present embodiment is dispersed in the PBS cushioning liquid of pH value (7.4,6.5) and the vinegar of pH value 5.0 In sour ammonium cushioning liquid (three kinds of buffer concentrations are 10mM), various concentrations Mn-IOSP is (with the concentration of Mn elements for test Meter) T in the cushioning liquid of different pH value1、T2Relaxation time, by T1、T2Relaxation time maps to pH and concentration, obtains Relation curve as shown in figure 5, as shown in Figure 5, in the cushioning liquid of pH 7.4 and pH 5.0, r2/r1Ratio be respectively 20.6 With 7.7.
By Mn-IOSP obtained in the present embodiment and Non-small Cell Lung Cancer A 549 co-incubation, according to the dense of Mn elements Degree is calculated, and adds the nano-particle complex Mn-IOSP aqueous dispersions of various concentrations (10 μM -100 μM), and each concentration uses 5* 106Individual Non-small Cell Lung Cancer A 549, with PBS by the Mn- on Non-small Cell Lung Cancer A 549 surface after 1 hour IOSP is rinsed out, and trypsin digestion cell simultaneously collects postdigestive cell with PBS, and postdigestive cell is transferred into diameter T is carried out in the nuclear magnetic tube of 5mm1、T2The MR imagings of weighting, as shown in Figure 6.From fig. 6 it can be seen that as addition Mn-IOSP is dense The rising of degree, T1、T2Relaxation effect strengthens, it can be seen that, T1、T2Imaging booster action effect and Mn-IOSP concentration (Mn elements Concentration) it is in obvious dependence.
The magnetic resonance imaging that experiment one, magnetic nanoparticle compound Mn-IOSP of the invention is used for contrast agent is tested.
Experimental technique：
(cell quantity 1*10 is used in the BALB/c male nude mouse thigh subcutaneous implantation A549 cells in 4-5 weeks mouse age7), and Nude mice after implantation tumor is raised 2 weeks again, until leg can observe with the naked eye small tumour.By tail vein to nude mice Injection contrast agent (described contrast agent is that 5mgMn-IOSP is dispersed in the PBS of 0.01M the dispersion liquid for being configured to 5mg/mL), Injection dosage is 200 μ L, and concentration is 1.1mg Mn/kg (nude mice body weight), uses 7.0T small animal imagings (Bruker BioSpec T 70/20USR) is carried out to nude mouse tumor position1、T2Weighted imaging.
Experimental result：
The magnetic resonance imaging of gained is as shown in fig. 7, injection detects the T of tumor locus after 3 hours1、T2Relaxation time occurs bright It is aobvious to change, T1Relaxation shortens, T2Relaxation shortens, it can be seen that, magnetic nanoparticle compound Mn-IOSP can be used for preparation and make Shadow agent, can be used for the T of tumor locus1、T2Bimodal is imaged.
Experiment two, magnetic nanoparticle compound Mn-IOSP of the invention is used for contrast agent to cell, tissue toxicity's test Experiment
Experimental technique：
1st, A549 cells are inoculated with 96 orifice plates, are 5000 per hole cell quantity, culture is separately added into not after 24 hours With the Mn-IOSP solution (with the densimeter of Mn elements) of concentration, suctioned out after adding 4h, the Mn- of cell surface is rinsed out with PBS After IOSP, RPMI-1640 culture mediums are added to be further cultured for 44 hours, and add the MTT solution of final concentration of 0.5mg/ml, 4 hours After remove unreacted MTT solution, add the DMSO of 200 μ L, detect the OD values of each group cell, cell is judged according to OD values Survival rate.
2nd, the BALB/c male nude mouse thigh subcutaneous implantation A549 cells in 4-5 weeks mouse age (use cell quantity 1*107), And raise the nude mice after implantation tumor again 2 weeks, until leg can observe with the naked eye small tumour, by tail vein to naked (described contrast agent is that 5mgMn-IOSP is dispersed in the PBS of 0.01M the dispersion for being configured to 5mg/mL to mouse injection contrast agent Liquid), injection dosage is 200 μ L, concentration is 1.1mg Mn/kg (nude mice body weight), and control group injects 200 μ L PBS, after 48 hours Putting to death nude mice carries out pathological section, is detected in accordance with standard H＆E decoration methods.
Experimental result：
1st, the cell survival rate under the Mn-IOSP solution of various concentrations is as shown in figure 8, from figure 8, it is seen that various concentrations Mn-IOSP solution without obvious acute cytotoxicity.
2nd, tumour transplatation nude mice injection contrast agent after H＆E staining tissue slides as shown in figure 9, from fig. 9, it can be seen that Mn-IOSP is without obvious tissue toxicity.

Claims (10)

1. it is a kind of to be used for T1、T2The magnetic nanoparticle compound of bimodal magnetic resonance contrast agent, it is characterised in that：Described magnetic Property nano-particle complex be three layers of nucleocapsid structure, described core is Fe3O4Nano particle, intermediate layer is load 5,10,15, The silicon dioxide layer of 20-2- ([4- benzamidos] urethanes) mangano-porphyrin hydrochloride, outermost layer is targeted integration element The acrylic acid polymer layer of the cyclic peptide group-cRGD of acceptor.
2. described in a kind of claim 1 for T1、T2The preparation of the magnetic nanoparticle compound of bimodal magnetic resonance contrast agent Method, it is characterised in that comprise the following steps：
2.1、OA@Fe3O4@nSiO2@mSiO2Preparation：
2.1.1, the Fe for first wrapping up oleic acid3O4Nano particle OA@Fe3O4It is dispersed in hexamethylene, obtains OA@Fe3O4Dispersion liquid；
2.1.2, in hexamethylene andIn CO-520, OA@Fe are added3O4Dispersion liquid, be well mixed, be subsequently adding ammoniacal liquor and Tetraethyl orthosilicate, OA@Fe3O4, tetraethyl orthosilicate andThe mass ratio of CO-520 is 1:9-11:120-140, in room temperature With it is closed under conditions of stirring reaction 4-8 hours, obtain wrap up one layer of OA@Fe of solid silica3O4, it is designated as OA@Fe3O4@ nSiO2；
2.1.3, in the mixed aqueous solution of hexadecyltrimethylammonium chloride and organic base triethanolamine, OA@Fe are added3O4@ nSiO2Aqueous dispersions and tetraethyl orthosilicate, now the pH of system is 9-10, OA@Fe3O4@nSiO2, tetraethyl orthosilicate and hexadecane The mass ratio of base trimethyl ammonium chloride is 1：15-25：300-400, reacts 0.5-1.5 hours at 60-100 DEG C, is wrapped up One layer of OA@Fe of mesoporous silicon oxide3O4@nSiO2, it is designated as OA@Fe3O4@nSiO2@mSiO2；
2.2、OA@Fe3O4@nSiO2@mSiO2The preparation of@PAA-cRGD：
2.2.1, polyacrylic acid is dispersed in the cushioning liquid of pH5.0-6.0,1- (3- dimethylamino-propyls) -3- ethyls are added Carbodiimide hydrochloride, N-hydroxy-succinamide and cyclic peptide c (RGDyK), polyacrylic acid, 1- (3- dimethylamino-propyls) -3- Ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide, the mol ratio of cyclic peptide c (RGDyK) are 1-3:0.5-1.5:1-3: 0.1-1, adjusts the pH to 7.0-7.5 of system, reacts 10-12 hours at room temperature, and the mix products dialysis of gained falls remnants not After the small molecule of reaction, PAA-cRGD solution is obtained；
2.2.2, by OA@Fe3O4@nSiO2@mSiO2Dispersion in deionized water, adds PAA-cRGD solution and ammoniacal liquor, now body The pH of system is 8-10, OA@Fe3O4@nSiO2@mSiO2It is 1 with the mass ratio of PAA-cRGD:1.5-2.5, ultrasonic mixing is uniform, side Stirring side is added dropwise isopropanol so that PAA-cRGD is deposited on OA@Fe3O4@nSiO2@mSiO2On surface, OA@Fe are obtained3O4@ nSiO2@mSiO2@PAA-cRGD；
2.3rd, the preparation of 5,10,15,20-2- ([4- benzamidos] urethanes) mangano-porphyrin hydrochloride：
2.3.1, in methyl alcohol, 5,10,15,20-2- ([the 4- tert-butyl groups-benzamido] urethanes) porphyrins and four water Close manganese acetate reaction, 5,10,15,20-2- ([the 4- tert-butyl groups-benzamido] urethanes) porphyrins and four acetate hydrates The mol ratio of manganese is 1：5-10, flows back 10-14 hours at 60-80 DEG C, obtains 5,10,15,20-2- ([4- benzamidos] Urethanes) mangano-porphyrin；
2.3.2, in dichloromethane, 5,10,15,20-2- ([4- benzamidos] urethanes) mangano-porphyrins and chlorination The Isosorbide-5-Nitrae of hydrogen-dioxane solution reaction, 5,10,15,20-2- ([4- benzamidos] urethanes) mangano-porphyrins and chlorine The mol ratio for changing hydrogen is 1：50-150, at room temperature reaction sloughs N-boc blocking groups in 10-14 hours, obtains 5,10,15,20-2- ([4- benzamidos] urethanes) mangano-porphyrin hydrochloride；
2.4th, the preparation of Mn-IOSP：
By OA@Fe3O4@nSiO2@mSiO2The reaction that@PAA-cRGD are scattered in the mixed solution equipped with deionized water and isopropanol is held In device, 5,10,15,20-2- ([4- benzamidos] urethanes) mangano-porphyrin HCI solutions, OA@Fe are added3O4@ nSiO2@mSiO2@PAA-cRGD and 5,10,15,20-2- ([4- benzamidos] urethanes) mangano-porphyrin hydrochloride Mass ratio is 1：1-2, reaction vessel is placed in shaking table, is mixed 22-26 hours at 30-40 DEG C, is obtained for T1、T2Bimodulus The magnetic nanoparticle of state magnetic resonance contrast agent, is designated as Mn-IOSP.
3. according to claim 2 for T1、T2The preparation of the magnetic nanoparticle compound of bimodal magnetic resonance contrast agent Method, it is characterised in that：In step 2.1.2, the mass fraction for adding ammoniacal liquor is 25-30%；In step 2.2.2, ammoniacal liquor is added Concentration be 2mol/L.
4. according to claim 2 for T1、T2The preparation of the magnetic nanoparticle compound of bimodal magnetic resonance contrast agent Method, it is characterised in that：In step 2.2.1,1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides and N- are first added HOSu NHS, stirs 2h at room temperature, adds cyclic peptide c (RGDyK).
5. according to claim 2 for T1、T2The preparation of the magnetic nanoparticle compound of bimodal magnetic resonance contrast agent Method, it is characterised in that：In step 2.2.2, isopropanol was added dropwise to complete with 0.5-1.5 hours, final system reclaimed water and isopropanol Volume ratio be 1:8-10.
6. according to claim 2 for T1、T2The preparation of the magnetic nanoparticle compound of bimodal magnetic resonance contrast agent Method, it is characterised in that：In step 2.2.1, the mix products of gained are carried out with the bag filter that molecular cut off is 1000Da Analysis.
7. according to claim 2 for T1、T2The preparation of the magnetic nanoparticle compound of bimodal magnetic resonance contrast agent Method, it is characterised in that：Described cushioning liquid is MES cushioning liquid, and the concentration of MES is 50mM.
8. according to claim 2 for T1、T2The preparation of the magnetic nanoparticle compound of bimodal magnetic resonance contrast agent Method, it is characterised in that：The weight average molecular weight of described polyacrylic acid is 2000.
9. according to claim 2 for T1、T2The preparation of the magnetic nanoparticle compound of bimodal magnetic resonance contrast agent Method, it is characterised in that：The concentration of the 1,4- dioxane solutions of described hydrogen chloride is 3-4M.
10. according to claim 2 for T1、T2The system of the magnetic nanoparticle compound of bimodal magnetic resonance contrast agent Preparation Method, it is characterised in that：The rotating speed of the shaking table is 100rpm.
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