CN105169419A - Novel three-mode contrast agent and preparation method thereof - Google Patents
Novel three-mode contrast agent and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a novel three-mode contrast agent and a preparation method thereof. The contrast agent consists of a hollow mesoporous silicon oxide shell, first gold nanoparticles which are arranged in a hollow cavity of the hollow mesoporous silicon oxide shell and are used as a core, and second gold nanoparticles and MnO nanoparticles which are uniformly dispersed in a shell layer of the hollow mesoporous silicon oxide shell. The three-mode contrast agent provided by the invention is prepared by designing an assembly structure, wherein a heterogeneous rattle structure constituted by the hollow mesoporous silicon oxide nanoparticles and the large core gold nanoparticles can arouse double scattering in a single particle; the Au nanoparticles and the MnO nanoparticles uniformly dispersed in the shell layer can enhance non-linear scattering, and can further enhance ultrasound imaging; in addition, by virtue of the MnO nanoparticles which are uniformly dispersed, the probability and the area of getting into contact with water molecules are improved, so that MR imaging is significantly enhanced; and by virtue of a nuclear-satellite structure formed by the gold nanoparticles, an X-ray absorption efficiency is significantly enhanced and a CT contrast effect is improved.
Description
Technical field
The invention belongs to nano biological field of medicaments, be specifically related to a kind ofly integrate three pattern contrast agent strengthening ultrasonic, nuclear-magnetism and CT tri-kinds of imaging effects and preparation method thereof and positive charged surface modification.
Background technology
Cancer is the major disease of serious threat human health, and early diagnosis and early intervention are direction and the focuses that cancer patient obtains that long term survival and the unique opportunity, particularly early diagnosis of improving prognosis have become current research and development.Molecular imaging is a kind of Noninvasive imaging modality of rapid rising in biomedical sector in recent years, refers to and utilizes specific receptor or part in molecular imaging agent target biology body, detects change biology of in vivo parton level in vitro.But, in molecular imaging methods numerous at present, as in nuclear-magnetism, ultrasonic, CT, PET, optoacoustic, any one single formation method all cannot reflect full detail (AccountsChem.Res.2008,41, the 1630-1640 of focus effectively; ChemSocRev.2012,41,2656-2672).For obtaining lesion information more comprehensively, now general method is exactly the conbined usage of multiple formation method, needs to design multiple contrast agent for this reason.And different contrast agent superposition use often causes great risk of toxicity, therefore multiple image-forming contrast medium is incorporated into one and will has great application prospect, this research direction is just becoming the study hotspot of material, chemistry and field of biomedical research at present.
Ultrasonic, these three kinds of imaging modes of nuclear-magnetism, CT be clinical at present in the molecular image diagnostic means that is most widely used, they have respective advantage respectively, as ultrasonic can Real-time and Dynamic imaging, temporal resolution is good, but sensitivity and resolution rate variance, nuclear-magnetism sensitivity and spatial resolution greatly, can realize pathological analysis, but time resolution rate variance, not dynamic, realtime imaging; CT imaging time and spatial resolution are all larger, but poor sensitivity.Therefore the combination of these three kinds of imaging means can realize having complementary advantages, shortcoming makes up, realize tumor early stage, efficiently diagnose.But there is no research report about the combination of these three kinds of imaging means and the preparation of corresponding integrated contrast agent at present, what exist is only combine between two, as ultrasonic with nuclear-magnetism (AdvFunctMater2011,21,2548-2555), nuclear-magnetism and CT (Biomaterials2013,34,3390-3401).Therefore, in order to realize, cancer is early stage, efficient, Precise Diagnosis, develops biological safety good, can realize strengthening ultrasonic contrast, NMR (Nuclear Magnetic Resonance) imaging and CT imaging three kinds of functions become to have most important theories realistic meaning and using value in three pattern contrast agent of one.We prepare the hollow mesopore silicon oxide of the amino functional of size adjustable in earlier stage, react that to obtain with gold be the heterogeneous rattle type structure of kernel further with gold chloride simultaneously, and size of cores is adjustable (CN102530969A), but this research report does not carry out ultrasonic and CT imaging research, simultaneously without the function of Enhanced MR imaging yet.
Summary of the invention
In order to realize, tumor is efficient, safety, Precise Diagnosis, the object of the present invention is to provide a kind ofly to strengthen ultrasonic, nuclear-magnetism, CT imaging function respectively in three pattern contrast agent and preparation technologies thereof of one.
At this, on the one hand, the invention provides a kind of ultrasonic/nuclear-magnetism/CT tri-pattern contrast agent, described contrast agent comprises: hollow mesopore silicon oxide shell, be arranged in first gold nano grain as kernel of the cavity of mesopore silicon oxide shell described in hollow and be dispersed in the second gold nano grain of shell and the MnO nano-particle of described hollow mesopore silicon oxide shell.
Three pattern contrast agent provided by the invention are obtained by constituent optimization design, and its component comprises the good inorganic component of silicon oxide, gold nano grain and MnO nano-particle three kinds of biological safeties.
Three pattern contrast agent provided by the invention are obtained by group structural design, double scattering in individual particle can be there is in the heterogeneous rattle structure that wherein hollow mesoporous monox nanometer granule and the large gold nano grain of kernel are formed, be dispersed in Au nano-particle in shell and MnO nano-particle can strengthen nonlinear scattering, both are for strengthening ultra sonic imaging further; In addition, homodisperse MnO nano-particle improves the probability that contacts with hydrone and area can significantly improve MR imaging, and " core-satellite " structure that gold nano grain is formed can significantly strengthen X-ray absorption efficiency, improves CT contrasting effects.
Preferably, the external diameter of described hollow mesopore silicon oxide shell is 350 ~ 450nm, and internal diameter is 200 ~ 300nm, and mesoporous pore size is 25 ~ 35nm.
Preferably, the particle diameter of described first gold nano grain is 40 ~ 60nm, and the particle diameter of described second gold nano grain is 2 ~ 8nm, and the particle diameter of described MnO nano-particle is 0.5 ~ 3nm.
Preferably, described MnO nano-particle is paramagnetic.
Preferably, described contrast agent also comprises the polymine of modifying in described hollow mesopore silicon oxide case surface.Modified through polymine positive electricity, cytophagy amount increases greatly, can more must absorb by tumor cell, can further improve the contrasting effects of three kinds of imaging patterns.
On the other hand, the present invention also provides the preparation method of above-mentioned three pattern contrast agent, comprises the following steps:
A) the hollow mesoporous monox nanometer Granular composite of amino functional is carried out hydro-thermal reaction in chlorauric acid solution, with obtained product A, described product A has the first gold nano grain produced in the cavity of described hollow mesopore silicon oxide as kernel, and homodisperse second gold nano grain in the shell of described hollow mesopore silicon oxide simultaneously;
B) product A is scattered in potassium permanganate solution carries out redox reaction, with dispersed Mn oxide in the shell of the hollow mesopore silicon oxide of product A further, and reduce under reducing atmosphere, thus obtained described ultrasonic/nuclear-magnetism/CT tri-pattern contrast agent.
The present invention adopt original position order autoreduction legal system for above-mentioned ultrasonic/nuclear-magnetism/CT tri-pattern contrast agent, preparation is simple, without any pollution, output is high, cost is low, efficiency is high, reproducible, is applicable to industrialization large-scale production.
Preferably, steps A) in, the concentration of chlorauric acid solution is 0.0125 ~ 0.05M, and the mass ratio of gold chloride and hollow mesoporous monox nanometer granule is 1:(2 ~ 4), hydrothermal temperature is 75 ~ 85 DEG C, and the hydro-thermal reaction time is 40 ~ 120 minutes.
Preferably, step B) in, the concentration of potassium permanganate solution is below 1.5M, and the reaction temperature of described redox reaction is room temperature ~ 60 DEG C, and the response time is 1 ~ 24 hour; Reducing atmosphere is the gaseous mixture of hydrogen or hydrogen and argon, and the reaction temperature of reducing under reducing atmosphere is more than 600 DEG C, and the response time is more than 2 hours.
Preferably, also comprise step C) by described ultrasonic/nuclear-magnetism/CT tri-pattern contrast agent is scattered in polyethylenimine solution, stirring at room temperature adsorb, prepare polyethyleneimine-modified ultrasonic/nuclear-magnetism/CT tri-pattern contrast agent.
Preferably, step C) in, polymine concentration is 20mg/ml ~ 2g/ml, and molecular weight is 650 ~ 12500.
Three pattern contrast agent provided by the invention can realize simultaneously various diseases especially cancer multi-mode diagnosis, clinical medicine application in there is extremely important meaning, clinical Transformation Potential is huge.
Accompanying drawing explanation
Fig. 1 is that in embodiment 1, particle diameter is the hollow mesoporous silicon oxide nanomaterial transmission electron microscope picture of the amino functional of about 400nm;
Fig. 2 is that in embodiment 1, particle diameter is the scanning electron microscope (SEM) photograph of about 400nm;
Fig. 3 be in embodiment 2 preparation take gold as the heterogeneous rattle structure of kernel, Au@HMSN/Au transmission electron microscope picture;
Fig. 4 is the transmission electron microscope picture of load P d nano-particle under the different temperatures prepared in embodiment 3-6, Fig. 4 a is that embodiment 3 obtains HMSN-Pd-30 transmission electron microscope picture, mean P d nanoparticle size 5nm in shell, Fig. 4 b is that embodiment 4 obtains HMSN-Pd-50 transmission electron microscope picture, mean P d nanoparticle size 6.4nm in shell, Fig. 4 c is that embodiment 5 obtains HMSN-Pd-70 transmission electron microscope picture, mean P d nanoparticle size 3.2nm in shell, Fig. 4 d is that embodiment 6 obtains HMSN-Pd-90 transmission electron microscope picture, mean P d nanoparticle size 2.3nm in shell, and Pd nano-particle soilless sticking,
Fig. 5 obtains three pattern contrast agent (Au@HMSN/Au/MnO) transmission electron microscope picture in embodiment 7;
Fig. 6 is three pattern contrast agent (Au HMSN/Au/MnO) the energy spectrogram obtained in embodiment 7;
Fig. 7 is the MH curve of the three pattern contrast agent (Au@HMSN/Au/MnO) obtained in embodiment 7;
Fig. 8 is the HMSN/MnO transmission electron microscope picture of preparation in embodiment 8;
Fig. 9 is HMSN, Au@HMSN/Au, Au@HMSN/Au/MnO, HMSN/MnO nitrogen adsorption desorption curve obtained respectively in embodiment 1,2,7,8;
Figure 10 is HMSN, Au@HMSN/Au, Au@HMSN/Au/MnO, HMSN/MnO pore size distribution curve obtained respectively in embodiment 1,2,7,8;
Figure 11 be HMSN, Au@HMSN/Au, Au@HMSN/Au/MnO obtained respectively in embodiment 1,2,7, ultravioletvisible absorption curve;
Figure 12 is HMSN, Au@HMSN/Au, Au@HMSN/Au/MnO obtained respectively in embodiment 1,2,7,9, Au@HMSN/Au/MnO-PEI surface charge change curve;
HMSN, Au@HMSN/Au, Au@HMSN/Au/MnO obtained respectively in Figure 13 embodiment 1,2,7,9, the FTIR spectrum of Au@HMSN/Au/MnO-PEI.
Detailed description of the invention
Further illustrate the present invention below in conjunction with accompanying drawing and following embodiment, should be understood that accompanying drawing and following embodiment are only for illustration of the present invention, and unrestricted the present invention.
One aspect of the present invention provides a kind of for strengthening the three pattern contrast agent that ultrasonic, nuclear-magnetism, CT tri-kinds of imaging functions are integrated, it is obtained by constituent optimization design and structural design, kernel is large gold nano grain (the first gold nano grain), shell is mesopore silicon oxide shell, form heterogeneous rattle type structure, embed a large amount of little gold nano grains (the second gold nano grain) and MnO nano-particle in shell simultaneously.
In this contrast agent can there is double scattering in individual particle in heterogeneous rattle structure, is dispersed in Au nano-particle in shell and MnO nano-particle can strengthen nonlinear scattering, and both are for strengthening ultra sonic imaging further; In addition, homodisperse MnO nano-particle improves the probability that contacts with hydrone and area can significantly improve MR imaging, and " core-satellite " structure that gold nano grain is formed can significantly strengthen X-ray absorption efficiency, improves CT contrasting effects.Therefore, this contrast agent can be used as acoustic contrast agent, nuclear magnetism contrast agent and CT contrast agent, can strengthen ultra sonic imaging contrast respectively, NMR (Nuclear Magnetic Resonance) imaging contrast becomes image contrast with CT.
The grain diameter of three pattern contrast agent of the present invention can be 350 ~ 450nm, and be such as 400nm, granule has regular spherical morphology, the dispersibility of homogeneous particle diameter and height.Wherein the external diameter of mesopore silicon oxide shell can be 350 ~ 450nm, and internal diameter can be 200 ~ 300nm, and mesoporous pore size can be 25 ~ 35nm, and pore volume can be 0.12-0.38, and specific surface area can be 18 ~ 95m
2/ g.Preferably, in each mesopore silicon oxide hollow ball inside only containing a gold nano grain as kernel, this golden nanometer particle size can be 40 ~ 60nm, such as, be 50nm.Little gold nano grain (the second gold nano grain) in shell and MnO nano-particle dispersed, wherein the particle diameter of the second gold nano grain can be 2 ~ 8nm, and the particle diameter of MnO nano-particle can be 0.5 ~ 3nm.The load capacity of MnO nano-particle can be 6 ~ 16wt%.In addition, this MnO nano-particle is paramagnetic.
Preferably, can also at hollow mesopore silicon oxide case surface modifying polyethyleneimine.Contrast agent surface can be made like this in electropositivity, can more absorb by tumor cell, can further improve the contrasting effects of three kinds of imaging patterns.
Three pattern contrast agent of the present invention can adopt original position order autoreduction method to obtain.In one example, its preparation process comprises
1) the hollow mesoporous monox nanometer granule (HMSN) of amino functional is prepared;
2) HMSN is scattered in chlorauric acid solution, utilize amino preparing with gold with the redox reaction of gold chloride to be the heterogeneous rattle type structure of kernel, embed the less gold nano grain of a large amount of sizes (Au@HMSN/Au) in shell simultaneously;
3) above-mentioned product is scattered in potassium permanganate solution, remaining amino and potassium permanganate generation redox reaction is utilized to prepare the MnO nano-particle be dispersed in silicon oxide shell, and high temperature reduction under reducing atmosphere, construct three mode ultrasound contrast agent---Au@HMSN/Au/MnO;
4) dispersion of materials of above-mentioned preparation is in polyethylenimine solution, and stirring at room temperature is adsorbed, and prepares three pattern contrast agent of polyethyleneimine-modified, i.e. Au@HMSN/Au/MnO-PEI.
Wherein, the preparation method of HMSN is not limit, and preferably employing achieves external diameter is 350 ~ 450nm, and internal diameter is 200 ~ 300nm, and aperture is the method for 25 ~ 35nm, such as can see prior art document (CN102530969A).In one example, using aminopropyl triethoxysilane (APTES) as organosilicon source, water, ethanol, ammonia and TEOS volume ratio: 10:71.6:3.14:6, prepare solid silica kernel time 40-50min, APTES and TEOS volume ratio 2:5, shell response time 70-80min, etching agent ammonium carbonate concentration 0.4-0.6M, etch period 40min ~ 120min, temperature 80 DEG C.Preferably, the hollow mesoporous monox nanometer granule (HMSN) of the amino functional of size 400nm is prepared.
About the preparation of Au@HMSN/Au, also can see prior art document (such as CN102530969A).In one example, with the mass ratio of gold chloride and hollow mesoporous monox nanometer granule for 1:(2 ~ 4) ratio HMSN is scattered in concentration is in the chlorauric acid solution of 0.0125 ~ 0.05M, carry out hydro-thermal reaction, hydrothermal temperature can be 75 ~ 85 DEG C, the hydro-thermal reaction time is can 40 ~ 120 minutes, prepare the gold nano grain of size of cores 40 ~ 60nm, form Au@HMSN/Au.Wherein, preferably select gold chloride concentration 0.05M, gold chloride and HMSN mass ratio are 1:2.7, reaction temperature 80 DEG C, and time 2 h, prepares the gold nano grain of size of cores 50nm.
After HMSN and gold chloride react obtained Au@HMSN/Au, still have remaining amino can further with step 3) in potassium permanganate react, obtained MnO nano-particle, realization order autoreduction reacts.
In step 3) in, the concentration of potassium permanganate solution can be below 1.5M, is preferably between 0.2 ~ 1.5M, is more preferably 0.2 ~ 1M, more preferably 0.4 ~ 0.6M.The amount ratio of Au@HMSN/Au and potassium permanganate solution can be 5 ~ 10g:1L.Reaction temperature can be between room temperature ~ 60 DEG C, and be preferably 25 ~ 40 DEG C, the response time can be 1 ~ 24 hour, is preferably 2 ~ 5 hours.Potassium permanganate load capacity can be 15% ~ 35%.By Au@HMSN/Au and potassium permanganate solution generation redox reaction, can in silicon oxide shell dispersed Mn oxide (MnOx).Reduce under high-temperature reductibility atmosphere further again, three pattern contrast agent (Au@HMSN/Au/MnO) can be obtained.Wherein reducing atmosphere can be the gaseous mixture of hydrogen or hydrogen and argon, such as 5%H
2-95%Ar, the reaction temperature of reducing under reducing atmosphere can be more than 600 DEG C, and the response time can be more than 2 hours.
It should be noted, above-mentioned steps 2) and step 3) can not exchange, because potassium permanganate is strong oxidizer, all amino can be consumed, after exchanging, the oxidoreduction of gold nano grain cannot be realized.
Through above-mentioned steps 3) the Au@HMSN/Au/MnO surface electronegative that obtains, be unfavorable for being engulfed by tumor cell.Therefore, preferably positive electricity modification is carried out to its surface, with can more absorb by tumor cell.Polymine (PEI) is preferably used to carry out positive electricity modification.Modified through polymine positive electricity, cytophagy amount increases greatly, can further improve the contrasting effects of three kinds of imaging patterns.And polymine, except positive electricity modification, can also improve the dispersibility of three pattern contrast agent.In step 4) in, selected polymine concentration can be 20mg/ml ~ 2g/ml, and be preferably 100mg/ml ~ 200mg/ml, molecular weight can be 650 ~ 12500, and such as 600,1300,1800,2000,10000 etc., be preferably 1800.
Step 2), 3) in the gold nano grain that produces and MnO nano-particle reducing agent used be step 1) in preparation amino functional hollow mesoporous monox nanometer granule on amino, without the need to additional exogenous reductant, can step be simplified, save cost.
Step 2), 3) after, the size of three pattern contrast agent still with step 1) the HMSN carrier dimensions prepared is consistent, such as, be 400nm.
At the mesoporous SiO of the hollow of functionalization
2in the method for ball situ synthesis gold nano grain, in hollow cavity, the gold nano grain that fabricated in situ particle diameter is adjustable, forms heterogeneous core/shell structure and avoids the first synthesis gold then many tedious steps of coated shell, and exacting terms.The core/shell structure mesopore silicon oxide spheres of obtained with gold nano grain is core has important application in fields such as molecular imaging, biological medicine, catalysis.
Step 3) in, after the hollow mesoporous monox nanometer granule of amino functional and potassium permanganate react, shell aperture becomes greatly, illustrates that potassium permanganate has the effect of reaming.
In addition, said method is not limited to preparation Au@HMSN/Au/MnO, such as, in above-mentioned steps 2) in, except preparing except gold nano grain, the amino in the hollow mesoporous monox nanometer granule of amino functional can also reduce Pd source (such as K
2pdCl
6) and Pt source (such as K
2ptCl
6) produce the noble metal nano particles such as Pd and Pt nano-particle, thus evenly the noble metal nano particles such as Pd nano-particle and Pt nano-particle is embedded in the shell of HMSN.Therefore, the present invention can also provide HMSN/Pd, HMSN/Pt, HMSN/Pd/MnO, HMSN/Pt/MnO etc.By regulating and controlling the temperature of reduction reaction, the noble metal nano particles of different-grain diameter can be prepared.Such as at reduction K
2pdCl
6time, when reaction temperature is between 30 ~ 90 DEG C, the Pd granule that mean diameter is 2 ~ 7nm can be prepared.
First the present invention utilizes the original position hydrophobic layer protective seletion etching method of document and patent report to prepare the hollow mesoporous monox nanometer granule of amino functional; Then utilizing order restoring method first to react with gold chloride to prepare with gold is the heterogeneous rattle structure of kernel, and the gold nano grain that in shell, load is less, reacts with potassium permanganate further and prepare shell equally loaded manganese oxide nano granule; Polymine positive electricity modification is carried out on last surface.
Exemplarily, the technological means of each technical solution problem provided by the invention is specifically described below.Other alternative steps that can reach equivalent effect also can be omitted or use to certain should understanding in following steps, and each feature in each step neither be necessary or replaceable regularly and not, and just illustratively illustrate.
(1) the hollow mesoporous monox nanometer granule (HMSN) of synthesizing amino functionalization:
A certain amount of dehydrated alcohol, deionized water and ammonia mixing, after stirring a period of time, add a certain amount of silicon source (ethyl orthosilicate) fast, the magnetic stirring regular hour, can be observed solution and to be creamy white shape under the condition of 20-40 DEG C.Subsequently by after organo silane coupling agent (as the aminopropyl trimethoxysilane) Homogeneous phase mixing of a certain amount of ethyl orthosilicate and functional group, add rapidly above-mentioned solution, magnetic stirring a period of time, after product is centrifugal, obtain homogeneity core/shell SiO
2nanoparticle is stand-by.The product obtained in above-mentioned is dispersed in a certain amount of alkaline solution (as Na
2cO
3solution), vigorous stirring a period of time at a certain temperature, realized the preparation of hollow or the mesoporous SiO2 nano-particle of core/shell by regulation and control etch period and the parameter such as etching agent concentration and consumption.Repeatedly, lyophilization is stand-by in centrifugal washing.
(2) be interior dyskaryosis rattle structure (Au HMSN/Au) with gold nano grain:
Hollow mesoporous monox nanometer granule and a certain amount of golden presoma (such as gold chloride is 1:(2 ~ 4 with the mass ratio of hollow mesoporous monox nanometer granule) of the amino functional that (1) is obtained) simply mix hydro-thermal certain hour and can obtain, concrete technology exactly: by the hollow SiO of the amino functional that (1) obtains
2ball ultrasonic disperse 40min ~ 60min in the chlorauric acid solution of finite concentration (such as 0.0125 ~ 0.05M), lucifuge, then 75 ~ 85 DEG C of water-bath hydro-thermal 60min-120min are placed in, until yellow becomes pink, centrifugal after washing repeatedly, until supernatant clarification, lyophilization is stand-by.
(3) shell load manganese oxide particle is interior dyskaryosis rattle structure (Au HMSN/Au/MnO) with gold nano grain:
The Au@HMSN/Au (2) obtained mixes with a certain amount of potassium permanganate (such as Au@HMSN/Au is 5 ~ 10g:1L with the amount ratio of potassium permanganate solution), reaction a period of time can obtain Au@HMSN/Au/MnO, what (2) obtained by concrete technology exactly is interior dyskaryosis rattle structure disperses 2h-4h in the potassium permanganate solution of finite concentration (such as below 1.5M) with gold nano grain, then centrifugal after washing repeatedly, until supernatant clarification, lyophilization is stand-by.Then reduce under high-temperature reductibility atmosphere, obtain three pattern contrast agent (Au@HMSN/Au/MnO).
Three pattern contrast agent of the present invention are made up of silicon oxide, manganese oxide and gold nano grain, adopt original position order autoreduction method to obtain by rational structural design.The double scattering utilizing the heterogeneous small bell shape structure of outer silica shell and inner gold nano grain kernel composition to realize in individual particle, utilizes the MnO nano-particle that embeds in shell and Au nano-particle to realize nonlinear scattering, jointly realizes the function strengthening ultra sonic imaging; In addition, homodisperse MnO nano-particle is utilized can also to realize strengthening NMR (Nuclear Magnetic Resonance) imaging; " core-satellite " structure of Au nano-particle composition in the Au nano-particle of kernel and shell is utilized to realize the function of enhanced CT imaging.This three patterns contrast agent is positive electricity through the modified surface of polyethylene imine beautify, can be absorbed by tumor cell in large quantities, realizes the living imaging effect strengthening VX2 tumor.In the present invention, the preparation condition of three pattern contrast agent is gentle, simple, pollution-free and output is high, reproducible, is applicable to industrialization large-scale production; Can realize simultaneously various diseases especially cancer multi-mode diagnosis, clinical medicine application in there is extremely important meaning, clinical Transformation Potential is huge.
Exemplify embodiment below further to describe the present invention in detail.Should understand equally; following examples are only used to further illustrate the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.The technological parameter etc. that following example is concrete is also only an example in OK range, and namely those skilled in the art can be done in suitable scope by explanation herein and select, and do not really want the concrete numerical value being defined in Examples below.
Embodiment 1
Prepare the hollow mesoporous monox nanometer granule of amino functional: the ammonia mixing of 71.6ml dehydrated alcohol, 10ml deionized water and 3.14ml, under the condition of 30 DEG C, stir 30min; Add 6ml ethyl orthosilicate fast, magnetic stirring 45min; After the 3-aminopropyl trimethoxysilane Homogeneous phase mixing of 5ml ethyl orthosilicate and 2ml, add rapidly above-mentioned solution, magnetic stirring 80min, after product is centrifugal, obtain the homogeneity solid core/shell mesoporous monox nanometer ball of high degree of dispersion.The Na of the product dispersion 0.6mol/L after centrifugal
2cO
3in solution.Scattered colloidal sol is stirred 60min under 80 DEG C of conditions.The centrifugal rear deionized water wash of product 3 times, lyophilization, obtains HMSN.
Embodiment 2
The mesoporous SiO2 nano-particle material of hollow of 100mg amino functional embodiment 1 prepared impregnated in the 0.05MHAuCl4 solution of 15ml, ultrasonic disperse 30min, 2h is reacted with being placed in 80 DEG C of water-baths, formation take gold as the heterogeneous rattle structure of kernel, the gold nano grain that surface load is simultaneously little, obtain Au@HMSN/Au, the centrifugal after washing of product 3 times, lyophilization.
Embodiment 3
The hollow mesoporous monox nanometer impregnated with particles of 100mg amino functional embodiment 1 prepared, in 15ml deionized water, then wherein adds the K of 12mg
2pdCl
6, ultrasonic disperse 30min, reacts 2h with being placed in 30 DEG C of water-baths, forms the nano-particle of shell load P d, HMSN-Pd-30, the centrifugal after washing of product 3 times, lyophilization.
Embodiment 4
According to embodiment 3 preparation technology, the hollow mesoporous monox nanometer impregnated with particles of 100mg amino functional embodiment 1 prepared, in 15ml deionized water, then wherein adds the K of 12mg
2pdCl
6, ultrasonic disperse 30min, react 2h with being placed in 50 DEG C of water-baths, subsequent step, as embodiment 3, obtains HMSN-Pd-50.
Embodiment 5
According to embodiment 3 preparation technology, the hollow mesoporous monox nanometer impregnated with particles of 100mg amino functional embodiment 1 prepared, in 15ml deionized water, then wherein adds the K of 12mg
2pdCl
6, ultrasonic disperse 30min, react 2h with being placed in 70 DEG C of water-baths, subsequent step, as embodiment 3, obtains HMSN-Pd-70.
Embodiment 6
According to embodiment 3 preparation technology, the hollow mesoporous monox nanometer impregnated with particles of 100mg amino functional embodiment 1 prepared, in 15ml deionized water, then wherein adds the K of 12mg
2pdCl
6, ultrasonic disperse 30min, react 2h with being placed in 90 DEG C of water-baths, subsequent step, as embodiment 3, obtains HMSN-Pd-90.
Embodiment 7
According to the synthesis technique of embodiment 2, the heterogeneous rattle structural material being kernel by the gold of the 100mg of preparation in embodiment 2 is scattered in the KMnO of the 0.4M of 15ml
4in solution, under room temperature, react 4h, the centrifugal after washing of product 3 times, lyophilization, with (5%H under reducing atmosphere at being placed on 900 DEG C
2-95%Ar) reduction, obtain Au@HMSN/Au/MnO.
Embodiment 8
Embodiment 2 and embodiment 7 process are inverted, according to embodiment 7 technique, by the hollow mesoporous monox nanometer impregnated with particles of the 100mg amino functional of preparation in embodiment 1 in the KMnO of the 0.4M of 15ml
4in solution, under room temperature, react 4h, the centrifugal after washing of product 3 times, lyophilization, then according to embodiment 2 technique, by the 0.05MHAuCl of the material soaking of above-mentioned preparation in 15ml
4in solution, ultrasonic disperse 30min, reacts 2h with being placed in 80 DEG C of water-baths, the centrifugal after washing of product 3 times, and lyophilization is still HMSN/MnO.
Embodiment 9
Be scattered in polymine (MW=1800) solution of the 200mg/ml of 30ml by the 100mgAu HMSN/Au/MnO of preparation in embodiment 7, stirred at ambient temperature 24h, centrifugal washing 3 times, lyophilization, obtains Au HMSN/Au/MnO-PEI.
In the present invention, the pore volume related to, aperture and specific surface area calculate according to Barrett – Joyner – Halenda (BJH) and Brunauer – Emmett – Teller (BET) method respectively, and pore-size distribution calculates according to Barrett – Joyner – Halenda (BJH) method.
Fig. 1 is that in embodiment 1, particle diameter is the hollow mesoporous silicon oxide nanomaterial transmission electron microscope picture of the amino functional of about 400nm.The particle diameter of nanoparticle is 400nm as can be seen from Figure, has the dispersibility of regular spherical morphology, homogeneous particle diameter and height.
Fig. 2 is that in embodiment 1, particle diameter is the scanning electron microscope (SEM) photograph of about 400nm, demonstrates the dispersibility and mesoporous of regular spherical morphology and height intuitively.After process is in the basic conditions described, spherical morphology can be kept preferably.
Fig. 3 be in embodiment 2 preparation take gold as the heterogeneous rattle structure of kernel, Au@HMSN/Au transmission electron microscope picture, the spherical morphology of material can be found out intuitively from figure, each hollow ball inside is only containing a gold nano grain, golden nanometer particle size is 50nm, form rattle structure, be conducive to double scattering in individual particle to occur, simultaneously in shell, dispersed little gold nano grain and the large gold nano grain of kernel form " core-satellite " structure, are conducive to X-ray influx and translocation CT imaging.
Fig. 4 is the transmission electron microscope picture of load P d nano-particle under the different temperatures prepared in embodiment 3-6, Fig. 4 a is that embodiment 3 obtains HMSN-Pd-30 transmission electron microscope picture, mean P d nanoparticle size 5nm in shell, Fig. 4 b is that embodiment 4 obtains HMSN-Pd-50 transmission electron microscope picture, mean P d nanoparticle size 6.4nm in shell, Fig. 4 c is that embodiment 5 obtains HMSN-Pd-70 transmission electron microscope picture, mean P d nanoparticle size 3.2nm in shell, Fig. 4 d is that embodiment 6 obtains HMSN-Pd-90 transmission electron microscope picture, mean P d nanoparticle size 2.3nm in shell, and Pd nano-particle soilless sticking.
Fig. 5 obtains three pattern contrast agent (Au@HMSN/Au/MnO) transmission electron microscope picture in embodiment 7, to be can visually see the pattern (spherical) of nanoparticle and particle diameter (400nm) by figure, there is regular spherical morphology, the dispersibility of homogeneous particle diameter and height, consistent with Fig. 3 structure, simultaneously in shell gold and Mn element dispersed, here the same with Au@HMSN/Au heterogeneous rattle structure can realize double scattering in individual particle, the nonlinear scattering that in shell, MnO and gold grain can realize strengthening strengthens ultra sonic imaging, homodisperse MnO nano-particle can realize strengthening NMR (Nuclear Magnetic Resonance) imaging, " core-satellite " structure that gold nano grain is formed can realize enhanced CT imaging.
Fig. 6 is three pattern contrast agent (Au HMSN/Au/MnO) the energy spectrogram obtained in embodiment 7, by the peak of figure Mn, Au, Si, proves that Au nano-particle and manganese oxide successfully synthesize.
Fig. 7 is the MH curve of the three pattern contrast agent (Au@HMSN/Au/MnO) obtained in embodiment 7, and the MnO nano-particle synthesized as we can see from the figure is paramagnetic.
Fig. 8 is the HMSN/MnO transmission electron microscope picture of preparation in embodiment 8, intuitively to the existence without gold nano grain, can illustrate that it is impracticable for preparing Au nano-particle after first preparing manganese oxide from figure.
Fig. 9 is HMSN, Au@HMSN/Au, Au@HMSN/Au/MnO, HMSN/MnO nitrogen adsorption desorption curve obtained respectively in embodiment 1,2,7,8, and these four kinds of materials are all mesoporous materials as can be seen from Fig., and specific surface area is consistent.
Figure 10 is HMSN, Au@HMSN/Au, Au@HMSN/Au/MnO, HMSN/MnO pore size distribution curve obtained respectively in embodiment 1,2,7,8, illustrates after reacting with potassium permanganate, and aperture becomes large, and potassium permanganate has the effect of reaming.
Figure 11 is HMSN, Au@HMSN/Au obtained respectively in embodiment 1,2,7, the ultravioletvisible absorption curve of Au@HMSN/Au/MnO.The existence of gold nano grain in Au@HMSN/Au, Au@HMSN/Au/MnO as we can see from the figure; Peak position is consistent, does not impact after showing potassium permanganate reaction to Au nanoparticle size.
Figure 12 is HMSN, Au@HMSN/Au, Au@HMSN/Au/MnO obtained respectively in embodiment 1,2,7,9, Au@HMSN/Au/MnO-PEI surface charge change curve, as we can see from the figure, the carrying out of different phase, its surface potential variation is obvious, finally obtain after Au@HMSN/Au/MnO-PEI by Au@HMSN/Au/MnO through PEI modification, its surface potential also by negative change just, illustrates PEI modification success in embodiment 9.
HMSN, Au@HMSN/Au, Au@HMSN/Au/MnO obtained respectively in Figure 13 embodiment 1,2,7,9, the FTIR spectrum of Au@HMSN/Au/MnO-PEI, can see that HMSN, Au@HMSN/Au all has amino vibration peak to exist from figure, and after changing from Au@HMSN/Au to Au@HMSN/Au/MnO, amino approach exhaustion is described, after further PEI modification procedure, N-H vibration peak reappears, and the success of PEI modification is described.
Claims (10)
1. ultrasonic/nuclear-magnetism/CT tri-pattern contrast agent, it is characterized in that, described contrast agent comprises: hollow mesopore silicon oxide shell, be arranged in first gold nano grain as kernel of the cavity of mesopore silicon oxide shell described in hollow and be dispersed in the second gold nano grain of shell and the MnO nano-particle of described hollow mesopore silicon oxide shell.
2. according to claim 1 ultrasonic/nuclear-magnetism/CT tri-pattern contrast agent, it is characterized in that, the external diameter of described hollow mesopore silicon oxide shell is 350 ~ 450nm, and internal diameter is 200 ~ 300nm, and mesoporous pore size is 25 ~ 35nm.
3. according to claim 1 and 2 ultrasonic/nuclear-magnetism/CT tri-pattern contrast agent, it is characterized in that, the particle diameter of described first gold nano grain is 40 ~ 60nm, and the particle diameter of described second gold nano grain is 2 ~ 8nm, and the particle diameter of described MnO nano-particle is 0.5 ~ 3nm.
4. according to any one of claim 1 to 3 ultrasonic/nuclear-magnetism/CT tri-pattern contrast agent, it is characterized in that, described MnO nano-particle is paramagnetic.
5. according to any one of claim 1 to 4 ultrasonic/nuclear-magnetism/CT tri-pattern contrast agent, it is characterized in that, described contrast agent also comprises the polymine of modifying in described hollow mesopore silicon oxide case surface.
6. according to any one of claim 1 to 5 ultrasonic/preparation method of nuclear-magnetism/CT tri-pattern contrast agent, it is characterized in that, comprise the following steps:
A) the hollow mesoporous monox nanometer Granular composite of amino functional is carried out hydro-thermal reaction in chlorauric acid solution, with obtained product A, described product A has the first gold nano grain produced in the cavity of described hollow mesopore silicon oxide as kernel, and homodisperse second gold nano grain in the shell of described hollow mesopore silicon oxide simultaneously;
B) product A is scattered in potassium permanganate solution carries out redox reaction, with dispersed Mn oxide in the shell of the hollow mesopore silicon oxide of product A further, and reduce under reducing atmosphere, thus obtained described ultrasonic/nuclear-magnetism/CT tri-pattern contrast agent.
7. preparation method according to claim 6, it is characterized in that, steps A) in, the concentration of chlorauric acid solution is 0.0125 ~ 0.05M, the mass ratio of gold chloride and hollow mesoporous monox nanometer granule is 1:(2 ~ 4), hydrothermal temperature is 75 ~ 85 DEG C, and the hydro-thermal reaction time is 40 ~ 120 minutes.
8. the preparation method according to claim 6 or 7, is characterized in that, step B) in, the concentration of potassium permanganate solution is below 1.5M, and the reaction temperature of described redox reaction is room temperature ~ 60 DEG C, and the response time is 1 ~ 24 hour; Reducing atmosphere is the gaseous mixture of hydrogen or hydrogen and argon, and the reaction temperature of reducing under reducing atmosphere is more than 600 DEG C, and the response time is more than 2 hours.
9. the preparation method according to any one of claim 6 to 8, it is characterized in that, also comprise step C) by described ultrasonic/nuclear-magnetism/CT tri-pattern contrast agent is scattered in polyethylenimine solution, stirring at room temperature adsorb, prepare polyethyleneimine-modified ultrasonic/nuclear-magnetism/CT tri-pattern contrast agent.
10. preparation method according to claim 9, is characterized in that, step C) in, polymine concentration is 20mg/ml ~ 2g/ml, and molecular weight is 650 ~ 12500.
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