CN103405788B - Contrast agent as well as preparation method and application thereof - Google Patents
Contrast agent as well as preparation method and application thereof Download PDFInfo
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- CN103405788B CN103405788B CN201310376707.8A CN201310376707A CN103405788B CN 103405788 B CN103405788 B CN 103405788B CN 201310376707 A CN201310376707 A CN 201310376707A CN 103405788 B CN103405788 B CN 103405788B
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- contrast agent
- nanoparticle
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Abstract
The invention provides a contrast agent as well as a preparation method and an application thereof. The contrast agent is formed by taking Mn3[Co(CN)6]2 nanometer particles as an inner core and a silica coating layer as a casing. The contrast agent which is high in relaxation rate, low in toxicity and high in fluorescent quantum yield can be used for T1-T2 dual-mode magnetic resonance imaging, magnetic resonance angiography, multiband bioluminescence imaging and dual-photon bioluminescence imaging.
Description
Technical field
The present invention relates to diagnosis imaging field, particularly a kind of contrast agent simultaneously with nuclear magnetic resonance and fluorescence imaging function, and its preparation method and application.
Background technology
According to Nature Biotechnol (Nature Biotechnology2007,25th volume, 217 pages) report, biomedical imaging technology plays very important effect in the early discovery of tumor, and wherein nuclear magnetic resonance and fluorescence imaging are use at present the most extensive is also the most effective imaging technique.Conventional magnetic resonance contrast agent has paramagnetic complex and superparamagnetic nanoparticle two kinds.Wherein paramagnetic complex contrast agent is as T1 contrast agent, is especially most widely used in clinical with Magnevist Solution (magnevist), but has had the heavy dose of use magnevist of report display to be easy to cause kidney origin system fibrosis, harmful.And superparamagnetic nanoparticle is as T2 contrast agent conventional at present, main representative is SPIO, although have very high image sensitivity, because the low signal of T2 imaging is easily by hemorrhage interference, also have impact on its practical application.Although there has been now report to realize T1-T2 Double-mode imaging by synthesis compound particle, but the interference between the synthesis step of its complexity and two kinds of imaging patterns, make its imaging effect unsatisfactory ([1] Biomaterials2011, the 32nd volume, 4584 pages; [2] Advanced Materials2011, the 23rd volume, 5392 pages).
Because nuclear magnetic resonance can provide high-resolution three dimensional structure information, and fluorescence imaging is the visual inspection carried out on cell dimensions, therefore, the combination of the two is compared with independent imaging, can increase the accuracy of diagnosis to a great extent.The method preparing the double mode radiography material of fluorescence and nuclear magnetic resonance common is at present by combining paramagnetic ion and quantum dot or magnetic core and fluorogen compound realized ([1] Angew Chem Int Edit2010 by coated method, 49th volume, 3976 pages; [2] J Am Chem Soc2007, the 129th volume, 8698 pages).But these methods are subject to the impact of quantum dot toxicity and fluorescence group stability, limit its application in biological.Therefore, develop a kind of contrast agent that simultaneously can realize the imaging of T1-T2 double-mode magnetic resonance and fluorescence imaging and become for medical diagnosis on disease the technical barrier that this area needs solution badly.
Summary of the invention
In view of this, the invention provides the contrast agent that a kind of relaxation rate is high, toxicity is low and fluorescence quantum yield is high, and its preparation method and application.
For achieving the above object, the invention provides a kind of contrast agent, described contrast agent is with Mn
3[Co (CN)
6]
2nanoparticle is kernel, with coated with silica layer for shell.
Preferably, the particle diameter of described contrast agent is 160 ~ 200nm, and specific surface area is 500 ~ 700m
2/ g, average pore size is 2 ~ 5nm.
Preferably, the particle diameter of described kernel is 150 ~ 180nm, and specific surface area is 150 ~ 250m
2/ g, average pore size is 3 ~ 10nm, and the shell thickness of described shell is 10 ~ 20nm.
Contrast agent provided by the invention is the coated Mn of core-shell silica
3[Co (CN)
6]
2nanoparticle, has good relaxation rate, can be used for Magnetic Resonance Angiography and T
1-T
2double-mode magnetic resonance imaging, can also provide the imaging of multiband bioluminescence, simultaneously can provide high-resolution two-photon biological fluorescence imaging, achieves the multi-functional of magnetic resonance and fluorescence imaging, can be used for medical imaging diagnosis.
The kernel Mn of this contrast agent
3[Co (CN)
6]
2nanoparticle is cobalt cyanate radical coordination compound nano cubic, it has face-centred cubic metal-organic framework, and not only specific surface area is large, and inner void is many, can well with water molecules to reach desirable nuclear magnetic resonance effect, and the optical property of manganese ion can be retained.Replace the thinking of compound particle by homogenous material, kernel silicon dioxide coated under be formed with the nuclear shell structure nano cube of better biocompatibility, can effectively avoid dissimilar contrast agent to synthesize the ill effect of composite contrast agent.
Present invention also offers a kind of preparation method of contrast agent, it comprises the steps:
1) by the mixed system of manganese salt and the water-soluble and ethanol of polyvinylpyrrolidone, solution A is obtained;
2) by soluble in water for cobalt cyanate, solution B is obtained;
3) by step 2) in the solution B that obtains add in the solution A obtained in step 1), to stir, centrifugal, obtain Mn
3[Co (CN)
6]
2nanoparticle;
4) Mn will obtained in step 3)
3[Co (CN)
6]
2nanoparticle dispersion, in alcoholic solution, adds tetraethyl orthosilicate after adding ammonia again, stir, centrifugal, namely obtain with Mn
3[Co (CN)
6]
2nanoparticle is kernel, the contrast agent being shell with coated with silica layer.
When preparing contrast agent, manganese salt can select manganese acetate, manganese chloride and manganese sulfate etc., and cobalt cyanate can select cobalt potassium cyanate, cobalt Sodium cyanate (NaOCN) etc., and preferably, manganese salt is preferably manganese acetate, and cobalt cyanate is preferably cobalt potassium cyanate.
In the preparation method of contrast agent of the present invention, in step 1), the ratio of water and ethanol can have influence on Mn
3[Co (CN)
6]
2the pattern of nanoparticle and size, preferably, in described step 1), the volume ratio of water and ethanol is (0-3): (0-1), and more preferably, in described step 1), the volume ratio of water and ethanol is 3:1.In addition, in described step 1), the mass ratio of manganese salt and polyvinylpyrrolidone is 1:(15-30).
In a preferred embodiment of the inventive method, fully react to make manganese salt and cobalt cyanate, the mol ratio of described manganese salt and cobalt cyanate is (1-5): (1-4), and can heat mixed solution after solution A and solution B mixing, stirring reaction is carried out under a fixed temperature, this reaction does not strictly limit mixing speed and mixing time, and preferably, mixing time is 0.5 ~ 2h.In addition, centrifugal again after also can leaving standstill certain hour after stirring, to make the nano cubic of synthesis, there is better crystal property and be easy to be separated.
In a preferred embodiment of the inventive method, Mn
3[Co (CN)
6]
2the ratio of the quality of nanoparticle and the volume of tetraethyl orthosilicate is (5-20): (20-50), Mn
3[Co (CN)
6]
2the unit of the quality of nanoparticle is mg, and the unit of the volume of tetraethyl orthosilicate is μ L.In order to obtain thicker coated with silica layer, step 4) can be repeatedly.
In step 4), add ammonia is that the addition of ammonia there is no considered critical, can select flexibly according to the actual requirements in order to make system be alkalescence.In addition, in order to make Mn
3[Co (CN)
6]
2more fully, the stirring in step 4) can be carried out at 20 DEG C ~ 40 DEG C, and its mixing speed and mixing time are without considered critical, and preferably, mixing time is 2h ~ 4h for nanoparticle and tetraethyl orthosilicate reaction.
Contrast agent of the present invention has following features:
1) relaxation rate is high, can realize T
1-T
2double-mode magnetic resonance imaging;
2) toxicity is low;
3) fluorescence quantum yield is high, can realize the imaging of multiband bioluminescence and two-photon biological fluorescence imaging.
Use the preparation method of this contrast agent, there is following effect:
1) method of the present invention is simple to operate, reproducible, is easy to realize suitability for industrialized production;
2) Mn
3[Co (CN)
6]
2the size of nanoparticle easily controls, and can meet the different needs.
Accompanying drawing explanation
Fig. 1 is S1 and Mn
3[Co (CN)
6]
2the X ray diffracting spectrum of nanoparticle;
Fig. 2 is Mn in embodiment 1
3[Co (CN)
6]
2the stereoscan photograph (b) of nanoparticle (a), S1 and high-resolution-ration transmission electric-lens photo (c) of S1;
Fig. 3 is Mn in embodiment 1
3[Co (CN)
6]
2nanoparticle (a) and S1(c) adsorption-desorption curve and Mn
3[Co (CN)
6]
2nanoparticle (b) and S1(d) pore size distribution curve;
Fig. 4 is Mn in embodiment 1
3[Co (CN)
6]
2nanoparticle (a) and S1(b) T
1-T
2double-mode magnetic resonance imaging picture and Mn
3[Co (CN)
6]
2nanoparticle (c) and S1(d) T
1and T
2relaxivity curve;
Fig. 5 is that S1 is dispersed in after in phosphate buffered solution, is injected the T after in the Mice Body constructing brain tumor model by tail vein
1and T
2image;
Fig. 6 is that S1 is dispersed in phosphate buffered solution the T injecting mouse brain
2perfusion Imaging figure, wherein (a) figure is the T of brain tumor model
2perfusion mri picture, (b) figure is the relation curve of magnetic resonance signal intensity and time;
Fig. 7 is that S1 is dispersed in after in phosphate buffered solution, enters the T at renal tract (a) and vascular site (b) after in normal mouse body by tail vein injection
1image;
Fig. 8 is Mn
3[Co (CN)
6]
2nanoparticle (a) and S1(b) by after cytophagy in respectively light field, excitation wavelength in the confocal laser microscope of 488nm and 403nm and excitation wavelength at the microscopical fluorescence imaging figure of the two-photon fluorescence of 720nm.
Detailed description of the invention
For enabling above-mentioned purpose, the feature and advantage of invention more become apparent, below the specific embodiment of the present invention is described in detail.
Set forth a lot of detail in the following description so that fully understand the present invention, but the present invention can also adopt other to be different from alternate manner described here to implement, those skilled in the art can when without prejudice to doing similar popularization when intension of the present invention, therefore the present invention is by the restriction of following public specific embodiment.
Raw material used in embodiments of the invention is as follows:
Manganese acetate, analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group
Polyvinylpyrrolidone (PVP), analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group
Ethanol, volume fraction >=99.7%, Chemical Reagent Co., Ltd., Sinopharm Group
Cobalt potassium cyanate, analytical pure, Acros organics company
Ammonia, concentration 25% to 28%, Chemical Reagent Co., Ltd., Sinopharm Group
Tetraethyl orthosilicate, analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group
The HJ-2A digital display double end magnetic stirring apparatus that the present invention adopts Shanghai Ju Na Science and Technology Ltd. to produce in an embodiment stirs, the LG10-2.4A table model high speed centrifuge adopting system in Beijing Jing to stand the production of centrifuge company limited carries out centrifugal, the JSM-6700M field emission scanning electron microscope adopting Japanese JEOL company to produce detects the pattern of particle and size, the H-800 transmission electron microscope adopting Japanese Hitachi company to produce detects the pattern of particle and size, the thing of D/MAX-cA X-ray diffractometer to contrast agent adopting Japanese Rigaku company to produce detects mutually, the specific surface area of ASAP2020 nitrogen adsorption desorption instrument to particle adopting Micromeritics company to produce is tested, the MKII x-ray photoelectron spectroscopy adopting VGESCALAB company to produce carries out valence state detection to contrast agent surface-element, L SM710 copolymerization Jiao adopting Zeiss company to produce affects the fluorescence imaging performance of microscope to contrast agent and detects, the nuclear magnetic resonance performance of Sigma HDX3.0T magnetic resonance imager to contrast agent adopting General Corporation (GE) to produce detects.
In the embodiment of the present invention, the method for testing of relevant data is as follows:
External nuclear magnetic resonance (In vitro MRI) operates execution at 25 DEG C, and wherein T1 weighted imaging adopts the spin-echo sequence of saturated reply, and Selecting All Parameters is TE=10ms, TR=4000,2000,1000,500,200,100ms, T2* weighted imaging adopts gradin-echo, and Selecting All Parameters is TR=120, TE=2.328,6.112,9.896,13.68,17.46,21.24ms, flip angle is 30 °, and bandwidth is 31.25Hz, and observation area is of a size of 180 × 180mm
2, layer is wide is 3mm.
Nuclear magnetic resonance in body (In vivo MRI) detects operation at 25 DEG C and performs, wherein T1 weighted imaging adopts quick free echo sequence, and Selecting All Parameters is TR/TE is 780/19.6ms, and number of shots (NEX) is 2, echo track length is 2, and observation area is of a size of 0.188 × 0.188mm
2, the number of plies 10 layers, interlamellar spacing is 2mm.
Fluorescence imaging analysis mainly detects the fluorescence signal in the Hela cell of endocytosis contrast agent, detailed process is that Hela cell is inoculated in the living cells culture dish of glass bottom, after hatching 24 hours with contrast agent, with PBS solution rinse Hela cell three times, then change the CO containing 10% hyclone into
2independent form culture medium, Hela cell maintains 37 degree, Image Acquisition is completed by laser scanning microscope, the camera lens used is the oil immersed type apochromat of 40 times, the exciting light of green fluorescence channel is 488 nanometer lasers, the exciting light of blue-fluorescence passage is 403 nanometer lasers, and the wavelength of two-photon laser is 720 nanometers, and scanning resolution is 1024 × 1024.
Embodiment 1
The preparation of contrast agent
1) manganese acetate of 0.075mmol and the polyvinylpyrrolidone of 0.3g are dissolved in the mixed system in 15mL ethanol and 5mL water, obtain solution A;
2) the cobalt potassium cyanate of 0.04mmol is dissolved in 10mL water, obtains solution B;
3) solution B is slowly added drop-wise in the solution A under magnetic agitation condition with Syringe injector, stirs 1h, then the troubled liquor of gained is left standstill 24 hours, centrifugal, washing afterwards, to dry, obtain Mn
3[Co (CN)
6]
2nanoparticle;
4) 18mg Mn is got
3[Co (CN)
6]
2nanoparticle dispersion, in 18mL ethanol, adds after ammonia and stirs 10 minutes, then add the tetraethyl orthosilicate of 68 μ L, stirs 2 hours, and centrifugal, washing afterwards, oven dry, namely obtain with Mn
3[Co (CN)
6]
2nanoparticle is kernel, the contrast agent S1 being shell with coated with silica layer.
As shown in Figure 1, S1 is by Mn
3[Co (CN)
6]
2with silicon dioxide composition, in collection of illustrative plates, the microspike at 20 ° of places indicates the existence of coated with silica layer;
As shown in Figure 2, Mn
3[Co (CN)
6]
2nanoparticle presents cubic, and as shown in arrow locations in figure, after passing through coated with silica, the obvious roughening in surface of S1, can determine the existence of coated with silica layer in conjunction with transmission electron microscope;
As shown in Figure 3, can find out that S1 has larger specific surface area and aperture by adsorption-desorption curve (c) of S1 with pore size distribution curve (d).
Embodiment 2
The T of S1
1-T
2double-mode magnetic resonance imaging effect
As shown in Figure 4, T
1under imaging pattern from low concentration to high concentration image by secretly brightening, T
2just contrary under imaging pattern, indicate the Double-mode imaging contrasting effects of S1;
As shown in Figure 5, what S1 can continue provides T at mouse brain knub position
1and T
2contrast imaging effect;
As shown in Figure 6, the curve declined in time by magnetic resonance signal in (b) figure describes the back brain T squeezing into S1
2the reduction of signal, and by contrast tumor tissues (in (a) 1 indication place) and normal structure (in (a) 2 indication places), can find out because S1 is in the enrichment of tumor locus, its T
2signal is starkly lower than normal structure;
As shown in Figure 7, S1 can be accumulated in renal tract by body-internal-circulation thus provide the radiography of lasting renal tract, and can provide outstanding T in the blood vessel
1imaging effect, demonstrates this nano cubic clearly as contrast agent flow path in the blood vessel.
Embodiment 3
The fluorescence imaging effect of S1
As shown in Figure 8, Mn has been engulfed
3[Co (CN)
6]
2nanoparticle (a) and S1(b) after tumor cell under multiband, present fluorescence signal.Wherein, faint blue light is presented at excitation wavelength fluorescence signal under 403nm, strong green glow is presented in excitation wavelength fluorescence signal imaging under 488nm, and when two-photon excitation, its excitation wavelength is under 720nm, fluorescence signal presents strong blue light, which illustrates S1 and can provide available fluorescence signal in multiple wave band and two-photon fluorescence imaging.
Although the present invention is described in conjunction with above embodiment, but the present invention is not defined to above-described embodiment, and only by the restriction of claims, those of ordinary skill in the art can easily modify to it and change, but do not leave essential idea of the present invention and scope.
Claims (9)
1. a contrast agent, is characterized in that, described contrast agent is with Mn
3[Co (CN)
6]
2nanoparticle is kernel, and with coated with silica layer for shell, wherein, described kernel has a cube block structure.
2. contrast agent according to claim 1, is characterized in that, the particle diameter of described contrast agent is 160 ~ 200nm, and specific surface area is 500 ~ 700m
2/ g, average pore size is 2 ~ 5nm.
3. contrast agent according to claim 1, is characterized in that, the particle diameter of described kernel is 150 ~ 180nm, and specific surface area is 150 ~ 250m
2/ g, average pore size is 3 ~ 10nm, and the shell thickness of described shell is 10 ~ 20nm.
4. a preparation method for contrast agent, is characterized in that, comprises the steps:
1) by the mixed system of manganese salt and the water-soluble and ethanol of polyvinylpyrrolidone, solution A is obtained;
2) by soluble in water for cobalt cyanate, solution B is obtained;
3) by step 2) in the solution B that obtains add step 1) in the solution A that obtains, to stir, centrifugal, obtain Mn
3[Co (CN)
6]
2nanoparticle;
4) by step 3) in the Mn that obtains
3[Co (CN)
6]
2nanoparticle dispersion, in alcoholic solution, adds tetraethyl orthosilicate after adding ammonia again, stir, centrifugal, namely obtain with Mn
3[Co (CN)
6]
2nanoparticle is kernel, the contrast agent being shell with coated with silica layer.
5. method according to claim 4, is characterized in that, described step 1) in manganese salt be selected from one in manganese acetate, manganese chloride and manganese sulfate, described step 2) in cobalt cyanate be selected from one in cobalt potassium cyanate, cobalt Sodium cyanate (NaOCN).
6. method according to claim 4, is characterized in that, described step 1) in the volume ratio of water and ethanol be (0-3): (0-1).
7. method according to claim 4, is characterized in that, described step 1) in the mass ratio of manganese salt and polyvinylpyrrolidone be 1:(15-30).
8. method according to claim 4, is characterized in that, the mol ratio of described manganese salt and cobalt cyanate is (1-5): (1-4).
9. method according to claim 4, is characterized in that, described step 3) middle Mn
3[Co (CN)
6]
2the ratio of the quality of nanoparticle and the volume of tetraethyl orthosilicate is (5-20): (20-50), wherein Mn
3[Co (CN)
6]
2the unit of the quality of nanoparticle is mg, and the unit of the volume of tetraethyl orthosilicate is μ L.
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| CN104244588B (en) * | 2014-04-30 | 2018-03-02 | 深圳光韵达光电科技股份有限公司 | The preparation method and modified laser sintered powder material of stereo circuit |
| CN105388136B (en) * | 2015-11-30 | 2018-05-29 | 中国科学技术大学 | A kind of fluorescence imaging probe and preparation method thereof, purposes |
| CN107941774B (en) * | 2017-12-27 | 2020-09-25 | 南昌大学 | Phosphate ratio fluorescence detection method based on metal organic framework composite material |
| CN110624117B (en) * | 2019-09-26 | 2021-09-24 | 南京林业大学 | T1/T2 bimodal nano contrast agent hollow MCO with redox response and preparation method and application thereof |
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