CN105727319A - Preparation and application of fluorescent-nuclear magnetic resonance bifuntional nano particles - Google Patents
Preparation and application of fluorescent-nuclear magnetic resonance bifuntional nano particles Download PDFInfo
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- CN105727319A CN105727319A CN201410775272.9A CN201410775272A CN105727319A CN 105727319 A CN105727319 A CN 105727319A CN 201410775272 A CN201410775272 A CN 201410775272A CN 105727319 A CN105727319 A CN 105727319A
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Abstract
The invention relates to a fluorescent-nuclear magnetic resonance bifuntional nano particle and an application thereof in the field of bio-medicinal imaging. With an organic polybasic acid and gadolinium salt as raw materials, carbon quantum dots containing gadolinium are synthesized through a hydrothermal method in a one-step manner. The carbon quantum dots have fluorescent characters and have both fluorescent and nuclear magnetic resonance functions after gadolinium doped, and then through tumor target group modification, a tumor target nano particle is produced. The nano particle achieves target fluorescent-nuclear magnetic resonance bifuntional imaging. The nano particle is simple in synthetic method, has high quantum yield and relaxation rate, has tumor target property and is hopeful in application in the field of bio-medicinal imaging.
Description
Technical field
The present invention relates to biomedical imaging field, specifically the preparation of a kind of fluorescence-nuclear magnetic resonance, NMR dual-functional nanometer microgranule and application.
Background technology
Molecular probe can by the distinctive signal of its own transmission, for instance optical, electrical, magnetic etc., and target interested is identified, therefore tumor cells image height relies on molecular probe.In nuclear magnetic resonance, NMR (MR) imaging, Gd (III) can pass through paramagnet shortening ambient water proton longitudinal relaxation time and namely increase T1 relaxation rate (1/T1), T1WI signal is made to increase (Coordin.Chem.Rev.2006,250,1562-79).As T1WI contrast medium, current Gd (III) mainly applies with the form of little molecular complexes chelating or nanostructured.Little molecule contrast medium relaxation rate is low, removes fast, and is unfavorable for MR molecular imaging.The nanostructured of Gd (III) mainly with inorganic nano-particle (such as Gd2O3、Gd2O(CO3)2) it is main, its relaxation rate is high, but has the shortcomings such as particle diameter is big, poorly water-soluble, toxicity are big, and due to the factor such as particle diameter, biocompatibility, in vivo often by reticuloendothelial system huge uptake, it is difficult to arrive tumor tissues (Adv.Funct.Mater.2008,18,766-76).Carbon quantum dot (carbondots, CDs) it is a kind of novel fluorescence nano material, there is the features such as particle diameter is little, toxicity is low, good biocompatibility, good water solubility, it is made to be used widely at biological field, including the aspect (Theranostics such as bio-sensing and bio-imaging, 2012,2,295-301；Angew.Chem.Int.Edit.,2010,49(38):6726-44).Carbon quantum dot has passive targeting, the research such as Huang finds that it can pass through permeability enhancing and retention effect is enriched with at tumor tissues, and clearance rate is very fast, only on a small quantity by reticuloendothelial system phagocytic (ACSnano, 2013,7 (7): 5684-5693).Comparing with inorganic nano-particle, Gd (III) contrast medium of high quantum production rate carbon quantum dot is more suitable for carrier imaging., the quantum yield complicated containing gadolinium carbon quantum dot preparation method having now been found that and relaxation rate are very low, there is certain gap (J.Mat.Chem., 2012,22 (44): 23327-30) with application request.Therefore, by the synthesis of simple method, there is tumor-targeting, high quantum production rate, the nano material of high relaxation rate significant for live body.
Summary of the invention
For at present existing containing gadolinium carbon quantum dot quantum yield and the problem such as relaxation rate is relatively low, preparation method is complicated, the invention provides a kind of method that a step prepares the nano material of high quantum production rate, high relaxation rate, cancer target fluorescence-nuclear magnetic resonance, NMR dual-functional nanometer microgranule and the application in the fields such as living imaging thereof is prepared after being then passed through cancer target base group modification.
The method is simple and easy to do, and gained nano material has higher quantum yield and relaxation rate, is highly soluble in water, is a kind of good difunctional image forming material of fluorescence-magnetic resonance.
The present invention is achieved through the following technical solutions:
Fluorescence provided by the invention-nuclear magnetic resonance, NMR dual-functional nanometer microgranule is prepared by following steps:
(1) gadolinium salt is dissolved in water, is added thereto to polyprotic acid aqueous solution, add polyprotic acid and the mol ratio adding gadolinium salt is 0.1-100:1；
(2) in the mixture in step (1), add polyamine aqueous solution, add polyamine and the mol ratio adding gadolinium salt is 0-500:1；
(3) being placed in autoclave by mixture, heating, to 110-300 DEG C, keeps 0.5-24 hour；
(4) after cooling, elimination insoluble matter, collect filtrate；
(5) adopt the method for one or two or more kinds in gel chromatography, dialysis or ultrafiltration, the filtrate that step (4) obtains is purified, dry after rotary evaporation concentration, obtain the carbon quantum dot containing gadolinium element.
Gadolinium salt described in step (1) is any one in Gadolinium trichloride, Digadolinium trisulfate, gadolinium or Gadolinium trinitrate, or arbitrarily several mixture formed with arbitrary proportion.
Polyprotic acid described in step (1) is any one in citric acid, tartaric acid, malic acid, succinic acid, maleic acid or Fumaric acid, or arbitrarily several mixture formed with arbitrary proportion.
Step (2) described polyamine is any one in carbamide, biuret, ethylenediamine or ethylenediamine polymer, or arbitrarily several mixture formed with arbitrary proportion.
Step (5) described drying means is vacuum drying or lyophilization.
The quantum yield of the nano material prepared reaches as high as 75.5%, and relaxation rate R1 is up to 17.95mM-1·S-1, R2 is up to 19.77mM-1·S-1。
Described nanoparticle can be applicable in medicine, medical image material and magnetic resonance-fluorescent dual module state image probe；Nanoparticle prepares cancer target nanoparticle after cancer target base group modification, it is possible to achieve cancer target fluorescence and the difunctional imaging of NMR (Nuclear Magnetic Resonance)-imaging.
Accompanying drawing explanation
Fig. 1 is fluorescence-nuclear magnetic resonance, NMR dual-functional nanometer microgranule TEM photo of preparing of the present invention and grain size distribution；
Fig. 2 is fluorescence-nuclear magnetic resonance, NMR dual-functional nanometer microparticle fluorescence spectrogram that the present invention prepares；
Fig. 3 is red watt of spectrogram of fluorescence-nuclear magnetic resonance, NMR dual-functional nanometer microgranule that the present invention prepares；
Fig. 4 be the nano material for preparing of the present invention to healthy mice at body T1WI image；
Fig. 5 is the cell imaging figure of fluorescence-nuclear magnetic resonance, NMR dual-functional nanometer microgranule that the present invention prepares.
Detailed description of the invention
Embodiment 1
Weigh 16mgGdCl3It is dissolved in 5mL water, separately takes 1.05g citric acid and be dissolved in 20mL water, the two is mixed, is placed in 50mL teflon-lined autoclave, is placed in Muffle furnace after sealing.By room temperature to 200 DEG C in 1 hour, keep this temperature 8 hours.After naturally cooling to room temperature, taking out liquid, filter with the polyethersulfone membranes of 0.22 μm, obtain filtrate, filtrate rotary evaporation is concentrated into 4mL.Separating this concentrate with glucosan G-25 gel, collect fluorescing fractions, rotary evaporation concentration postlyophilization, obtains brownish black solid nanoparticulate again.
Embodiment 2
CLT-1 is peptide-labeled: add the carboxyl of dicyclohexylcarbodiimide activation nano-particle surface in Gd-CDs, with backward reaction system adds the hydroxy activated carboxyl thiosuccimide of N-, then carboxyl forms stable amido link with the amino coupled on 1-azido-3-aminopropane, obtains Gd-CDs-N3.After grafting, Gd-CDs-N3The a part of converting carboxylate groups in surface is azido, and itself and end react through alkynyl-modified CLT1 small peptide, utilizes click chemistry reaction to modify upper CLT-1 peptide, it is achieved cancer target.
Embodiment 3
Property representation containing gadolinium carbon quantum dot:
1. particle size distribution
As it is shown in figure 1, observe the nanoparticle (accelerating potential 75kV, enlargement ratio 80000 times) of preparation with JEM-2000 transmission electron microscope (TEM), counting statistics obtains the particle diameter of this nano material mainly between 3.5～6.5nm.
2. fluorescence spectrum and quantum yield
As in figure 2 it is shown, fully dissolve this nano material with deionized water, take 2mL and be placed in silica dish, utilize the fluorescence emission spectrum under fluorescence spectrophotometer measurement different wave length exciting light, excitation wavelength respectively 300,320,340,360,380,400,420nm.
Choose quinine sulfate solution as reference sample, quinine sulfate is dissolved in the sulfuric acid solution of 0.1mol/L, prepare 3 parallel reference sample liquids of quinine sulfate (to ensure that its solution absorbance at 360nm place is not higher than 0.05, and fluorescent emission peak value does not spill over the detection limit of instrument).Exciting under 360nm wavelength, slit width is 5nm, measures its fluorescence emission curves, it is ensured that fluorescence maximum does not spill over, and calculates the peak area of fluorescence emission curves.Measure quinine sulfate reference ultraviolet absorption value under 360nm wavelength again, sample is configured to 3 parallel sample liquids respectively, and (parallel sample liquid is the aqueous solution of above-mentioned nano material, ensure that its solution absorbance at 320nm place is not higher than 0.05, and fluorescent emission peak value does not spill over the detection limit of instrument), take excitation wavelength 320nm, measure 3 sample liquids ultraviolet absorption value (ensureing that ultraviolet absorption value is not more than 0.05) at 320nm place, choosing crack width is that 5nm measures its fluorescence emission curves, then calculates the peak area of fluorescence emission curves.Bring the uv absorption numerical value of computed peak area and measurement into following formula:
In formula,Being ultraviolet absorption value for quantum yield QY, A, F is fluorescence emission curves integral area, and η is the index of refraction of solvent, and subscript S is reference, and X is testing sample,Recording the nano material that the method for the invention makes, its fluorescence quantum yield is up to 75.5%.
3. relaxation rate
Weigh the nano material that about 5mg embodiment prepares, accurately weighed, it is subsequently solubolized in 250 μ l concentrated nitric acids, after melting completely, is settled to 10ml with volumetric flask.With Gd elemental standards solution for reference, with ICP-atomic absorption spectrography (AAS), institute's Gd element in sample is carried out quantitatively.The gadolinium concentrations that result is the nano material prepared in embodiment 1 is 49 μm of ol/g., it is 0.4mmol/L mother solution that sample preparation becomes Gd molar concentration.Subsequently mother solution is diluted to respectively 0.2,0.1,0.05, tetra-concentration of 0.025mmol/L, cumulative volume is 5mL, is placed in the flat centrifuge tube of 5mL.With the nuclear magnetic resonance scanner IR sequencing T1 relaxation time: TW value is 5500ms；CPMG sequence measures the T2 time: TW value is 5500ms.Calculate r1, r2 value.The nano material that the method for the invention makes, its relaxation rate R1 is up to 17.95mM-1·S-1, R2 is up to 19.77mM-1·S-1。
4. infrared spectrum characterization
Fig. 3 shows 3435cm-1For the stretching vibration absworption peak of O-H, 2111cm-1For N3Stretching vibration peak, without this characteristic peak before graft N 3, and after grafting, have obvious characteristic peak, after reacting with alkynyl CLT1, this characteristic peak reduces, and N3 is described and alkynyl carries out covalent bond and causes N3 negligible amounts, 1720cm-1And 1612cm-1For the stretching vibration absworption peak of C=O, 1207-1035cm-1For the stretching vibration absworption peak of C-O, grafting CLT1 leading peak is narrower, and grafting postpeak becomes wider.The results of FT-IR shows, CLT1 has been grafted to nanoparticle surface, and C-O absworption peak is broadening, relevant with the short chain ether structure of CLT1 end, also illustrates that CLT1 is grafted to nanoparticle surface.
Embodiment 4
In body T1WI NMR (Nuclear Magnetic Resonance)-imaging
The nanoparticle that tumor-bearing mice the method for the invention makes is done enhanced ct scans, observes nanoparticle in body situation.Magnetic resonance parameters: Mini-Rat low-field nuclear magnetic resonance analyser, mice coil；SE sequence T1WI coronal scan: TR300ms, TE19.2ms, 100 × 100mm, slicewidth3mm, slicegap2mm.
With isoflurane and oxygen mix ventilation, mice is carried out gas anesthesia.To put on politef Mus bed after mouse anesthesia, unenhanced obtain T1WI image.The cancer target fluorescence that experiment mice makes through tail vein injection the method for the invention-nuclear magnetic resonance, NMR dual-functional nanometer microgranule, dosage is 0.1mmol/kg body weight.Gather 2min and 20min (Fig. 4) time point data respectively, observe enhancing situation, it is seen that the tumor locus of the tumor-bearing mice of injection Gd-CDs-CLT1 strengthens and apparently higher than the tumor-bearing mice of injection Gd-CDs, to show good cancer target ability.
Embodiment 5
Cell imaging
40mgGd-CDs-CLT1 nanoparticle is dissolved in the cell culture medium of 2mL and mix homogeneously.Tumor cell forms single cell suspension after trypsinization, with 1 × 104Density (Cells/ml) is planted in the culture dish of diameter 1cm, and each culture dish adds 1mL and is mixed with the culture fluid of carbon point, orifice plate is placed in incubator and hatches 24h (temperature is 37 DEG C, CO2It is 5%).By the PBS eluting 2 times of the cell 0.1M after having cultivated, culture fluid and dead cell are washed off completely.Microscope slide is placed on the object stage of fluorescence microscope, uses 405nm and 488nm to excite observation of cell form respectively.Confirm that Gd-CDs-CLT1 nanoparticle is as fluorescent probe labeled cell by tumor cell imaging (Fig. 5), compared with matched group (the non-Ghana grain of rice) cell, cell containing nanoparticle excites at 405nm and sends obvious blue light, excite at 488nm and send obvious green glow, it was demonstrated that nanoparticle may be used for labeled in vitro tumor cell.
Claims (8)
1. the preparation of fluorescence-nuclear magnetic resonance, NMR dual-functional nanometer microgranule, it is characterised in that: the preparation of described nanoparticle is made up of following steps:
(1) gadolinium salt is dissolved in water, is added thereto to polyprotic acid aqueous solution, add polyprotic acid and the mol ratio adding gadolinium salt is 0.1-100:1；
(2) in the mixture in step (1), add polyamine aqueous solution, add polyamine and the mol ratio adding gadolinium salt is 0-500:1；
(3) being placed in autoclave by mixture, heating, to 110-300 DEG C, keeps 0.5-24 hour；
(4) after cooling, elimination insoluble matter, collect filtrate；
(5) adopt the method for one or two or more kinds in gel chromatography, dialysis or ultrafiltration, the filtrate that step (4) obtains is purified, dry after rotary evaporation concentration, obtain the carbon quantum dot containing gadolinium element.
2. preparation method as claimed in claim 1, it is characterised in that: the gadolinium salt described in step (1) is any one in Gadolinium trichloride, Digadolinium trisulfate, gadolinium or Gadolinium trinitrate, or arbitrarily several mixture formed with arbitrary proportion.
3. preparation method as claimed in claim 1, it is characterized in that: the polyprotic acid described in step (1) is any one in citric acid, tartaric acid, malic acid, succinic acid, maleic acid or Fumaric acid, or arbitrarily several mixture formed with arbitrary proportion.
4. preparation method as claimed in claim 1, it is characterised in that: step (2) described polyamine is any one in carbamide, biuret, ethylenediamine or ethylenediamine polymer, or arbitrarily several mixture formed with arbitrary proportion.
5. preparation method as claimed in claim 1, it is characterised in that: step (5) described drying means is vacuum drying or lyophilization.
6. nano material obtained by either method in claim 1-5, it is characterised in that the quantum yield of this nano material reaches as high as 75.5%, and relaxation rate R1 is up to 17.95mM-1·S-1, R2 is up to 19.77mM-1·S-1。
7. the application of the fluorescence described in a claim 1-nuclear magnetic resonance, NMR dual-functional nanometer microgranule, it is characterised in that: described nanoparticle can be applicable in medicine, medical image material and magnetic resonance-fluorescent dual module state image probe.
8. the application of nanoparticle as claimed in claim 7, it is characterised in that: described nanoparticle prepares cancer target nanoparticle after cancer target base group modification, it is possible to achieve cancer target fluorescence and the difunctional imaging of NMR (Nuclear Magnetic Resonance)-imaging.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108557804A (en) * | 2018-05-23 | 2018-09-21 | 南京师范大学 | Preparation method of a kind of Gd, N codope carbon quantum dot and products thereof and application |
| CN109233828A (en) * | 2018-11-02 | 2019-01-18 | 广西医科大学 | A kind of preparation method and application of novel gadolinium base fluorescent carbon point |
| CN110229663A (en) * | 2019-06-26 | 2019-09-13 | 西北大学 | A kind of boration carbon quantum dot and its preparation method and application |
| CN113588607A (en) * | 2021-07-05 | 2021-11-02 | 山西大学 | Nano probe based on ratiometric fluorescence and colorimetric dual modes, preparation method thereof and application of nano probe in morin detection |
| CN114196399A (en) * | 2020-09-17 | 2022-03-18 | 广东量子墨滴生物科技有限公司 | Carbon nano-particle with near-infrared light emission characteristic and preparation method and application thereof |
| WO2023274298A1 (en) * | 2021-06-30 | 2023-01-05 | 澳门大学 | Quantum dot modified protein vaccine and preparation method therefor and application thereof |
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| CN103800922A (en) * | 2014-03-04 | 2014-05-21 | 南开大学 | Synthesis method and application of carbon-embedded gadolinium nano magnetic resonance imaging contrast agent |
Non-Patent Citations (1)
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108557804A (en) * | 2018-05-23 | 2018-09-21 | 南京师范大学 | Preparation method of a kind of Gd, N codope carbon quantum dot and products thereof and application |
| CN109233828A (en) * | 2018-11-02 | 2019-01-18 | 广西医科大学 | A kind of preparation method and application of novel gadolinium base fluorescent carbon point |
| CN109233828B (en) * | 2018-11-02 | 2021-07-27 | 广西医科大学 | Preparation method and application of gadolinium-based fluorescent carbon dots |
| CN110229663A (en) * | 2019-06-26 | 2019-09-13 | 西北大学 | A kind of boration carbon quantum dot and its preparation method and application |
| CN110229663B (en) * | 2019-06-26 | 2020-08-11 | 西北大学 | Borated carbon quantum dot and preparation method and application thereof |
| CN114196399A (en) * | 2020-09-17 | 2022-03-18 | 广东量子墨滴生物科技有限公司 | Carbon nano-particle with near-infrared light emission characteristic and preparation method and application thereof |
| CN114196399B (en) * | 2020-09-17 | 2023-08-01 | 广东量子墨滴生物科技有限公司 | Carbon nano particle with near infrared light emission characteristic and preparation method and application thereof |
| WO2023274298A1 (en) * | 2021-06-30 | 2023-01-05 | 澳门大学 | Quantum dot modified protein vaccine and preparation method therefor and application thereof |
| CN113588607A (en) * | 2021-07-05 | 2021-11-02 | 山西大学 | Nano probe based on ratiometric fluorescence and colorimetric dual modes, preparation method thereof and application of nano probe in morin detection |
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