CN103286311A - Multifunctional composite nanoparticle and preparation method and application thereof - Google Patents
Multifunctional composite nanoparticle and preparation method and application thereof Download PDFInfo
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- CN103286311A CN103286311A CN201210541696XA CN201210541696A CN103286311A CN 103286311 A CN103286311 A CN 103286311A CN 201210541696X A CN201210541696X A CN 201210541696XA CN 201210541696 A CN201210541696 A CN 201210541696A CN 103286311 A CN103286311 A CN 103286311A
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Abstract
The invention provides a multifunctional composite nanoparticle which is formed by combining a ferroferric oxide particle and a gold nanoparticle, wherein the ferroferric oxide particle forms a magnetic inner core and the gold nanoparticle forms an outer layer; and the diameter of the multifunctional composite nanoparticle is smaller than 100 nm. The preparation method of the multifunctional composite nanoparticle comprises the following steps: (a) the magnetic ferroferric oxide particle with functionalized surface sulfydryl is prepared; and (b) the magnetic ferroferric oxide particle with the functionalized surface sulfydryl is dissolved in a solution, and then gold chloride and a reducing agent is added into the solution so as to enable the gold nanoparticle to be grafted onto the ferroferric oxide particle to form the multifunctional composite nanoparticle, wherein the pH of the solution is adjusted to 7-10 before the reducing agent is added into the solution so as to control the diameter of the gold nanoparticle. The preparation method of the multifunctional composite nanoparticle is simple and efficient and has good repeatability. The multifunctional composite nanoparticle provided by the invention can remarkably enhance the effect of magnetic resonance imaging at a lower concentration, meanwhile can be used for bio-labelling by virtue of the gold nanoparticle, and is expected to bring the superiority of nanostructured drugs into play in the field of biological medicine.
Description
Technical field
The present invention relates to nanometer and technical field of biological material, particularly a kind of have multifunctional nano composite particles of carrying out magnetic resonance imaging and biomarker ability simultaneously and preparation method thereof.
Background technology
Cancer is one of high major disease of current fatal rate of not captured as yet, and the incidence of disease of cancer also is to increase year by year in recent years, has greatly endangered human life and health.Yet, the means of clinical employed cancer diagnosis and treatment are because its intrinsic limitation can not in time be made accurate judgement and effectively processing to cancer at present, tend to incur loss through delay the treatment time of cancer patient's the best, so scientific research begins to turn to and utilizes some emerging materials and technology to capture cancer.What wherein cause the extensive interest of people especially is exactly nano material and nanometer technology, and its small-size effect that has is highly suitable for the application of biomedicine field.
In numerous nano materials, ferriferrous oxide particles and gold nano-material are because it has excellent magnetism energy and optical property, excellent biological compatibility and being studied widely.At present, there has been number of research projects to show that ferroferric oxide nano granules has the effect that strengthens magnetic resonance radiography significantly and begun to use it for clinical abroad; And the surface local of gold nano-material etc. also make it at biological field bright application prospect be arranged from resonance effects (LSPR) and anti-photic cancellation, such as biomarker and image.Therefore, if these two kinds of functional materials can be combined, can realize the image of tumour and the variation of diagnosis, simultaneously the also effect of the development of tracking of knub and treatment more exactly.S.H.Sun, K.P.Johnston and N.J.Halas etc. are successively at Angew.Chem, AcsNano, reported the synthetic of multifunctional nanoparticles that a kind of magnetic ferroferric oxide particle and gold nano grain are compound on the Accounts ofChemical research, but the preparation method who reports is very complicated, repeatability is relatively poor with controllability, synthetic particle mostly is oil phase, need complicated last handling process, cause the product that obtains at last bad stability, microstructure in solution destroyed, be not used in transmission and application in the organism.
Summary is got up, and mainly there is the problem of following three aspects in the compound multifunctional nanoparticles of existing this kind magnetic ferroferric oxide particle and gold nano grain:
(1), preparation technology is too complicated, too much finishing process makes the structure/performance instability, poor repeatability;
(2), mostly present preparation process be to carry out in oil phase, product can not be directly used in the organism, needs the process of complicated back modification;
(3), homogeneity is relatively poor, mostly the combination of ferriferrous oxide particles and gold nano grain is to take place at random that controllability is relatively poor, causes last synergy undesirable.
Summary of the invention
The invention provides a kind of multifunctional nano composite particles and its preparation method and application, thereby solve problem such as this composite particles structure/performance instability and complicated process of preparation in the prior art.
The invention provides a kind of multifunctional nano composite particles, described multifunctional nano composite particles is compounded to form by ferriferrous oxide particles and gold nano grain, form magnetic kernel by described ferriferrous oxide particles, form skin by gold nano grain, the diameter of described multifunctional nano composite particles is below 100nm.
The diameter of described magnetic kernel is 20-95nm, and the diameter of described gold nano grain is 2-10nm.
The slow Henan rate r of described multifunctional nano composite particles
2Value is 100-500mM
-1S
-1, be preferably 200-300mM
-1S
-1, 241mM more preferably
-1S
-1
The present invention also provides a kind of preparation method of multifunctional nano composite particles, comprising: the mercapto-functionalized magnetic ferroferric oxide particle in step a) preparation surface; The step b) magnetic ferroferric oxide particle that described surface is mercapto-functionalized is dissolved in the solution, adds chlorauride and reducing agent and makes the gold nano grain grafting form described multifunctional nano composite particles to ferriferrous oxide particles; In step b), the pH with described solution before adding described reducing agent is adjusted to 7-10, thereby controls the diameter of described gold nano grain.
Described reducing agent is sodium borohydride, should be appreciated that, other are any, and chlorauride can be reduced to the reducing agent of gold all in this application available.
Described step a) comprises: be (40-100) with magnetic ferroferric oxide particle and amphipathic nature block polymer and oxolane according to mol ratio a1): (1-2): (1 * 10
5-5 * 10
5) mix after, add ultra-pure water, the brown solution that obtains after continuing to stir is dialysed in deionized water and is removed oxolane; A2) be (5-10) with ammoniacal liquor and mercaptopropyl trimethoxysilane according to mol ratio: (1-2) successively join in the above-mentioned solution, continue stirring and obtain the mercapto-functionalized magnetic ferroferric oxide particle in surface.
Described amphipathic nature block polymer is polystyrene-b-polyacrylic acid (PS
88-b-PAA
8.7), polycaprolactone-b-polyacrylic acid (PCL-b-PAA), polycaprolactone-b-polyethylene glycol (PCL-b-PEG) or polystyrene-b-PEO (PS-b-PEO).
The mol ratio of ferriferrous oxide particles and amphipathic nature block polymer polystyrene-b-polyacrylic acid and oxolane is 42:1:1.2 * 10
5, the mol ratio of ammoniacal liquor and mercaptopropyl trimethoxysilane is 8.69:1.
Described step b) comprises: in the solution of the mercapto-functionalized magnetic ferroferric oxide particle in described surface, successively add ultra-pure water, chlorauride and reducing agent; Wherein, the mole ratio of ultra-pure water, chlorauride, reducing agent and ferriferrous oxide particles is (1 * 10
5-2 * 10
5): (1-2): (0.5-2): (0.2-1), mix the back and continue to stir, obtain described multifunctional nano composite particles behind the solution centrifugal.
In step b), the described ultra-pure water of adding is 2.22mol.
In step b), the mol ratio of ultra-pure water, chlorauride and reducing agent is 1.66 * 10
5: 1.5:1.
The present invention provides the application of above-mentioned multifunctional nano composite particles on magnetic resonance imaging and biomarker ability again.
Gold nano grain concentration in the described multifunctional nano composite particles is that 20 μ g/ml have tangible mark effect.
By above-mentioned technological means, multifunctional nano composite particles of the present invention and preparation method and application's advantage comprises: (1) preparation method's novelty, at first amphipathic nature block polymer is self-assembled to the magnetic ferroferric oxide particle surface, utilize mercaptopropyl trimethoxysilane to introduce sulfydryl at amphipathic nature block polymer then, the gold nano that reduction is obtained is connected to mercapto-functionalized magnetic-particle surface by the effect of S-Au covalent bond at last; (2) building-up process is simply efficient, good reproducibility, since in concrete preparation process gold chloride be reduced to gold nano grain and be carried on mercapto-functionalized magnetic composite particles surface be one the step finish, simplify the method for at present general grafting gold nano grain, improved the grafting dispersiveness of whole nano particle afterwards simultaneously; (3) this multifunctional nano composite particles controllable size is below 100nm, and has monodispersity, is fit in vivo efficiently to be delivered under the complicated situation that lesions position is diagnosed and mark; (4) this multifunctional nano composite particles can significantly strengthen the magnetic resonance radiography effect under low concentration, can utilize gold nano grain to carry out biomarker and image simultaneously; Be expected at biomedicine field, particularly the advantage of the Clinics and Practices aspect of cancer performance Nano medication.
Description of drawings
Below in conjunction with the drawings and specific embodiments the present invention is described in further detail.
Fig. 1 is the preparation technology's flow chart with the multifunctional nano composite particles that carries out magnetic resonance imaging and biomarker ability simultaneously provided by the present invention;
Fig. 2 is the scanning (a) and transmission (b) electromicroscopic photograph according to the mercapto-functionalized magnetic composite particles of the technology preparation of Fig. 1;
Fig. 3 is the multifunctional nano composite particles low power (a) and high power (b) stereoscan photograph of carrying out magnetic resonance imaging and biomarker ability simultaneously that have according to the technology preparation of Fig. 1;
Fig. 4 is the multifunctional nano composite particles low power (a) and high power (b) transmission electron microscope photo according to the preparation of Fig. 1 technology;
Fig. 5 characterizes in external magnetic resonance imaging according to the multifunctional nano composite particles that Fig. 1 technology prepares;
Fig. 6 is l cell (L929) and the details in a play not acted out on stage, but told through dialogues imaging of breast cancer cell (MCF-7) behind multifunctional nano composite particles mark.A wherein, b are respectively the details in a play not acted out on stage, but told through dialogues images before and after the L929 mark; C, d are the imaging pictures before and after the MCF-7 mark;
Fig. 7 is that the multifunctional nano composite particles is to the toxicity sign of cell L929 and MCF-7;
Fig. 8 adds the transmission electron microscope photo that the preceding pH value of solution value of sodium borohydride is adjusted to the 8.0 multifunctional nano composite particles that make;
Fig. 9 adds the transmission electron microscope photo that the preceding pH value of solution value of sodium borohydride is adjusted to the 9.5 multifunctional nano composite particles that make.
The specific embodiment
Provide preferred embodiment of the present invention below, and be described in detail, enable to understand better function of the present invention, characteristics.
At ambient temperature, with magnetic ferroferric oxide particle (Fe
3O
4) and amphipathic nature block polymer polystyrene-b-polyacrylic acid (PS
88-b-PAA
8.7) with oxolane (THF) be Fe according to mol ratio
3O
4: PS
88-b-PAA
8.7: THF=42:1:1.2 * 10
5Ratio (be 10mg Fe
3O
4, 10mg PS-b-PAA and 10ml THF) mix after, in this solution, add the 40ml ultra-pure water, continue to stir the 24h that in deionized water, dialyses behind the 30min.With ammoniacal liquor (NH
3.H
2O) be NH in molar ratio with mercaptopropyl trimethoxysilane (MPTMS)
3.H
2O:MPTMS=8.69:1(is 1g ammoniacal liquor and 150mgMPTMS) join in the solution after the above-mentioned dialysis, continue to stir that to obtain particle diameter behind the 24h be the crosslinked magnetic kernel of mercapto-functionalized shell about 60nm.
In the above-mentioned colloidal solution 15ml that obtains, in molar ratio 1.66 * 10
5: 1.5:1 successively adds the chlorauride (HAuCl of 120ml ultra-pure water, 4ml0.01M
4) with the sodium borohydride (NaBH of 6ml0.01M
4), wherein add pH value of solution value before the sodium borohydride and be adjusted to about 8.0 with the NaOH of 0.01M, mix the back and continue stirring 6h, obtain the compound multifunctional nanoparticles of tri-iron tetroxide and gold nano grain behind the solution centrifugal.
Embodiment 2
The compound Nano composite granules of magnetic composite particles, tri-iron tetroxide and the gold nano grain that the mercapto-functionalized shell that makes in above-described embodiment is crosslinked carries out transmission and ESEM respectively and characterizes, its separately shape characteristic and structure respectively shown in Fig. 2-4.As figure shows, the diameter of the granuloplastic magnetic kernel of magnetic ferroferric oxide is about about 50-70nm, and the diameter of composite particles is about about 60-80nm.
The multifunctional nano composite particles of last resulting nucleocapsid structure is tested its radiography ability in medical magnetic resonance imager (1.5T).The result shows the slow Henan rate r of this composite particles in external environment
2Value has reached 241mM
-1S
-1(Fig. 5), and along with the increase of iron content in the solution, the T of reagent
2The nuclear-magnetism image of weight is more black, has shown that tangible signal descends.In normal cell l cell (L929) and cancer cell (MCF-7), test the mark function of synthetic multifunctional nano composite particles simultaneously.After the result shows that these two kinds of cells and this multifunctional nano composite particles (20 μ g/ml) are hatched jointly, under dark field microscope, can obviously see the scattered light of white, confirm significant mark effect (Fig. 6).In addition, though the gold concentration up to 100 μ g/ml also not to cell toxigenicity (Fig. 7).
Embodiment 3
Basic recipe is constant, only changes the pH value that adds the preceding solution of sodium borohydride, obtains following several embodiment, and gained TEM photo is shown in Fig. 8-9:
(a) the pH value of solution is adjusted to 8.0(Fig. 8 before the adding sodium borohydride)
(b) the pH value of solution is adjusted to 9.5(Fig. 9 before the adding sodium borohydride)
Can obtain as drawing a conclusion from the transmission electron microscope analysis result, raising along with pH value of solution value before the adding sodium borohydride, grafting diminishes to the gold nano grain on the magnetic microsphere, illustrate that the pH value of regulator solution can effectively regulate and control the size of the gold nano grain of reduction, confirmed that also this method has good adjustability.
Embodiment 4
At ambient temperature, with magnetic ferroferric oxide particle (Fe
3O
4) and amphipathic nature block polymer polystyrene-b-polyacrylic acid (PS
88-b-PAA
8.7) with oxolane (THF) be Fe according to mol ratio
3O
4: PS
88-b-PAA
8.7: THF=42:1:1.2 * 10
5Ratio mix after, add the 40ml ultra-pure water in this solution, continue to stir the 24h that in deionized water, dialyses behind the 30min.With ammoniacal liquor (NH
3.H
2O) be NH in molar ratio with mercaptopropyl trimethoxysilane (MPTMS)
3.H
2O:MPTMS=8.69:1 joins in the solution after the above-mentioned dialysis, continues to stir that to obtain particle diameter behind the 24h be the crosslinked magnetic kernel of mercapto-functionalized shell about 60nm.
In the above-mentioned colloidal solution 15ml that obtains, in molar ratio 1.66 * 10
5: 1.5:1 successively adds the chlorauride (HAuCl of 120ml ultra-pure water, 4ml0.01M
4) with the sodium borohydride (NaBH of 6ml0.01M
4), wherein add pH value of solution value before the sodium borohydride and be adjusted to about 7.0 with the NaOH of 0.01M, mix the back and continue stirring 6h, obtain the compound multifunctional nanoparticles of tri-iron tetroxide and gold nano grain behind the solution centrifugal.
Characterize by transmission and ESEM, the diameter of the granuloplastic magnetic kernel of magnetic ferroferric oxide is about about 50-70nm, and the diameter of composite particles is about about 60-80nm, and wherein, the diameter of gold nano grain is about 10nm.By the magnetic resonance imager analysis, the slow Henan rate r of this composite particles in external environment
2Value has reached 241mM
-1S
-1This composite particles has monodispersity, is fit in vivo efficiently to be delivered under the complicated situation that lesions position is diagnosed and mark.
Embodiment 5
At ambient temperature, with magnetic ferroferric oxide particle (Fe
3O
4) and amphipathic nature block polymer polystyrene-b-polyacrylic acid (PS
88-b-PAA
8.7) with oxolane (THF) be Fe according to mol ratio
3O
4: PS
88-b-PAA
8.7: THF=42:1:1.2 * 10
5Ratio mix after, add the 40ml ultra-pure water in this solution, continue to stir the 24h that in deionized water, dialyses behind the 30min.With ammoniacal liquor (NH
3.H
2O) be NH in molar ratio with mercaptopropyl trimethoxysilane (MPTMS)
3.H
2O:MPTMS=8.69:1 joins in the solution after the above-mentioned dialysis, obtains the crosslinked magnetic kernel of mercapto-functionalized shell that particle diameter is 60nm after continuing to stir 24h.
In the above-mentioned colloidal solution 15ml that obtains, in molar ratio 1.66 * 10
5: 1.5:1 successively adds the chlorauride (HAuCl of 120ml ultra-pure water, 4ml0.01M
4) with the sodium borohydride (NaBH of 6ml0.01M
4), wherein add pH value of solution value before the sodium borohydride and be adjusted to about 10.0 with the NaOH of 0.01M, mix the back and continue stirring 6h, obtain the compound multifunctional nanoparticles of tri-iron tetroxide and gold nano grain behind the solution centrifugal.
Characterize by transmission and ESEM, the diameter of the granuloplastic magnetic kernel of magnetic ferroferric oxide is about about 50-70nm, and the diameter of composite particles is about about 60-80nm, and wherein, the diameter of gold nano grain is about 2nm.By the magnetic resonance imager analysis, the slow Henan rate r of this composite particles in external environment
2Value has reached 241mM
-1S
-1This composite particles has monodispersity, is fit in vivo efficiently to be delivered under the complicated situation that lesions position is diagnosed and mark.
Embodiment 6
At ambient temperature, with magnetic ferroferric oxide particle (Fe
3O
4) with amphipathic nature block polymer polycaprolactone-b-polyacrylic acid (PCL-b-PAA) and oxolane (THF) be Fe according to mol ratio
3O
4: PCL-b-PAA:THF=10:1:1 * 10
5Ratio mix after, add the 40ml ultra-pure water in this solution, continue to stir the 24h that in deionized water, dialyses behind the 30min.With ammoniacal liquor (NH
3.H
2O) be NH in molar ratio with mercaptopropyl trimethoxysilane (MPTMS)
3.H
2O:MPTMS=5:1 joins in the solution after the above-mentioned dialysis, continues to stir that to obtain particle diameter behind the 24h be the crosslinked magnetic kernel of mercapto-functionalized shell about 20nm.
In the above-mentioned colloidal solution 15ml that obtains, in molar ratio 1.66 * 10
5: 1.5:1 successively adds the chlorauride (HAuCl of 120ml ultra-pure water, 4ml0.01M
4) with the sodium borohydride (NaBH of 6ml0.01M
4), wherein add pH value of solution value before the sodium borohydride and be adjusted to about 8.0 with the NaOH of 0.01M, mix the back and continue stirring 5h, obtain the compound multifunctional nanoparticles of tri-iron tetroxide and gold nano grain behind the solution centrifugal.
Characterize by transmission and ESEM, the diameter of the granuloplastic magnetic kernel of magnetic ferroferric oxide is about about 20-30nm, and the control of the diameter of composite particles is below 100nm.By the magnetic resonance imager analysis, the slow Henan rate r of this composite particles in external environment
2Value has reached 100mM
-1S
-1This composite particles has monodispersity, is fit in vivo efficiently to be delivered under the complicated situation that lesions position is diagnosed and mark.
At ambient temperature, with magnetic ferroferric oxide particle (Fe
3O
4) with amphipathic nature block polymer polycaprolactone-b-polyethylene glycol (PCL-b-PEG) and oxolane (THF) be Fe according to mol ratio
3O
4: PCL-b-PEG:THF=20:1:5 * 10
5Ratio mix after, add the 40ml ultra-pure water in this solution, continue to stir the 12h that in deionized water, dialyses behind the 20min.With ammoniacal liquor (NH
3.H
2O) be NH in molar ratio with mercaptopropyl trimethoxysilane (MPTMS)
3.H
2O:MPTMS=10:1 joins in the solution after the above-mentioned dialysis, obtains the crosslinked magnetic kernel of mercapto-functionalized shell that particle diameter is 40nm after continuing to stir 24h.
In the above-mentioned colloidal solution 15ml that obtains, in molar ratio 1.66 * 10
5: 1.5:1 successively adds the chlorauride (HAuCl of 120ml ultra-pure water, 4ml0.01M
4) with the sodium borohydride (NaBH of 6ml0.01M
4), wherein add pH value of solution value before the sodium borohydride and be adjusted to about 8.0 with the NaOH of 0.01M, mix the back and continue stirring 7h, obtain the compound multifunctional nanoparticles of tri-iron tetroxide and gold nano grain behind the solution centrifugal.
Characterize by transmission and ESEM, the diameter of the granuloplastic magnetic kernel of magnetic ferroferric oxide is about about 40-50nm, and the control of the diameter of composite particles is below 100nm.By the magnetic resonance imager analysis, the slow Henan rate r of this composite particles in external environment
2Value has reached 200mM
-1S
-1This composite particles has monodispersity, is fit in vivo efficiently to be delivered under the complicated situation that lesions position is diagnosed and mark.
At ambient temperature, with magnetic ferroferric oxide particle (Fe
3O
4) with amphipathic nature block polymer polystyrene-b-PEO (PS-b-PEO) and oxolane (THF) be Fe according to mol ratio
3O
4: PS-b-PEO:THF=40:1:1 * 10
5Ratio mix after, add the 40ml ultra-pure water in this solution, continue to stir the 24h that in deionized water, dialyses behind the 20min.With ammoniacal liquor (NH
3.H
2O) be NH in molar ratio with mercaptopropyl trimethoxysilane (MPTMS)
3.H
2O:MPTMS=8:1 joins in the solution after the above-mentioned dialysis, obtains the crosslinked magnetic kernel of mercapto-functionalized shell that particle diameter is 60nm after continuing to stir 24h.
In the above-mentioned colloidal solution 15ml that obtains, in molar ratio 1.66 * 10
5: 1.5:1 successively adds the chlorauride (HAuCl of 120ml ultra-pure water, 4ml0.01M
4) with the sodium borohydride (NaBH of 6ml0.01M
4), wherein add pH value of solution value before the sodium borohydride and be adjusted to about 8.0 with the NaOH of 0.01M, mix the back and continue stirring 8h, obtain the compound multifunctional nanoparticles of tri-iron tetroxide and gold nano grain behind the solution centrifugal.
Characterize by transmission and ESEM, the diameter of the granuloplastic magnetic kernel of magnetic ferroferric oxide is about about 60-70nm, and the control of the diameter of composite particles is below 100nm.By the magnetic resonance imager analysis, the slow Henan rate r of this composite particles in external environment
2Value has reached 300mM
-1S
-1This composite particles has monodispersity, is fit in vivo efficiently to be delivered under the complicated situation that lesions position is diagnosed and mark.
Embodiment 9
At ambient temperature, with magnetic ferroferric oxide particle (Fe
3O
4) with amphipathic nature block polymer styrene-b-polyacrylic acid (PS-b-PAA) and oxolane (THF) be Fe according to mol ratio
3O
4: PS-b-PAA:THF=100:2:1 * 10
5Ratio mix after, add the 40ml ultra-pure water in this solution, continue to stir the 36h that in deionized water, dialyses behind the 60min.With ammoniacal liquor (NH
3.H
2O) be NH in molar ratio with mercaptopropyl trimethoxysilane (MPTMS)
3.H
2O:MPTMS=8.69:1 joins in the solution after the above-mentioned dialysis, obtains the crosslinked magnetic kernel of mercapto-functionalized shell that particle diameter is 60nm after continuing to stir 24h.
In the above-mentioned colloidal solution 15ml that obtains, in molar ratio 1.66 * 10
5: 1.5:1 successively adds the chlorauride (HAuCl of 120ml ultra-pure water, 4ml0.01M
4) with the sodium borohydride (NaBH of 6ml0.01M
4), wherein add pH value of solution value before the sodium borohydride and be adjusted to about 8.0 with the NaOH of 0.01M, mix the back and continue stirring 6h, obtain the compound multifunctional nanoparticles of tri-iron tetroxide and gold nano grain behind the solution centrifugal.
Characterize by transmission and ESEM, the diameter of the granuloplastic magnetic kernel of magnetic ferroferric oxide is about about 70-80nm, and the control of the diameter of composite particles is below 100nm.By the magnetic resonance imager analysis, the slow Henan rate r of this composite particles in external environment
2Value has reached 500mM
-1S
-1This composite particles has monodispersity, is fit in vivo efficiently to be delivered under the complicated situation that lesions position is diagnosed and mark.
At ambient temperature, with magnetic ferroferric oxide particle (Fe
3O
4) and amphipathic nature block polymer polystyrene-b-polyacrylic acid (PS
88-b-PAA
8.7) with oxolane (THF) be Fe according to mol ratio
3O
4: PS
88-b-PAA
8.7: THF=42:1:1.2 * 10
5Ratio mix after, add the 40ml ultra-pure water in this solution, continue to stir the 24h that in deionized water, dialyses behind the 30min.With ammoniacal liquor (NH
3.H
2O) be NH in molar ratio with mercaptopropyl trimethoxysilane (MPTMS)
3.H
2O:MPTMS=8.69:1 joins in the solution after the above-mentioned dialysis, continues to stir that to obtain particle diameter behind the 24h be the crosslinked magnetic kernel of mercapto-functionalized shell about 60nm.
In the above-mentioned colloidal solution that obtains, successively add ultra-pure water, chlorauride (HAuCl
4) and sodium borohydride, wherein, the mole ratio of ultra-pure water, chlorauride, reducing agent and ferriferrous oxide particles is 1 * 10
5: 1:0.5:0.2, the pH value of solution value is adjusted to about 8.0 with the NaOH of 0.01M before the adding sodium borohydride, mixes the back and continues stirring 6h, obtains the compound multifunctional nanoparticles of tri-iron tetroxide and gold nano grain behind the solution centrifugal.
Characterize by transmission and ESEM, the diameter control of composite particles is below 100nm.By the magnetic resonance imager analysis, the slow Henan rate r of this composite particles in external environment
2Value has reached 241mM
-1S
-1This composite particles has monodispersity, is fit in vivo efficiently to be delivered under the complicated situation that lesions position is diagnosed and mark.
Embodiment 11
At ambient temperature, with magnetic ferroferric oxide particle (Fe
3O
4) and amphipathic nature block polymer polystyrene-b-polyacrylic acid (PS
88-b-PAA
8.7) with oxolane (THF) be Fe according to mol ratio
3O
4: PS
88-b-PAA
8.7: THF=42:1:1.2 * 10
5Ratio mix after, add the 40ml ultra-pure water in this solution, continue to stir the 24h that in deionized water, dialyses behind the 30min.With ammoniacal liquor (NH
3.H
2O) be NH in molar ratio with mercaptopropyl trimethoxysilane (MPTMS)
3.H
2O:MPTMS=8.69:1 joins in the solution after the above-mentioned dialysis, continues to stir that to obtain particle diameter behind the 24h be the crosslinked magnetic kernel of mercapto-functionalized shell about 60nm.
In the above-mentioned colloidal solution that obtains, successively add ultra-pure water, chlorauride (HAuCl
4) and sodium borohydride, wherein, the mole ratio of ultra-pure water, chlorauride, reducing agent and ferriferrous oxide particles is 2 * 10
5: 1:0.5:0.2, the pH value of solution value is adjusted to about 8.0 with the NaOH of 0.01M before the adding sodium borohydride, mixes the back and continues stirring 6h, obtains the compound multifunctional nanoparticles of tri-iron tetroxide and gold nano grain behind the solution centrifugal.
Characterize by transmission and ESEM, the diameter control of composite particles is below 100nm.By the magnetic resonance imager analysis, the slow Henan rate r of this composite particles in external environment
2Value has reached 241mM
-1S
-1This composite particles has monodispersity, is fit in vivo efficiently to be delivered under the complicated situation that lesions position is diagnosed and mark.
Embodiment 12
At ambient temperature, with magnetic ferroferric oxide particle (Fe
3O
4) and amphipathic nature block polymer polystyrene-b-polyacrylic acid (PS
88-b-PAA
8.7) with oxolane (THF) be Fe according to mol ratio
3O
4: PS
88-b-PAA
8.7: THF=42:1:1.2 * 10
5Ratio mix after, add the 40ml ultra-pure water in this solution, continue to stir the 24h that in deionized water, dialyses behind the 30min.With ammoniacal liquor (NH
3.H
2O) be NH in molar ratio with mercaptopropyl trimethoxysilane (MPTMS)
3.H
2O:MPTMS=8.69:1 joins in the solution after the above-mentioned dialysis, continues to stir that to obtain particle diameter behind the 24h be the crosslinked magnetic kernel of mercapto-functionalized shell about 60nm.
In the above-mentioned colloidal solution that obtains, successively add ultra-pure water, chlorauride (HAuCl
4) and sodium borohydride, wherein, the mole ratio of ultra-pure water, chlorauride, reducing agent and ferriferrous oxide particles is 1 * 10
5: 2:0.5:0.2, the pH value of solution value is adjusted to about 8.0 with the NaOH of 0.01M before the adding sodium borohydride, mixes the back and continues stirring 6h, obtains the compound multifunctional nanoparticles of tri-iron tetroxide and gold nano grain behind the solution centrifugal.
Characterize by transmission and ESEM, the diameter control of composite particles is below 100nm.By the magnetic resonance imager analysis, the slow Henan rate r of this composite particles in external environment
2Value has reached 241mM
-1S
-1This composite particles has monodispersity, is fit in vivo efficiently to be delivered under the complicated situation that lesions position is diagnosed and mark.
Embodiment 13
At ambient temperature, with magnetic ferroferric oxide particle (Fe
3O
4) and amphipathic nature block polymer polystyrene-b-polyacrylic acid (PS
88-b-PAA
8.7) with oxolane (THF) be Fe according to mol ratio
3O
4: PS
88-b-PAA
8.7: THF=42:1:1.2 * 10
5Ratio mix after, add the 40ml ultra-pure water in this solution, continue to stir the 24h that in deionized water, dialyses behind the 30min.With ammoniacal liquor (NH
3.H
2O) be NH in molar ratio with mercaptopropyl trimethoxysilane (MPTMS)
3.H
2O:MPTMS=8.69:1 joins in the solution after the above-mentioned dialysis, obtains the crosslinked magnetic kernel of mercapto-functionalized shell that particle diameter is 60nm after continuing to stir 24h.
In the above-mentioned colloidal solution that obtains, successively add ultra-pure water, chlorauride (HAuCl
4) and sodium borohydride, wherein, the mole ratio of ultra-pure water, chlorauride, reducing agent and ferriferrous oxide particles is 1 * 10
5: 1:2:0.2, the pH value of solution value is adjusted to about 8.0 with the NaOH of 0.01M before the adding sodium borohydride, mixes the back and continues stirring 6h, obtains the compound multifunctional nanoparticles of tri-iron tetroxide and gold nano grain behind the solution centrifugal.
Characterize by transmission and ESEM, the diameter control of composite particles is below 100nm.By the magnetic resonance imager analysis, the slow Henan rate r of this composite particles in external environment
2Value has reached 241mM
-1S
-1This composite particles has monodispersity, is fit in vivo efficiently to be delivered under the complicated situation that lesions position is diagnosed and mark.
Embodiment 14
At ambient temperature, with magnetic ferroferric oxide particle (Fe
3O
4) and amphipathic nature block polymer polystyrene-b-polyacrylic acid (PS
88-b-PAA
8.7) with oxolane (THF) be Fe according to mol ratio
3O
4: PS
88-b-PAA
8.7: THF=42:1:1.2 * 10
5Ratio mix after, add the 40ml ultra-pure water in this solution, continue to stir the 24h that in deionized water, dialyses behind the 30min.With ammoniacal liquor (NH
3.H
2O) be NH in molar ratio with mercaptopropyl trimethoxysilane (MPTMS)
3.H
2O:MPTMS=8.69:1 joins in the solution after the above-mentioned dialysis, obtains the crosslinked magnetic kernel of mercapto-functionalized shell that particle diameter is 60nm after continuing to stir 24h.
In the above-mentioned colloidal solution that obtains, successively add ultra-pure water, chlorauride (HAuCl
4) and sodium borohydride, wherein, the mole ratio of ultra-pure water, chlorauride, reducing agent and ferriferrous oxide particles is 1 * 10
5: 1:0.5:1, the pH value of solution value is adjusted to about 8.0 with the NaOH of 0.01M before the adding sodium borohydride, mixes the back and continues stirring 6h, obtains the compound multifunctional nanoparticles of tri-iron tetroxide and gold nano grain behind the solution centrifugal.
Characterize by transmission and ESEM, the diameter control of composite particles is below 100nm.By the magnetic resonance imager analysis, the slow Henan rate r of this composite particles in external environment
2Value has reached 241mM
-1S
-1This composite particles has monodispersity, is fit in vivo efficiently to be delivered under the complicated situation that lesions position is diagnosed and mark.
The present invention is according to suitable prescription, pH value of solution value before the control reduction, prepared the compound multifunctional nano composite particles of magnetic ferroferric oxide particle and gold nano grain, resulting multifunctional nano composite particles has the ability that strengthens magnetic resonance radiography significantly, characterizes the slow Henan rate r of its radiography ability in external environment
2Reached 241mM
-1S
-1, be about the twice of like product Feridex I.V. of external clinical use at present.Cell experiment can be observed bright scattered light after showing that this material is engulfed by normal and cancer cell efficiently under dark field microscope, confirmed to change material and had good biomarker function.
Above-described, be preferred embodiment of the present invention only, be not in order to limiting scope of the present invention, the above embodiment of the present invention can also make a variety of changes.Be that simple, the equivalence that every claims according to the present patent application and description are done changes and modification, all fall into the claim protection domain of patent of the present invention.The present invention not detailed description be the routine techniques content.
Claims (10)
1. multifunctional nano composite particles, described multifunctional nano composite particles is compounded to form by ferriferrous oxide particles and gold nano grain, it is characterized in that, form magnetic kernel by described ferriferrous oxide particles, form skin by gold nano grain, the diameter of described multifunctional nano composite particles is below 100nm.
2. multifunctional nano composite particles according to claim 1 is characterized in that, the diameter of described magnetic kernel is 20-95nm, and the diameter of described gold nano grain is 2-10nm.
3. multifunctional nano composite particles according to claim 1 is characterized in that, the slow Henan rate r of described multifunctional nano composite particles
2Value is 100-500mM
-1S
-1, be preferably 200-300mM
-1S
-1, 241mM more preferably
-1S
-1
4. the preparation method of a multifunctional nano composite particles comprises:
The mercapto-functionalized magnetic ferroferric oxide particle in step a) preparation surface;
The step b) magnetic ferroferric oxide particle that described surface is mercapto-functionalized is dissolved in the solution, adds chlorauride and reducing agent and makes the gold nano grain grafting form described multifunctional nano composite particles to ferriferrous oxide particles;
It is characterized in that in step b), the pH with described solution before adding described reducing agent is adjusted to 7-10, thereby controls the diameter of described gold nano grain.
5. preparation method according to claim 4 is characterized in that, described step a) comprises:
A1) be (40-100) with magnetic ferroferric oxide particle and amphipathic nature block polymer and oxolane according to mol ratio: (1-2): (1 * 10
5-5 * 10
5) mix after, add ultra-pure water, the brown solution that obtains after continuing to stir is dialysed in deionized water and is removed oxolane;
A2) be (5-10) with ammoniacal liquor and mercaptopropyl trimethoxysilane according to mol ratio: (1-2) successively join in the above-mentioned solution, continue stirring and obtain the mercapto-functionalized magnetic ferroferric oxide particle in surface.
6. preparation method according to claim 5 is characterized in that, described amphipathic nature block polymer is polystyrene-b-polyacrylic acid, polycaprolactone-b-polyacrylic acid, polycaprolactone-b-polyethylene glycol or polystyrene-b-PEO.
7. preparation method according to claim 5 is characterized in that, the mol ratio of ferriferrous oxide particles and amphipathic nature block polymer polystyrene-b-polyacrylic acid and oxolane is 42:1:1.2 * 10
5, the mol ratio of ammoniacal liquor and mercaptopropyl trimethoxysilane is 8.69:1.
8. preparation method according to claim 4 is characterized in that, described step b) comprises: in the solution of the mercapto-functionalized magnetic ferroferric oxide particle in described surface, successively add ultra-pure water, chlorauride and reducing agent; Wherein, the mole ratio of ultra-pure water, chlorauride, reducing agent and ferriferrous oxide particles is (1 * 10
5-2 * 10
5): (1-2): (0.5-2): (0.2-1), mix the back and continue to stir, obtain described multifunctional nano composite particles behind the solution centrifugal.
9. preparation method according to claim 8 is characterized in that, in step b), the mol ratio of ultra-pure water, chlorauride and reducing agent is 1.66 * 10
5: 1.5:1.
10. according to each described multifunctional nano composite particles application on magnetic resonance imaging and biomarker ability among the claim 1-3.
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| CN104162665A (en) * | 2014-08-29 | 2014-11-26 | 华东理工大学 | Gold-organic silicon-gold multilayer core-shell nano-structure and preparing method and application thereof |
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Cited By (4)
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Application publication date: 20130911 |