CN107955606B - Double-rare-earth-doped carbon spot magnetic resonance/CT/fluorescence multi-mode imaging probe and preparation method thereof - Google Patents
Double-rare-earth-doped carbon spot magnetic resonance/CT/fluorescence multi-mode imaging probe and preparation method thereof Download PDFInfo
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Abstract
The invention aims to provide a novel double-rare-earth-doped carbon spot magnetic resonance/CT/fluorescence multi-mode imaging probe and a preparation method thereof, belonging to the technical field of medical imaging material preparation. The double-rare-earth-doped carbon-point magnetic resonance/CT/fluorescence multi-mode imaging probe is a gadolinium and ytterbium co-doped carbon point consisting of carbon, nitrogen, oxygen, gadolinium and ytterbium elements, and the expression is Gd/Yb @ CDs. The invention also provides a preparation method of the double-rare earth doped carbon spot magnetic resonance/CT/fluorescence multi-mode imaging probe, the preparation method has simple preparation process, the prepared nano probe does not need to be further modified, and the longitudinal relaxation efficiency can reach 6.65mM‑1s‑1。
Description
Technical Field
The invention belongs to the technical field of medical image material preparation, and particularly relates to a double-rare earth doped carbon spot magnetic resonance/CT/fluorescence multi-modal imaging probe and a preparation method thereof.
Background
The magnetic resonance imaging technology has the outstanding advantages of being noninvasive to a human body, tomographic scanning three-dimensional images in any direction, high in resolution, capable of providing diagnosis and evaluation in both form and function and the like, and becomes one of important means for clinical disease diagnosis. The clinical use of magnetic resonance contrast agents can improve the resolution and sensitivity of imaging, improve image quality, and enhance contrast and readability. However, the various imaging techniques have advantages and disadvantages due to different implementation principles, and cannot provide comprehensive information of diseases by using a traditional single diagnosis mode, so that the diagnosis of various complex diseases is limited to a certain extent. Therefore, the magnetic resonance imaging and other imaging technologies such as CT imaging, fluorescence imaging, ultrasonic imaging and the like are combined for use, so that the effect of complementary advantages can be achieved, more rapid and accurate information can be provided for clinical diagnosis of diseases, and meanwhile, the magnetic resonance imaging and various treatment modes can be combined together, namely, the diagnosis and treatment integrated reagent based on the magnetic resonance imaging is developed, so that the diseases can be treated in time and monitored in real time.
Disclosure of Invention
The invention aims to provide a novel double-rare-earth-doped carbon-point magnetic resonance/CT/fluorescence multi-mode imaging probe and a preparation method thereof, the probe is a Gd/Yb @ CDs nano probe suitable for MRI/CT/FI multi-mode imaging, and the longitudinal relaxation efficiency of the Gd/Yb @ CDs nano probe can reach 6.65mM-1s-1Is higher than clinically used Gd-DTPA (3.69 mM)-1s-1) Is the reported Gd @ CDs (5.88 mM)-1s-1) 1.13 times of.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
a double-rare-earth-doped carbon-point magnetic resonance/CT/fluorescence multi-mode imaging probe is a gadolinium and ytterbium co-doped carbon point consisting of carbon, nitrogen, oxygen, gadolinium and ytterbium elements, and the expression is Gd/Yb @ CDs.
In the above technical solution, the ytterbium element may be replaced by dysprosium or holmium element.
In the technical scheme, the double-rare earth doped carbon point magnetic resonance/CT/fluorescence multi-mode imaging probe is in a monodisperse sphere shape, and the average particle size is 5.26 +/-0.93 nm.
In the above technical solution, the percentages of the carbon, nitrogen, oxygen, gadolinium and ytterbium elements are 30.35%, 8.67%, 32.20%, 7.40% and 21.38%, respectively.
A preparation method of a double-rare earth doped carbon spot magnetic resonance/CT/fluorescence multi-mode imaging probe comprises the following steps:
step 1, adding Na2EDTA、GdCl3、YbCl3And L-arginine is dissolved in deionized water, and the mixture is stirred by magnetic force to obtain colorless transparent solution;
step 3, transferring the supernatant obtained in the step 2 into a dialysis membrane, and dialyzing with ultrapure water;
and 4, filtering the dialyzed solution by using a microfiltration membrane, and freeze-drying to obtain Gd/Yb @ CDs.
In the above technical solution, the GdCl3Can also be replaced by DyCl3Or HoCl3。
In the above technical solution, the Na2EDTA、GdCl3、YbCl3And L-arginine in a molar ratio of 250.00:3.34:30.06: 70.00.
In the technical scheme, the magnetic stirring time in the step 1 is 15 min.
In the technical scheme, the rotating speed of the supernatant fluid collected by centrifugation in the step 2 is 11000rpm, and the time is 20 min.
In the technical scheme, the pore diameter of the microfiltration membrane in the step 4 is 0.22 μm.
The invention has the beneficial effects that:
the double-rare-earth-doped carbon dot magnetic resonance/CT/fluorescence multi-modal imaging probe provided by the invention is a gadolinium and ytterbium co-doped carbon dot consisting of carbon, nitrogen, oxygen, gadolinium and ytterbium elements, the probe is suitable for magnetic resonance imaging, CT imaging and fluorescence imaging, and the longitudinal relaxation efficiency can reach 6.65mM-1s-1Is higher than clinically used Gd-DTPA (3.69 mM)-1s-1)。
Compared with Gd @ CDs, the double-rare-earth-doped carbon spot magnetic resonance/CT/fluorescence multi-mode imaging probe provided by the invention not only increases the CT imaging function, but also has reported Gd @ CDs (5.88 mM) in longitudinal relaxation efficiency-1s-1) 1.13 times of.
Gd and Yb in the double-rare-earth-doped carbon-point magnetic resonance/CT/fluorescence multi-mode imaging probe provided by the invention cannot leak.
The double-rare earth doped carbon spot magnetic resonance/CT/fluorescence multi-mode imaging probe provided by the invention has higher chemical stability and lower toxicity.
The double rare earth doped carbon spot magnetic resonance/CT/fluorescence multi-modal imaging probe provided by the invention has great application potential as a local contrast enhancement probe in MRI/CT/FI imaging.
The preparation method of the double-rare-earth-doped carbon spot magnetic resonance/CT/fluorescence multi-mode imaging probe provided by the invention has the advantages that the preparation process is simple, the prepared nano probe does not need to be further modified, and the longitudinal relaxation efficiency can reach 6.65mM-1s-1。
Drawings
The present invention will be described in further detail with reference to the accompanying drawings and specific embodiments.
FIG. 1 is an HRTEM image of Gd/Yb @ CDs nanoparticles prepared according to an example of the present invention.
FIG. 2 is an XPS spectrum of Gd/Yb @ CDs nanoparticles prepared according to an example of the present invention.
FIG. 3 is an FTIR spectrum of Gd/Yb @ CDs nanoparticles prepared according to an example of the present invention.
FIG. 4 is a diagram of Gd/Yb @ CDs nanoparticles prepared according to an embodiment of the present invention3+To let outA situation chart is disclosed.
FIG. 5 shows the cell viability of HeLa cells and 4T1 cells after incubation with different concentrations of Gd/Yb @ CDs for 4h and 24 h.
FIG. 6 is a spectrum of UV-Vis of Gd/Yb @ CDs prepared according to an example of the invention, wherein FIG. 6A is an absorption spectrum and FIG. 6B is an excitation/emission fluorescence spectrum.
FIG. 7 is an image of cells after 2h incubation of HeLa cells with Gd/Yb @ CDs (1mg/mL), where (A) is a bright field image; (B) is a fluorescence image.
FIG. 8 is an in vitro MRI imaging of different concentrations of Gd/Yb @ CDs nanoparticles and Gd-DTPA prepared according to an example of the invention.
FIG. 9 shows the longitudinal relaxation efficiencies 1/T of Gd/Yb @ CDs nanoparticles and Gd-DTPA prepared according to an embodiment of the present invention1A linear plot of contrast agent concentration.
FIG. 10 is an in vitro CT imaging of various concentrations of Gd/Yb @ CDs nanoparticles prepared in accordance with an example of the invention and a solution of iobitol.
FIG. 11 is a graph of the CT values of Gd/Yb @ CDs nanoparticles and a solution of iobitol prepared according to an example of the present invention as a function of the nanoparticle concentration.
Detailed Description
The present invention will be described in detail with reference to the accompanying drawings.
The double-rare-earth-doped carbon-point magnetic resonance/CT/fluorescence multi-mode imaging probe provided by the invention is a gadolinium and ytterbium co-doped carbon point consisting of carbon, nitrogen, oxygen, gadolinium and ytterbium elements, has an expression of Gd/Yb @ CDs, is in a monodisperse sphere shape, and has an average particle size of 5.26 +/-0.93 nm. The ytterbium element can be replaced by dysprosium or holmium element. Preferably, the percentage contents of the carbon, nitrogen, oxygen, gadolinium and ytterbium elements are respectively 30.35%, 8.67%, 32.20%, 7.40% and 21.38%.
The invention provides a preparation method of a double-rare earth doped carbon spot magnetic resonance/CT/fluorescence multi-mode imaging probe, which comprises the following steps:
step 1, adding Na2EDTA、GdCl3、YbCl3And L-arginine are dissolved in deionized water, and are magnetically stirred for 15min to obtain a colorless transparent solution; what is preferredThe above Na2EDTA、GdCl3、YbCl3And L-arginine in a molar ratio of 250.00:3.34:30.06: 70.00; the GdCl3Can also be replaced by DyCl3Or HoCl3;
step 3, transferring the supernatant obtained in the step 2 into a dialysis membrane, and dialyzing with ultrapure water;
and 4, filtering the dialyzed solution by using a microfiltration membrane with the pore diameter of 0.22 mu m, and freeze-drying to obtain Gd/Yb @ CDs.
Examples
Using balance Na2EDTA(93.06mg,0.25mmol),GdCl3(0.88mg,3.34μmol),YbCl3(8.48mg, 30.06. mu. mol) and L-arginine (12.54mg, 0.07mmol) were dissolved in 20mL of deionized water, and the beaker was placed on a magnetic stirrer and stirred for 15min to give a colorless transparent solution. The solution was transferred to a 50 ml teflon reaction kettle and placed in an oven for reaction at 200 ℃ for 10 h. After it was cooled to room temperature, the supernatant was collected by centrifugation at 11000rpm for 20min to remove the black precipitate, which was repeated three times. The resulting brownish yellow supernatant was transferred to a dialysis membrane (MWCO 1000) and dialyzed against ultrapure water for 24 h. The water was changed every 4h to remove excess unreacted material. And filtering the finally obtained solution by using a 0.22 mu m microfiltration membrane, and freeze-drying the filtered solution by using a vacuum freeze dryer to obtain Gd/Yb @ CDs nano particles. The elemental analysis results prove that the percentage contents of carbon, nitrogen, oxygen, gadolinium and ytterbium in the Gd/Yb @ CDs nano particles are respectively 30.35%, 8.67%, 32.20%, 7.40% and 21.38%.
GdCl in the above embodiment3Replacement by DyCl3Or HoCl3And correspondingly preparing Gd/Dy @ CDs nano particles or Gd/Ho @ CDs nano particles.
FIG. 1 is an HRTEM photograph of Gd/Yb @ CDs nanoparticles prepared in example, from which it can be seen that: the Gd/Yb @ CDs nanoparticles are monodisperse spheroidal with an average particle size of about 5.26 +/-0.93 nm (FIG. 1A); a clear lattice fringe can be seen in fig. 1B with a lattice spacing of 0.213nm, corresponding to the (100) plane of graphitic carbon, consistent with previous literature reports.
FIGS. 2 and 3 are XPS and FTIR spectra of Gd/Yb @ CDs nanoparticles prepared according to the practice of the present invention, respectively, and it can be seen from FIG. 2 that the Gd/Yb @ CDs nanoparticles are composed of C1 s (284.5eV), N1 s (399.2eV) and O1 s (531.1eV), Gd 3d (1186eV) and Yb 4d (184.6eV) elements, demonstrating the successful incorporation of the rare earth elements Gd and Yb into the carbon dots. It can be seen from FIG. 3 that the FT-IR spectra of Gd/Yb @ CDs and CDs show similar absorption bands: in 3500-3200 cm-1The absorption peak at (1) corresponds to O-H and N-H stretching vibration at 1100cm-1Is in C-N stretching vibration, and the peak of the COO-group is from 1632cm-1It became 1615cm-1Possibly due to Gd3+/Yb3+And the carboxyl group of EDTA/L-arginine. These characteristic peaks further demonstrate the presence of hydroxyl, carboxylic acid and amino groups, consistent with the XPS results. Gd (Gd)3+And Yb3+After chelation, the peak shape of the integral FT-IR spectrum has no obvious change, which shows that the doping of the rare earth Gd/Yb has no obvious influence on the surface functional group of the carbon dot.
Taking into account the free Gd3+Can inhibit Ca in vivo2+The channels in turn induced severe cytotoxicity (e.g., cardiovascular and neuro-cytotoxicity), therefore, we placed dialysis bags (MWCO ═ 1000) containing Gd/Yb @ CDs in serum solution for dialysis for 24h, removed 0.4mL at intervals, and measured Gd/Yb @ CDs for Gd/OES3+Leakage, as shown in FIG. 4, in which&Representing Gd in the initial nanoparticle3+The content of (a). As can be seen from FIG. 4, almost no Gd was detected in the serum solution3+Possibly due to Gd3+There is a strong interaction with the carbon dots.
Toxicity of Gd/Yb @ CDs on HeLa and 4T1 cells was investigated using the MTT method. FIG. 5 shows the viability of HeLa cells and 4T1 cells after incubation with different concentrations of Gd/Yb @ CDs for 4h and 24h, where the viability of the cells for each Gd/Yb @ CDs concentration in FIG. 5 is marked a, b, c, d from left to right, and is only indicated when the Gd/Yb @ CDs concentration is 0. As can be seen from fig. 5: after 4h incubation, the survival and proliferation of both cell lines were almost unaffected. And the cell survival rate is still over 85 percent even if the concentration of Gd/Yb @ CDs is as high as 1mg/mL after the culture solution is prolonged to 24 hours. These preliminary experimental results indicate that the prepared Gd/Yb @ CDs have lower toxicity. This low toxicity also stems from the higher chemical stability of Gd/Yb @ CDs. Compared with semiconductor quantum dots with heavy metal toxicity, the low toxicity of Gd/Yb @ CDs enables the semiconductor quantum dots to have potential application prospects in the fields of biology and medicine.
FIG. 6 is a spectrum diagram of UV-Vis of Gd/Yb @ CDs, wherein FIG. 6A is an absorption spectrum and FIG. 6B is an excitation/emission fluorescence spectrum. As can be seen from fig. 6: CDs and Gd/Yb @ CDs exhibit the same absorption peak at 273nm, which corresponds to the n → pi transition of C ═ O. Under 365nm UV lamp illumination, the Gd/Yb @ CDs pale yellow aqueous solution exhibited bright blue fluorescence (FIG. 6A inset). Gd/Yb @ CDs also exhibit dependent stimulated emission behavior, a prevalent phenomenon caused by surface state emission traps of different energies. As the excitation wavelength changes, the corresponding surface state emission traps dominate, resulting in an excitation wavelength dependent phenomenon. As can be seen from fig. 6B: when the excitation wavelength was changed from 320nm to 370nm, the emission peak was shifted from 407nm to 463 nm. When the sample was excited at 340nm, the maximum fluorescence emission intensity was 418 nm. The quantum yield using quinine sulfate as a reference solution was 16.84%, slightly higher than 13.4% for Gd @ CDs. In addition, the fluorescence stability of Gd/Yb @ CDs is researched under a 365nm ultraviolet lamp, and the luminous intensity is still unchanged when the Gd/Yb @ CDs is exposed under the ultraviolet lamp for 2 hours, so that the Gd/Yb @ CDs have excellent optical stability.
To investigate the performance of Gd/Yb @ CDs in fluorescence imaging, we incubated HeLa cells with 1mg mL-1And co-incubating Gd/Yb @ CDs for 2 h. Images were captured using a fluorescence microscope in bright and dark fields, respectively. FIG. 7 is an image of cells after 2h incubation of HeLa cells with Gd/Yb @ CDs (1mg/mL), where (A) is a bright field image; (B) is a fluorescence image. FIG. 7 shows that the treated cells still maintain intact morphology in bright field; in the dark field, HeLa cells showed very strong blue fluorescence. Furthermore, we can see that Gd/Yb @ CDs are mainly localized in the cytoplasm, which is consistent with previously reported behavior of CDsThe same is true. This suggests that Gd/Yb @ CDs may enter the intracellular domain through the cell membrane barrier within a short period of time.
To investigate the Gd/Yb @ CDs nanoparticles at T1Performance in MR imaging, first, water tube imaging of aqueous solutions of nanoparticles of different concentrations was determined using deionized water as a control. Magnevist (Gd-DTPA), an FDA approved and widely used clinical contrast agent, was selected as the control group. With Gd3+Increased concentration (0-0.36 mM), two groups of T1The weighted MR image signal was gradually brightened (FIG. 8, where a represents Gd-DTPA and b represents Gd/Yb @ CDs), but the Gd/Yb @ CDs nanoparticles prepared in this example performed better at the same concentration. To further quantitatively assess the contrast effect, longitudinal relaxation times (T.sub.L) of Gd/Yb @ CDs solutions and Gd-DTPA at different concentrations were measured using a 9.4T standard inversion recovery pulse sequence1)。T1Reciprocal value of (d) and Gd3+There is a good linear relationship between the concentrations of (A) and (B), the slope of the fitted line being the longitudinal relaxation efficiency (r)1) And are commonly used to evaluate the performance of MRI contrast agents. R of Gd/Yb @ CDs1The value was 6.65mM-1s-1(FIG. 9), higher than clinical Gd-DTPA (r)1=3.69mM-1s-1) Is the reported Gd @ CDs (particle size 12nm, r)1=5.88mM-1S-1) 1.13 times of. The strong relaxivity of Gd/Yb @ CDs is mainly due to the fact that the particle size is small, the S/V value can be increased, the binding capacity of metal ions and water molecules is increased, and in addition, the existence of hydrophilic groups promotes r to a certain extent1Enhancement of (3).
The rare earth elements Yb and Gd have inherent X-ray absorption capability, so the Gd/Yb @ CDs nano particles can also be used for CT imaging. Lopidol, a clinically common CT contrast agent, was used as a control group. Two sets of water tube CT images (FIG. 10) were tested at 120kV X-ray energy, with Yb3+And increasing the concentration of I, the CT brightness is gradually increased. In contrast, Gd/Yb @ CDs showed a higher contrast effect than iodohydrin at the same concentration. For further quantitative evaluation of the effect of CT contrast, the X-ray attenuation capacity of Gd/Yb @ CDs was measured. As shown in FIG. 11, HU value and Yb3+Or a good linear relationship between the concentrations of I, Gd/Yb @ CDs have a slope of about 45.42HU Lg-1Is significantly higher than iobitridol (31.83HU L g)-1). This is mainly due to the attenuation coefficient of Yb (3.88 cm at 100 keV)2A damping factor of 1.94cm at 100keV,/g) greater than I2In terms of/g). In summary, the results indicate that Gd/Yb @ CDs have great potential as local contrast enhancement probes in MRI/CT imaging.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.
Claims (7)
1. The double-rare-earth-doped carbon dot magnetic resonance/CT/fluorescence multi-mode imaging probe is characterized in that gadolinium and ytterbium codope carbon dots are composed of carbon, nitrogen, oxygen, gadolinium and ytterbium, the expression is Gd/Yb @ CDs, the double-rare-earth-doped carbon dot magnetic resonance/CT/fluorescence multi-mode imaging probe is in a monodisperse sphere shape, and the average particle size is 5.26 +/-0.93 nm.
2. The dual rare earth doped carbon spot magnetic resonance/CT/fluorescence multi-modality imaging probe of claim 1, wherein the percentage of carbon, nitrogen, oxygen, gadolinium and ytterbium elements is 30.35%, 8.67%, 32.20%, 7.40% and 21.38%, respectively.
3. The method for preparing the double rare earth doped carbon spot magnetic resonance/CT/fluorescence multi-modal imaging probe according to claim 1, which is characterized by comprising the following steps:
step 1, adding Na2EDTA、GdCl3、YbCl3And L-arginine is dissolved in deionized water, and the mixture is stirred by magnetic force to obtain colorless transparent solution;
step 2, transferring the colorless and transparent solution obtained in the step 1 into a reaction kettle, reacting for 10 hours at 200 ℃, and collecting supernatant through centrifugation after the solution is cooled to room temperature;
step 3, transferring the supernatant obtained in the step 2 into a dialysis membrane, and dialyzing with ultrapure water;
and 4, filtering the dialyzed solution by using a microfiltration membrane, and freeze-drying to obtain Gd/Yb @ CDs.
4. The method for preparing a dual rare earth doped carbon spot magnetic resonance/CT/fluorescence multi-modal imaging probe according to claim 3, wherein the Na is2EDTA、GdCl3、YbCl3And L-arginine in a molar ratio of 250.00:3.34:30.06: 70.00.
5. The method for preparing a double rare earth doped carbon spot magnetic resonance/CT/fluorescence multi-modal imaging probe according to claim 3, wherein the magnetic stirring time in step 1 is 15 min.
6. The method for preparing a double rare earth doped carbon point magnetic resonance/CT/fluorescence multi-modal imaging probe according to claim 3, wherein the rotating speed of the supernatant collected by centrifugation in the step 2 is 11000rpm, and the time is 20 min.
7. The method for preparing a double rare earth doped carbon spot magnetic resonance/CT/fluorescence multi-modal imaging probe according to claim 3, wherein the aperture of the micro-filtration membrane in the step 4 is 0.22 μm.
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