CN102000350B - Folic acid receptor targeting type nano gold particles and preparation method thereof - Google Patents
Folic acid receptor targeting type nano gold particles and preparation method thereof Download PDFInfo
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Abstract
The invention discloses folic acid receptor targeting type nano gold particles and a preparation method thereof. The invention relates to nano gold particles, and provides folic acid receptor targeting type nano gold particles, and a preparation method and application thereof. The folic acid receptor targeting type nano gold particles are composed of glutathione, nano gold particles and folic acid. The preparation method comprises the following steps of: adding a chloroauric acid solution and a trisodium citrate solution into water, evenly mixing, heating with a microwave oven, and cooling to obtain a solution A; adding a glutathione solution into the solution A, stirring and dialyzing to obtain a solution B; and adding NHS and DCC into the solution B, evenly stirring, adding folic acid, mixing and dialyzing to obtain the folic acid receptor targeting type nano gold particles. The folic acid receptor targeting type nano gold particles can specifically recognize cells with high-level folic acid receptor expression on surface, can be used as a molecular probe for detecting tumor cells, and has wide application range in tumor cell detection.
Description
Technical field
The present invention relates to nanogold particle, particularly a kind of folacin receptor targeting type nanogold particle and preparation method thereof.
Background technology
Nanogold particle (GNPs) is applied in the biomedical research more and more widely.Nanogold particle possesses lot of advantages as imaging agents; With respect to other materials; Nanogold particle self has very strong surface plasma resonance, and (Surface PlasmonResonance, SPR) absorption and scattering properties make it help more detecting in medical science as contrast agent application.Nanogold particle is insensitive to the light effect of floating, and shows excellent biological compatibility and no cytotoxicity.Another major reason of nanogold particle extensive use is that it is easy to carry out bio-modification; The surface of nanogold particle combines with sulfydryl, amino and disulphide etc. easily; Especially through forming golden sulfur (Au-S) key, can biomolecule such as polypeptide, nucleic acid and protein be attached to the nanogold particle surface, after the surface of nanogold particle is modified; Can make nanogold particle have molecular targeted function, be applied to the early diagnosis of tumor.
Glutathion (GSH) is as a kind of natural micromolecule tripeptides; Its particular chemical structure is arranged, and have good water-solubility and chemical stability, can stably be combined in the surface of nanogold particle; Make nanogold particle can further modify (Chen W.; Tu X., Guo X, Fluorescent gold nanoparticles-based fluorescence sensor for Cu
2+Ions.Chem.Commun.2009:1736-1738.).Nanogold particle after folate molecule can be modified with glutathion is through forming the surface that covalent bond is connected to nanogold particle, and (folate receptors FR) is the strand glycoprotein of anchor on glycerol phosphate phthalein inositol in the cell membrane to folacin receptor.Folacin receptor has the affinity of height to folic acid and analog thereof, and has basic characteristics such as saturability, reversibility and competitiveness.In tumor research, find; Folic acid metabolism in most of tumor cell is vigorous; The folacin receptor of tumor cell surface is apparently higher than the folacin receptor on normal tissue cell surface, and based on these characteristics, folacin receptor has received concern widely as the molecular target of tumor cell.
Summary of the invention
First purpose of the present invention is to provide a kind of folacin receptor targeting type nanogold particle.
Second purpose of the present invention is to provide a kind of method for preparing of folacin receptor targeting type nanogold particle.
Forming of said a kind of folacin receptor targeting type nanogold particle by nanogold particle, folic acid and glutathion; The sulfydryl of said glutathion and the surface of nanogold particle form golden sulfur (Au-S) key, and the carboxyl in the said glutathion and the amino of said folic acid form amido link.
The mol ratio of said nanogold particle, folic acid and glutathion can be 1: (1～2): (1～3).
The method for preparing of said a kind of folacin receptor targeting type nanogold particle may further comprise the steps:
1) with chlorauric acid solution and citric acid three sodium solution add in the entry mixed solution, mixed solution is heated postcooling promptly gets solution A;
2) glutathione solution is added in the solution A, stir, get solution B after the dialysis;
3) in solution B, add N-hydroxy-succinamide (NHS) and dicyclohexylcarbodiimide (DCC), add folic acid behind the stirring and evenly mixing, restir, dialysis promptly gets product folacin receptor targeting type nanogold particle.
In step 1), the volume ratio of said chlorauric acid solution, citric acid three sodium solution and water can be 1: 5: 94; The mass concentration of said chlorauric acid solution can be 1%, and the mass concentration of said citric acid three sodium solution can be 1%, and said heating can be adopted microwave heating, and the temperature of heating can be 100～120 ℃, and the time of heating can be 1～10min.
In step 2) in, the concentration of said glutathion can be 0.1mol/L, and the volume ratio of said glutathione solution and solution A can be 1: 200, and the time of stirring can be 8～16h, and the time of dialysis can be 6～12h.
In step 3), the concentration of said N-hydroxy-succinamide can be 0.05mol/L, and the volume ratio of said N-hydroxy-succinamide and solution B can be 1: 400; The concentration of said dicyclohexylcarbodiimide can be 0.05mol/L, and the volume ratio of said dicyclohexylcarbodiimide and solution B can be 1: 400; The volume ratio of said folic acid and solution B can be 1: 200; The time of restir can be 8～16h, and the time of dialysis can be 12～24h.
The cell that a kind of folacin receptor targeting type nanogold particle according to the invention can the specific recognition surface has high-level folacin receptor to express can be used as the molecular probe that detects tumor cell, in tumor cell detects, has widely and uses.
Folacin receptor targeting type nanogold particle among the present invention detects through transmission electron microscope, and particle diameter is the spherical structure of homogeneous between 13～15nm.Through infrared spectrum characterization, folate molecule forms amido link through self amino and the carboxyl in the glutathion, is combined in the surface of nanogold particle.Characterize through X-ray diffraction, show that the surface of nanogold particle exists glutathion and folic acid.Raman spectrum shows that nanogold particle combines through golden sulfur (Au-S) key with glutathion.The MTT experiment shows that folacin receptor targeting type nanogold particle has good cell activity and biocompatibility.The folic acid that laser confocal scanning draws the gold nano grain surface combines with the folacin receptor generation specificity of HeLa cell surface, and is positioned in the Cytoplasm, can be used for the diagnosis of tumor cell.
Folacin receptor targeting type nanogold particle among the present invention is compared with existing nanogold particle has many advantages:
1) good stability is being lower than under the salt concentration conditions of 0.5mol/L and pH value is all can keep good stable property between 3～11.
2) do not have significant cytotoxicity, used glutathion molecule is littler, more helps the picked-up of cell to nanogold particle, has excellent biological compatibility.
3) have good folacin receptor targeting property, can be used as the molecular probe that detects tumor cell, in lesion detection, have widely and use.
Description of drawings
Fig. 1 is the transmission electron microscope picture of folacin receptor targeting type nanogold particle.In Fig. 1, scale is 100nm.
Fig. 2 is the ultraviolet-visible absorption spectroscopy figure of folacin receptor targeting type nanogold particle.In Fig. 2, abscissa is wavelength (nm), and vertical coordinate is an absorbance, and curve 1 is a nanogold particle, and curve 2 is a folacin receptor targeting type nanogold particle.
Fig. 3 is the x-ray photoelectron collection of illustrative plates of folacin receptor targeting type nanogold particle.Abscissa is binding energy (eV), and vertical coordinate is step-by-step counting.In Fig. 3, the photoelectron spectroscopy peak from left to right is respectively Au4f, S2p, C1s, N1s and 01s.
Fig. 4 is the plain narrow spectrogram of gold dollar.In Fig. 4, abscissa is binding energy (eV), and vertical coordinate is step-by-step counting; Au4f is divided into Au 4f5/2 and Au 4f7/2, and binding energy is respectively because AuCl at 87.5eV and 84.0eV
4 -Determined with Au.
The narrow spectrogram of Fig. 5 element sulphur.In Fig. 5, abscissa is binding energy (eV), and vertical coordinate is step-by-step counting; The S2p spectrum is divided into 162.1eV and 163.6eV, is respectively the S-H key, the binding energy in the Au-S key.
The narrow spectrogram of Fig. 6 nitrogen element.In Fig. 5, abscissa is binding energy (eV), and vertical coordinate is step-by-step counting; The N1s spectrum can be divided into 2 peaks, and respectively at 398.85eV and 400.6eV, the position of this binding energy is represented respectively-NH
2With the N the among-NHCO.
Fig. 7 is Raman spectrogram figure.In Fig. 7, abscissa is Raman shift (cm
-1), vertical coordinate is an intensity; Curve a is without the nanogold particle of modifying, and curve b is the nanogold particle of modifying through glutathion, and curve c is the nanogold particle through glutathion and folacin receptor modification.
Fig. 8 cultivates the cell survival situation cartogram behind the 24h altogether for the folacin receptor targeting type nanogold particle of variable concentrations and HeLa cell and fibroblast normally.In Fig. 8, abscissa is the concentration (μ g/ml) of folacin receptor targeting type nanogold particle, and vertical coordinate is cell survival rate (%); A is the HeLa cell, and B is normal fibroblast, and Control is not for adding the blank of folacin receptor targeting type nanogold particle.
Fig. 9 is the folacin receptor targeting type nanogold particle that passes through the FITC modified of same dose and the laser confocal scanning figure behind Hela cell and the A549 co-culture of cells 2h.In Fig. 9, A is the Hela cell, and B is the A549 cell.
Figure 10 be behind folacin receptor targeting type nanogold particle and HeLa cell and the A549 co-culture of cells 2h in intracellular location scattergram.In Figure 10, A is the Hela cell, and its scale is 0.5 μ m, and wherein C is a nucleus, and D is the partial enlarged drawing of A, and its scale is 100nm, and B is the A549 cell, and its scale is 1 μ m.
The testing result figure that Figure 11 combines with the HeLa cell of folacin receptor high expressed for folacin receptor targeting type nanogold particle.In Figure 11, abscissa be cell concentration (individual/ml), vertical coordinate is absorbance changing value Δ A; ■ is the HeLa cell, ● be fibroblast, ▲ be not celliferous cell culture fluid.
The specific embodiment
The preparation of embodiment 1 folacin receptor targeting type nanogold particle
1) with citric acid three sodium solution mixing under room temperature of 94ml ultra-pure water, 1ml 1% chlorauric acid solution and 5ml 1%, puts into microwave oven and heat 1～10min, naturally cool to room temperature, get solution A, put into 4 ℃ of refrigerators and preserve.
2) get solution A 10ml, add 100 μ l 0.1mol/L glutathione solution, stirred overnight at the uniform velocity gets solution B with the mixed liquor 6h that dialyses.
3) in solution B, add the N-hydroxy-succinamide (NHS) of 50 μ l 0.05mol/L and the dicyclohexylcarbodiimide (DCC) of 50 μ l 0.05mol/L; Stirring at room 1h; Add 50 μ l folic acid then; Stir 12h, the mixed liquor 12h that dialyses is promptly got product folacin receptor targeting type nanogold particle, wherein the mol ratio of nanogold particle, folic acid and glutathion is 1: 1: 2.
Embodiment 2Hela cell and fibroblastic cultivation
Conventional method according to cell culture is cultivated Hela cell and fibroblastic cultivation; Take the logarithm respectively the Hela cell and the fibroblast of trophophase; With 0.25% trypsin 0.02%EDTA Digestive system digestion 5min, adding PBS adjustment cell density is 1.5 * 10
6Individual/ml, dilute the adjustment cell concentration with PBS respectively then, to be detected.
The evaluation of embodiment 3 folacin receptor targeting type nanogold particles
Use exceptionally photometer observation folacin receptor targeting type nanogold particle (referring to Fig. 1 and 2) of transmission electron microscope and ultraviolet; It is thus clear that it is claret folacin receptor targeting type nanogold particle; Granule is the very ball-type structure of rule under the transmission electron microscope; Size ratio is than homogeneous, and particle diameter is about 20nm, favorable dispersibility.
The x-ray photoelectron collection of illustrative plates of folacin receptor targeting type nanogold particle shows that the surface of (referring to Fig. 3～6) nanogold particle has folic acid and glutathion to exist.In Fig. 3, the photoelectron spectroscopy peak from left to right is respectively Au 4f, S2p, C1s, N1s and O1s.Fig. 4 is the plain narrow spectrum of gold dollar, and the binding energy of Au 4f 5/2 and Au 4f 7/2 is respectively because AuCl at 87.5eV and 84.0eV
4 -Determined with Au.Fig. 5 is the narrow spectrum of element sulphur, can be divided into 162.1eV and 163.6eV, is respectively the S-H key, the binding energy in the Au-S key; Fig. 6 is the narrow spectrum of nitrogen element, and the N1s spectrum can be divided into 2 peaks, and respectively at 398.85eV and 400.6eV, the position of this binding energy is represented respectively-NH
2With the N the among-NHCO.
The Raman spectrum experiment shows that nanogold particle among the curve a is not owing to modify, and it shows very weak Raman absorbing state at low-frequency region, does not almost have characteristic peak, and at 249.9cm
-1There is 1 absworption peak at the place, is the typical Raman absworption peak of Au-Cl key, and nanogold particle is in order to keep stability, and there is 1 static electric double layer structure on its surface, wherein mainly is AuCl
4 -In the nanogold particle of modifying through glutathion at 291.317cm
-1There is 1 very strong Raman absworption peak at the place, has confirmed that glutathion and nanogold particle are through Au-S be connected (referring to Fig. 7).
The folacin receptor targeting type nanogold particle and the HeLa cell of variable concentrations are cultivated 24h altogether with normal fibroblast, detect the survival (referring to Fig. 8) of cell again.The cell survival situation that adds the folacin receptor targeting type nanogold particle of variable concentrations does not have significant difference with the cell survival situation that does not add folacin receptor targeting type nanogold particle; And after increasing folacin receptor targeting type nanogold particle concentration; The certain limit inner cell still shows good survival rate, shows that folacin receptor targeting type nanogold particle has the good cell compatibility.
Folacin receptor targeting type nanogold particle and the Hela cell and the A549 co-culture of cells 2h through the FITC modified of same dose, the variation of laser confocal microscope observation of cell (referring to Fig. 9).Visible from Fig. 9 A: the Hela surface of cell membrane has many green phosphor (being folacin receptor targeting type nanogold particle) absorption; Also visible green fluorescence in the section H ela cell, and as not occurring green phosphor basically in A549 surface of cell membrane among Fig. 9 B of contrast and the cell.This kind phenomenon why occurring, is because the folacin receptor high expressed in the Hela cell is expressed and the folacin receptor in the A549 cell is low.Folacin receptor targeting type nanogold particle can combine with the folacin receptor specificity of Hela cell high expressed; And the Hela cell surface is almost completely covered by fluorescence; The cancerous cell that has shown folacin receptor targeting type nanogold particle and folacin receptor high expressed has higher joint efficiency, can be used as the instrument of this quasi-cancer cell early diagnosis.The above results shows that also the activity that is modified at the folic acid on gold nano grain surface is not affected, and when hatching with the HeLa cell, can combine with folacin receptor specifically, and target cell is discerned by gold nano grain.Prove that prepared folacin receptor targeting type nanogold particle has good targeting property to the cell of folacin receptor high expressed.
Behind folacin receptor targeting type nanogold particle and HeLa cell and A549 co-culture of cells 2h, again transmission electron microscope observation folacin receptor targeting type nanogold particle in intracellular location distribution situation (referring to Figure 10).As can be seen from the figure, folacin receptor targeting type nanogold particle has distribution in the HeLa cell, in the A549 cell, then fails to find to have the distribution of folacin receptor targeting type nanogold particle.Find also that simultaneously folacin receptor targeting type nanogold particle does not get in the nucleus; Because it is that the phagocytosis of mediation of the folacin receptor through the cell surface high expressed gets in the intracellular endosome that folacin receptor targeting type nanogold particle gets in the cell; These endosomes discharge folacin receptor targeting type nanogold particle under lysosomal effect; Therefore observed gold nano grain all is in the Cytoplasm under the transmission electron microscope, and this explains that from another angle folacin receptor targeting type nanogold particle has targeting property to the cell of folacin receptor high expressed.
Folacin receptor targeting type nanogold particle can detect through following method with the situation that combines of the HeLa cell of folacin receptor high expressed:
1) the folacin receptor targeting type nanogold particle solution of getting 300 μ l 10nmol/L places the centrifuge tube of 500 μ l, to its Hela cell suspension that adds 100 μ l variable concentrations, slightly shake mixing after, under 4 ℃ condition, hatch 30min.
2) these centrifuge tubes of hatching completion being collected, is the centrifugal 5min of 1000rpm with the rotating speed, collects supernatant, characterizes the light absorption value at 528nm place under the record variable concentrations condition with the UV, visible light spectrophotometric spectra.Matched group is the fibroblast of same concentrations gradient, and blank control group is the no phenol red DMEM culture medium that contains folacin receptor targeting type nanogold particle, does not add cell, tests repetition 5 times for every group.Calculate behind the folacin receptor targeting type nanogold particle solution centrifugal with centrifugal before at the absorbance changing value at 528nm place, i.e. Δ A=A0-A1 (A0=blank control group absorbance, the centrifugal absorbance of supernatant afterwards of A1=).
Along with the increase of HeLa cell concentration, the value of Δ A also becomes big (referring to Figure 11) thereupon, show that the folacin receptor targeting type nanogold particle that is combined in cell surface is just many more, so after centrifugal, the folacin receptor targeting type nanogold particle in the supernatant is just few more.And in the low fibroblast of expressing of folacin receptor; Increase along with concentration; Too big variation does not take place in the value of Δ A; This is because folacin receptor targeting type nanogold particle can not effectively, stably be adsorbed on cell surface; Can not reduce the amount of folacin receptor targeting type nanogold particle in the supernatant along with the sedimentation of cell, this result is similar with the blank group, has explained that once more folacin receptor targeting type nanogold particle has the function of the cancerous cell of specific recognition folacin receptor high expressed.Along with the reduction of HeLa cell detection concentration, when cell concentration is 10～100/ml, folacin receptor targeting type nanogold particle and HeLa cell combine to demonstrate good linear relationship.Its linear equation is A=1.0465+0.0857C, R=0.9984, and wherein A is an absorbance, and C is a cell concentration, and R is a correlation coefficient.When cell concentration is 10/ml; Hela cell and fibroblastic changing value do not have notable difference through statistical analysis; Therefore; The bottom line that detects cancerous cell based on folacin receptor targeting type nanogold particle system is 100/ml, and the detection bottom line of this comparatively easy detection method has approached 90 cells that document is reported.
Claims (1)
1. folacin receptor targeting type nanogold particle; It is characterized in that said a kind of folacin receptor targeting type nanogold particle is made up of nanogold particle, folic acid and glutathion; The sulfydryl of said glutathion and the surface of nanogold particle form golden sulfide linkage, and the carboxyl in the said glutathion and the amino of said folic acid form amido link;
The mol ratio of said nanogold particle, folic acid and glutathion is 1: 1: 2;
The method for preparing of said a kind of folacin receptor targeting type nanogold particle may further comprise the steps:
1) with chlorauric acid solution and citric acid three sodium solution add in the entry mixed solution, mixed solution is heated postcooling promptly gets solution A; The volume ratio of said chlorauric acid solution, citric acid three sodium solution and water is 1: 5: 94; The mass concentration of said chlorauric acid solution is 1%, and the mass concentration of said citric acid three sodium solution is 1%; The said thermal recovery microwave heating that adds, the temperature of heating is 100～120 ℃, the time of heating is 1～10min;
2) glutathione solution is added in the solution A, stir, get solution B after the dialysis; The concentration of said glutathion is 0.1mol/L, and the volume ratio of said glutathione solution and solution A is 1: 200; The time of stirring is 8～16h, and the time of dialysis is 6～12h;
3) in solution B, add N-hydroxy-succinamide and dicyclohexylcarbodiimide, stirring and evenly mixing adds folic acid, restir, and dialysis promptly gets product folacin receptor targeting type nanogold particle; The concentration of said N-hydroxy-succinamide is 0.05mol/L, and the volume ratio of said N-hydroxy-succinamide and solution B is 1: 400; The concentration of said dicyclohexylcarbodiimide is 0.05mol/L, and the volume ratio of said dicyclohexylcarbodiimide and solution B is 1: 400; The volume ratio of said folic acid and solution B is 1: 200; The time of restir is 8～16h, and the time of dialysis is 12～24h.
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| CN102671217B (en) * | 2012-06-05 | 2014-04-23 | 东华大学 | Preparation of CT/MR bimodal imaging nano contrast medium with folate targeting function |
| CN103212056B (en) * | 2013-05-07 | 2015-07-08 | 东南大学 | Preparation based on gold, silver, gold-silver mixture and glutathione/chitosan, and application of preparation |
| CN103990138B (en) * | 2013-05-21 | 2017-04-19 | 中国人民解放军第二军医大学 | Layer-by-layer assembled nanogold composite drug delivery carrier system, preparation method and application thereof |
| CN104614518B (en) * | 2015-01-26 | 2016-06-15 | 珠海丽珠试剂股份有限公司 | A kind of gold colloidal covalent labeling method for quickly detecting |
| CN106475569B (en) * | 2015-09-01 | 2019-01-25 | 中国科学院高能物理研究所 | A kind of preparation method of metal nanometer cluster, nanocluster obtained by this method and the contrast agent comprising the nanocluster |
| CN115105611A (en) * | 2022-05-22 | 2022-09-27 | 上海交通大学 | Preparation of folic acid modified Gd-Gold nanocluster self-assembly, product and application thereof |
| CN115105610A (en) * | 2022-05-22 | 2022-09-27 | 上海交通大学 | Preparation of folic acid modified Mn-Gold nanocluster self-assembly, product and application thereof |
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