CN111437400A - Preparation method of core-shell structure dendrimer CT/MR imaging contrast agent - Google Patents

Preparation method of core-shell structure dendrimer CT/MR imaging contrast agent Download PDF

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CN111437400A
CN111437400A CN202010176250.6A CN202010176250A CN111437400A CN 111437400 A CN111437400 A CN 111437400A CN 202010176250 A CN202010176250 A CN 202010176250A CN 111437400 A CN111437400 A CN 111437400A
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rgd
stirring
peg
solution
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CN111437400B (en
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郭睿
刘仁娜
史向阳
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Donghua University
National Dong Hwa University
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    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
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Abstract

The invention relates to a preparation method of a core-shell structure dendrimer CT/MR imaging contrast agent, which comprises the steps of constructing a core-shell structure dendrimer based on supermolecule host-guest assembly, modifying a targeting molecule PEG-RGD and zwitterionic propane sultone (1,3-PS), and chelating gadolinium ions on the surface. The core-shell structure dendrimer CT/MR imaging contrast agent prepared by the invention has good dispersibility and biocompatibility, a nonspecific protein adsorption resistance function and a good targeting CT/MR imaging effect, and provides a new idea for developing a novel bimodal nano contrast agent.

Description

Preparation method of core-shell structure dendrimer CT/MR imaging contrast agent
Technical Field
The invention belongs to the field of molecular imaging, and particularly relates to a preparation method of a core-shell structure dendrimer CT/MR imaging contrast agent.
Background
In recent years, with the rapid development of nanotechnology and molecular imaging, a plurality of nano contrast agents applied to the field of tumor diagnosis appear, and especially, the application of nano carriers realizes the construction of a multifunctional multi-modal nano probe (the same nano platform integrates a plurality of contrast agents) for accurate tumor diagnosis. The CT imaging technology has higher spatial resolution and shorter image acquisition time, but has the defects of poor soft tissue resolution and harm to human bodies due to higher radioactivity. Magnetic resonance imaging (MR) has excellent resolution on soft tissue and no radiation damage to the human body, but is expensive and takes a long time to acquire images. Given the disadvantages of each imaging technique, a single imaging technique has not met the need for accurate diagnosis of disease. Therefore, the combination of two or more imaging technologies can overcome the defect of single imaging and enhance the accuracy and reliability of diagnostic information.
A multifunctional CT/MR imaging contrast agent is developed, the respective advantages of CT and MR imaging technologies are combined, so that the sensitivity and the accuracy of diagnosis are greatly improved, the defects of the traditional medical imaging contrast agent can be overcome, and the multifunctional CT/MR imaging contrast agent has great value in clinical application, can reduce the toxic and side effects of the contrast agent on patients on one hand, and can provide more comprehensive diagnosis information on the other hand.
In order to integrate two contrast agents and endow the contrast agents with multiple functions on the same platform, a carrier is generally needed, among numerous carrier materials, polyamide-amine dendrimers (PAMAM) are widely used as carriers for loading contrast agents or drugs for diagnosis and treatment of tumors due to the fact that a large number of functional groups capable of being modified are arranged on the surface of PAMAM and a large hydrophobic cavity is arranged inside PAMAM, compared with low-generation dendrimers, the high-generation dendrimers have better three-dimensional size and more stable molecular structure, but due to the limitation of the existing synthesis method, the synthesis of the high-generation dendrimers faces huge challenges due to the complexity of the purification method, therefore, lower-generation dendrimers are proposed as reactive monomers and then connected together by a certain method to achieve the purpose of rapidly synthesizing the high-generation dendrimers, the high-generation dendrimers of surface amino groups are taken as cores by the high-generation dendrimers of surface amino groups, the lower-generation dendrimers of surface carboxyl groups are taken as shells, and more functional bonds can be generated between the amino groups of the high-generation dendrimers modified on the surface of the surface macromolecules under the catalysis of 1- (3-dimethylaminopropyl) -3-ethyl imine (EDC), the surface of a dendrimer, the surface-modified macromolecule, the surface-modified macromolecules, the surface of a hydrophilic dendrimer, a hydrophilic surface-grafted amine dendrimer, a hydrophilic surface-grafted macromolecule, a hydrophilic surface-grafted dendrimer, a grafted-based dendrimer, a-grafted-based dendrimer, a-grafted-based imaging material.
However, in the face of the complicated immune system of human body, the carrier material also needs to have the nonspecific adsorption of impedance protein, so as to escape the recognition of reticuloendothelial system (RES), prolong the blood circulation time in vivo, and increase the probability of the nano material reaching the focus (Fang C, Bhattarai N, Sun C, et al. Small,2010,5(14):1637 and 1641). recently, the research on the amphiphilic modified dendrimer can effectively prolong the blood circulation time in vivo (L iu JY, Xiong ZJ, et al. ACS appl. mater. interface 2019,11,1521 and 215221). The new surface modification enables the material to have extremely low nonspecific protein adsorption, thus widening the way for the application of the material in vivo.
The results of the documents and patents on the aspect of retrieving the CT/MR bimodal contrast agent at home and abroad show that: at present, the preparation of core-shell structure dendrimer which is prepared by modifying the surface of core-shell structure dendrimer with targeting molecule RGD and zwitterion 1,3-PS, chelating gadolinium ion and internally wrapping gold nanoparticles and the report of the preparation in CT/MR imaging are not found.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of a core-shell structure dendrimer CT/MR imaging contrast agent, and the prepared contrast agent has good dispersibility and biocompatibility, a nonspecific protein adsorption resistance function and a good targeted CT/MR imaging effect.
The invention provides a preparation method of a core-shell structure dendrimer CT/MR imaging contrast agent, which comprises the following steps:
(1) dissolving β -cyclodextrin β -CD, N' -carbonyldiimidazole CDI and fifth generation polyamidoamine dendrimer G5 in dimethyl sulfoxide DMSO solution respectively, mixing β -CD and CDI solution, stirring and reacting for 6-8h to obtain reaction liquid, dripping the reaction liquid into G5 solution, stirring and reacting for 70-80h at room temperature, dialyzing, freeze-drying to obtain G5-CD, dropwise adding chloroauric acid aqueous solution into G5-CD aqueous solution, stirring and reacting for 15-30min, then adding precooled sodium borohydride aqueous solution, stirring and reacting for 3-4h in ice bath, dialyzing, freeze-drying to obtain a main molecule (Au)0)50-G5-CD；
(2) Respectively dissolving 1-adamantane acetic acid Ad-COOH, EDC and NHS in a DMSO solution, adding EDC into the Ad-COOH solution, stirring and reacting at room temperature for 30-40min, adding NHS, and stirring and reacting at room temperature for 3-4h to obtain an activated Ad-COOH solution; dropwise adding the mixture into a DMSO solution in which third-generation polyamide-amine dendrimer G3 is dissolved, stirring at room temperature for reaction for 3-4 days, dialyzing, and freeze-drying to obtain an object molecule G3-Ad;
(3) the host molecule (Au)0)50Respectively dissolving G5-CD and a guest molecule G3-Ad in ultrapure water, mixing at room temperature, stirring, reacting for 20-30h, and obtaining the core-shell structure dendrimer (Au) through the action of a supramolecular host and a guest0)50-G5-CD/Ad-G3 solution, dialyzed, lyophilized to obtain (Au)0)50-G5-CD/Ad-G3, denoted as Au CSTDs;
(4) dissolving COOH-PEG-RGD in DMSO, adding EDC and NHS for activation to obtain an activated COOH-PEG-RGD solution; then dropwise adding the mixture into DMSO solution of Au CSTDs, and stirring and reacting for 3-4 days at room temperature; finally dialyzing, and freeze-drying to obtain (Au)0)50-G5-CD/Ad-G3-PEG-RGD；
(5) Will (Au)0)50Respectively dissolving-G5-CD/Ad-G3-PEG-RGD and chelating agent diethylene pentaacetate DTPA in ultrapure water, mixing at room temperature, stirring for reaction for 24-30h, dialyzing, and freeze-drying to obtain (Au)0)50-G5-CD/Ad-G3-PEG-RGD-DTPA；
(6) Will (Au)0)50Respectively dissolving-G5-CD/Ad-G3-PEG-RGD-DTPA and gadolinium nitrate in ultrapure water, mixing at room temperature, stirring for reaction for 24-30h, then dropwise adding 1,3-PS solution, stirring for reaction for 24-30h, dialyzing, and freeze-drying to obtain (Au)0)50G5-CD/Ad-G3-PEG-RGD-DTPA (Gd) -PS, marked as RGD-Gd @ Au CSTDs-PS, namely the core-shell structure dendrimer CT/MR imaging contrast agent.
The molar ratio of CDI to β -CD in the step (1) is 10-15:1, and the molar ratio of β -CD to G5 is 18-20: 1.
The molar ratio of G5-CD to chloroauric acid in the step (1) is 1: 50-52; the molar ratio of the sodium borohydride to the chloroauric acid is 3-4: 1.
The molar ratio of EDC, NHS and Ad-COOH in the step (2) is 10-15:10-15: 1; the molar ratio of G3 to Ad-COOH was 1: 1.3-1.5.
(Au) in the step (3)0)50The molar ratio of G5-CD to G3-Ad was 1: 10.
The molar ratio of COOH-PEG-RGD to Au CSTDs in the step (4) is 10-12: 1; the molar ratio of EDC, NHS and COOH-PEG-RGD is 10-15:10-15: 1.
The preparation process of the COOH-PEG-RGD is as follows:
respectively dissolving polyethylene glycol molecules MA L-PEG-COOH with one end being carboxyl and the other end being maleimide group and polypeptide RGD in DMSO, uniformly mixing, stirring at room temperature for reaction for 24-30h, dialyzing, and freeze-drying to obtain the polyethylene glycol molecules COOH-PEG-RGD modified by the polypeptide RGD, wherein the molar ratio of MA L-PEG-COOH to RGD is 1: 1.2-1.5.
(Au) in the step (5)0)50The molar ratio of the-G5-CD/Ad-G3-PEG-RGD to DTPA is 1: 28-30.
(Au) in the step (6)0)50-G5-CD/Ad-G3-PEG-RThe molar ratio of GD-DTPA, gadolinium nitrate and 1,3-PS is 1:28-30: 90-100.
According to the invention, β -cyclodextrin with surface modification, a fifth generation of dendritic macromolecule G5 with gold nanoparticles wrapped inside and a third generation of adamantane with surface modification, G3 are respectively synthesized, a core-shell structure dendritic macromolecule nano platform is constructed by utilizing the recognition effect of a host and an object, then a targeting molecule RGD and zwitterion 1,3-PS are modified on the surface of the core-shell structure dendritic macromolecule, and gadolinium ions are chelated on the surface, so that the CT/MR contrast agent with a specific targeting function and a nonspecific protein adsorption resistance function is obtained.
The invention is by nuclear magnetic resonance (1H NMR) to characterize β -CD (host molecule) and Ad (object molecule) modified on the dendrimer, two-dimensional nuclear magnetism (2D ROESY) to characterize core-shell structure dendrimer constructed by the interaction of the host and the object, Transmission Electron Microscope (TEM) and Atomic Force Microscope (AFM) to characterize the surface morphology and size of the host and the object unit and the constructed core-shell structure dendrimer, ultraviolet visible absorption spectroscopy (UV-vis), inductively coupled plasma atomic emission (ICP-OES), Zeta potential, hydrated particle size test, transmission electron microscope test and other methods to characterize the physical and chemical properties of the material, then to evaluate the cytotoxicity of the contrast agent by CCK8 method, to evaluate the nonspecific protein adsorption resistance by in vitro protein adsorption test, and finally to characterize the diagnostic effect of the prepared core-shell structure dendrimer with bimodal contrast function on tumor cells and tumor tissues by in vitro and in vitro CT/MR imaging.
Advantageous effects
(1) The invention has simple synthesis process, mild and controllable reaction conditions, easy operation and lower cost, all the used materials are environment-friendly materials, and the prepared CT/MR contrast agent has good biocompatibility;
(2) the CT/MR contrast agent prepared by the invention takes G5 as a core G3 as a shell by a supramolecular host-object method, and the surface of the contrast agent is modified with targeting molecules and zwitterions, so that the contrast agent has good stability, has larger size than common nanoparticles, can be effectively enriched at a tumor part, and has good CT/MR imaging effect;
(3) the core-shell structure dendrimer CT/MR contrast agent prepared by the invention has potential application in the field of molecular imaging diagnosis.
Drawings
FIG. 1 is a schematic view of the process of the present invention;
FIG. 2 shows G5-CD (a), G3-Ad (b) prepared according to the invention1H NMR spectrum;
FIG. 3 is a 2D NOESY map of Au CSTDs prepared according to the present invention;
FIG. 4 shows COOH-PEG-RGD (a), (Au) prepared by the present invention0)50-G5-CD/Ad-G3-PEG-RGD (b) and (Au)0)50Of G5-CD/Ad-G3-PEG-RGD-DTPA (c)1H NMR spectrum;
FIG. 5 shows (Au) prepared by the present invention0)50-G5-CD/Ad-G3-mPEG (a) and (Au)0)50G5-CD/Ad-G3-mPEG-DTPA (b)1H NMR spectrum;
FIG. 6 shows (Au) prepared by the present invention0)50UV-Vis spectra of G5-CD, Au CSTDs (a), Gd @ Au CSTDs-PS, RGD-Gd @ AuCSTDs-PS (b);
FIG. 7 is a high resolution TEM image and particle size distribution histogram of Gd @ Au CSTDs-PS (a) and RGD-Gd @ Au CSTDs-PS (b) prepared according to the present invention;
FIG. 8 shows G3-Ad (a), (Au) prepared according to the present invention0)50Atomic Force Microscope (AFM) images of G5-CD (b), Au CSTDs (c), Gd @ Au CSTDs-PS (d), and RGD-Gd @ Au CSTDs-PS (e);
FIG. 9 is a graph showing the dimensional stability of Gd @ Au CSTDs-PS and RGD-Gd @ Au CSTDs-PS prepared according to the present invention;
FIG. 10 shows the UV-vis spectra of BSA protein (a) and the RGD-Gd @ Au CSTDs and RGD-Gd @ Au CSTDs-PS prepared according to the present invention with different concentrations incubated with BSA (1mg/m L) for 2h, centrifuged to remove the precipitate, and the absorbance at 278nm was measured, and the absorbance difference is the UV absorbance difference (b) before and after centrifugation;
FIG. 11 is a graph (a) and 1/T of the MR images of Gd @ Au CSTDs-PS and RGD-Gd @ Au CSTDs-PS prepared according to the present invention at a gadolinium concentration in the range of 0.08-0.64mM1Linear plot with Gd concentration (b);
FIG. 12 is a CT image (a) of Gd @ Au CSTDs-PS and RGD-Gd @ Au CSTDs-PS nanoparticles prepared by the invention in the range of gold concentration of 0.005-0.08M and a linear relation (b) of X-ray attenuation and gold or iodine concentration;
FIG. 13 shows the cell viability (a) of 4T1 cells treated with different gold concentrations (0-200. mu.M) for 24 hours, as measured by the CCK8 method, of Gd @ Au CSTDs-PS and RGD-Gd @ Au CSTDs-PS prepared in the present invention; au content of phagocytic material of 4T1 cells (b) after 4 hours of treatment with Gd @ Au CSTDs-PS and RGD-Gd @ Au CSTDs-PS at different gold concentrations (0-200 μ M);
FIG. 14 shows MR images (a), CT images (b), MR values (c) and CT values (d) of tumor sites in mice at different time points after tail vein injection of Gd @ Au CSTDs-PS and RGD-Gd @ Au CSTDs-PS (Au: 0.1M,150 μ L), and FIG. 15 shows distribution of Gd @ Au CSTDs-PS (a) and RGD-Gd @ Au CSTDs-PS (b) in hearts, livers, spleens, lungs, kidneys and tumors of mice after tail vein injection.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.
Example 1
Weighing 16.36mg β -CD and 23.38mg CDI, respectively dissolving in 5m L DMSO, mixing and stirring for reaction for 6-8h, weighing G515 mg, dissolving in 5m L DMSO, slowly dripping a mixed solution of β -CD and CDI into a DMSO solution of G5, stirring for reaction for 70-80h at room temperature, transferring a reaction solution into a dialysis bag with the molecular weight cutoff of 10000Da after the reaction is finished, dialyzing in ultrapure water for 3 days, finally freeze-drying to obtain a solid product G5-CD, and storing at-20 ℃.
Weighing 15mg of G5-CD, dissolving the G5-CD in 15m L ultrapure water, dropwise adding 396 mu L chloroauric acid aqueous solution (30mg/m L) under the ice bath condition, stirring for reacting for 15-30min, weighing 5.45mg of sodium borohydride, pouring precooled 1m L ultrapure water into the solution, fully dissolving the solution, and quickly adding the solution into the ultrapure waterAnd stirring and reacting the mixed solution for 3 to 4 hours under the ice-bath condition. After the reaction was completed, the reaction solution was transferred to a dialysis bag having a molecular weight cut-off of 1000Da and dialyzed in ultrapure water for 3 days. Finally, the solid product (Au) is obtained after freeze drying0)50-G5-CD, stored at-20 ℃.
Weighing 2.04mg of 1-adamantane acetic acid (Ad-COOH), dissolving in 2m L DMSO, respectively weighing EDC, NHS20.14mg and 12.09mg, dissolving in 3m L DMSO solution, adding EDC into Ad-COOH solution, stirring at room temperature for reaction for 30-40min, adding NHS solution, stirring at room temperature for reaction for 3-4h to obtain activated Ad-COOH solution, weighing G350 mg, dissolving in 5m L DMSO, dropwise adding EDC/NHS activated Ada-COOH solution into G3 solution, reacting for 3 days under magnetic stirring, dialyzing in ultrapure water by using a dialysis bag with molecular weight cutoff of 1000Da after the reaction is finished, and finally freeze-drying to obtain a solid product G3-Ad, and storing at-20 ℃.
According to (Au)0)50The molar ratio of-G5-CD to G3-Ad was 1:10, and 25.4mg of dried G3-Ad (Au)0)50-G5-CD15.23mg, respectively dissolving in 5m L ultrapure water, mixing, reacting at room temperature for 20-30h under magnetic stirring, dialyzing in ultrapure water by using a dialysis bag with cut-off molecular weight of 10000Da after the reaction is finished, and finally freeze-drying to obtain a solid product Au CSTDs which is stored at-20 ℃.
Weighing 13.34mg of MA L-PEG-COOH and 4.61mg of RGD, respectively dissolving in 3m L DMSO, mixing and stirring at room temperature for reaction for 24-30h, dialyzing with a dialysis bag with cut-off molecular weight of 1000Da for 3 days after the reaction is finished, freeze-drying to obtain a solid product COOH-PEG-RGD, and storing at-20 ℃.
Weighing 12mg COOH-PEG-RGD, 12.79mg EDC and 7.68mg NHS, respectively dissolving in 3m L DMSO, adding EDC to activate for 30-40min under uniform stirring, adding NHS to activate for 3-4h to obtain activated COOH-PEG-RGD solution, weighing 20mg (Au)0)50dissolving-G5-CD/Ad-G3 in 5m L DMSO, slowly adding activated COOH-PEG-RGD solution, stirring at room temperature for reaction for 3-4 days, dialyzing with dialysis bag with molecular weight cutoff of 3000Da for 3 daysAnd finally freeze-drying to obtain a solid product (Au)0)50-G5-CD/Ad-G3-PEG-RGD, stored at-20 ℃.
Weighing 22mg (Au)0)50Respectively dissolving-G5-CD/Ad-G3-PEG-RGD and 7.11mg DTPA in 4m L ultrapure water, uniformly mixing, stirring at room temperature for reaction for 24-30h, dialyzing with a dialysis bag with the molecular weight cutoff of 1000Da for 3 days after the reaction is finished, and finally freeze-drying to obtain a solid product (Au)0)50-G5-CD/Ad-G3-PEG-RGD-DTPA, stored at-20 ℃.
Weighing 30mg (Au)0)50Respectively dissolving-G5-CD/Ad-G3-PEG-RGD-DTPA and 5.36mg gadolinium nitrate in 4m L ultrapure water, stirring and reacting for 24-30h at room temperature, then dropwise adding 450 mu L1, 3-PS solution (13.7mg/m L), stirring and reacting for 24-30h, dialyzing for 3 days by using a dialysis bag with molecular weight cutoff of 1000Da after the reaction is finished, finally freeze-drying to obtain a solid product RGD-Gd Au CSTDs-PS, and storing at-20 ℃.
Comparative example 1
Respectively dissolving 10mg of mPEG-COOH, 9.59mg of EDC and 5.75mg of NHS in 3m L ultrapure water, adding EDC to activate for 30-40min under the condition of uniform stirring, then adding NHS to activate for 3-4h to obtain activated mPEG-COOH solution, and weighing 30mg of Au (Au)0)50Dissolving G5-CD/Ad-G3 in 5m L ultrapure water, slowly adding the activated mPEG-COOH solution into the ultrapure water, stirring the solution at room temperature for reacting for 3 to 4 days, dialyzing the solution for 3 days by using a dialysis bag with the molecular weight cutoff of 3000Da after the reaction is finished, and finally freeze-drying the solution to obtain a solid product (Au)0)50G5-CD/Ad-G3-mPEG, stored at-20 ℃.
Weighing 25mg (Au)0)50Respectively dissolving-G5-CD/Ad-G3-mPEG and 8.25mg DTPA in 3m L ultrapure water, uniformly mixing, stirring at room temperature for reaction for 24-30h, dialyzing for 3 days by using a dialysis bag with the molecular weight cutoff of 1000Da after the reaction is finished, and finally freeze-drying to obtain a solid product (Au)0)50-G5-CD/Ad-G3-mPEG-DTPA, stored at-20 ℃.
Weighing 30mg (Au)0)50-G5-CD/Ad-G3-mPEG-DTPA and 5.36mg gadolinium nitrate were dissolved in 4m L ultrapure water, respectively, and the strips were taken at room temperatureStirring and reacting for 24-30h, then dropwise adding 450 mu L1, 3-PS solution, stirring and reacting for 24-30h, dialyzing for 3 days by using a dialysis bag with the molecular weight cutoff of 1000Da after the reaction is finished, finally freeze-drying to obtain a solid product Gd @ AuCSTDs-PS, and storing at-20 ℃.
Example 2
The G5-CD, G3-Ad, Au CSTDs, COOH-PEG-RGD, (Au) in example 1 were weighed out respectively0)50G5-CD/Ad-G3-PEG-RGD and (Au)0)505mg of each of-G5-CD/Ad-G3-PEG-RGD-DTPA dissolved in 500. mu. L D2And in O, performing hydrogen spectrum analysis. Of G5-CD1The results of H NMR characterization are shown in FIG. 2(a), where the proton peak at chemical shifts 2.2-3.4ppm represents the methylene proton peak of G5, and the proton peaks at chemical shifts 3.5-4.1ppm and 5.0ppm represent the proton peaks in the β -CD molecular structure, indicating that β -CD has been successfully modified on the surface of G5. by integrating the proton peak regions of G5 and β -CD, 10.9 β -CD molecules are modified on each G5 surface, and G3-Ad1H NMR results are shown in FIG. 2(b), the proton peak at chemical shift 1.6-1.9ppm represents the proton peak in the molecular structure of adamantyl group, and the proton peak at chemical shift 2.3-3.2ppm represents the proton peak on amide bond in G3, indicating that Ad-COOH has been successfully modified on the surface of G3. By integrating the proton peak areas of G3 and Ad-COOH, it was calculated that 1.2 Ad-COOH molecules were surface modified per G3.
The 2D NOESY characterization results of Au CSTDs are shown in FIG. 3, and significant related cross signals appear between the adamantyl group at the chemical shift of 1.6-1.9ppm and the β -CD group at the chemical shift of 3.5-4.1ppm, so that the interaction and tight combination of the adamantyl group and β -CD can be shown, and the host molecule (Au CSTDs) is proved at the same time0)50G5-CD and a guest molecule G3-Ad successfully construct the core-shell structure dendrimer Au CSTDs through the host-guest action of adamantane and cyclodextrin. Of COOH-PEG-RGD1As shown in FIG. 4(a), the chemical shift peaks at 3.4-3.6ppm and 6.75-7.05ppm are characteristic peaks of polyethylene glycol and RGD, respectively. The integration can obtain that each polyethylene glycol is modified with 0.76 RGD molecules. (Au)0)50of-G5-CD/Ad-G3-PEG-RGD1The characterization results of H NMR are shown in FIG. 4(b), and the chemical shift peaks at 3.4-3.6ppm and 2.2-3.3ppm correspond to the characteristic peaks of polyethylene glycol and dendrimer, respectively, and the chemical shift peak at 6.75-7.05ppm corresponds to the characteristic peak of RGD. After integration, 8.28 PEG molecules and 6.3 RGD molecules are modified on each core-shell structure dendrimer. (Au)0)50of-G5-CD/Ad-G3-PEG-RGD-DTPA1As shown in FIG. 4(c), the chemical shift peaks at 3.4-3.6ppm, 2.2-3.3ppm and 6.75-7.05ppm were identified as the peaks characteristic to polyethylene glycol, dendrimer and RGD, respectively, and the chemical shift peak at 3.78ppm was identified as the peak characteristic to DTPA. The integration can obtain 26.7 DTPA molecules modified on each core-shell structure dendrimer.
Example 3
The samples of comparative example 1 (Au)0)50G5-CD/Ad-G3-mPEG and (Au)0)505mg of each of-G5-CD/Ad-G3-mPEG-DTPA dissolved in 500. mu. L D2And in O, performing hydrogen spectrum analysis. (Au)0)50of-G5-CD/Ad-G3-mPEG1The characterization result of H NMR is shown in FIG. 5(a), the chemical shift peaks appearing at 3.5-3.65ppm and 2.2-3.3ppm correspond to the characteristic peaks of polyethylene glycol and dendrimer respectively, and 10.4 mPEG are modified on each core-shell structure dendrimer through integration. (Au)0)50of-G5-CD/Ad-G3-mPEG-DTPA1The results of H NMR characterization are shown in FIG. 5(b), and the chemical shift peaks at 3.5-3.65ppm and 2.2-3.3ppm correspond to the characteristic peaks of polyethylene glycol and dendrimer, respectively, and the chemical shift peak at 3.78ppm corresponds to the characteristic peak of DTPA. The integration can obtain 21.7 DTPA molecules modified on each core-shell structure dendrimer.
Example 4
G5-CD, G3-Ad, (Au) in example 1 were weighed separately0)500.5mg each of G5-CD, Au CSTDs, RGD-Gd @ Au CSTDs-PS and Gd @ Au CSTDs-PS in comparative example 1 were dissolved in 1m L ultrapure water, respectively, and subjected to hydrodynamic size and surface zeta potential tests (as shown in Table 1). The hydrated particle diameters were 119.3nm, 110.2nm, 94.0nm, 105.7nm, 135.3nm and 115.8nm, respectively, and the potentials were 29.8mV, 23.4mV, 26.5mV, G,37.7mV, 8.3mV and 5.2 mV. It can be seen from the data that the surface potential of the material is reduced from 37.7mV to 8.3mV, which provides a guarantee for low cytotoxicity of the material. As can be seen from the hydrodynamic particle size of the nanoparticles, the dendrimer assembly platform is small in size and has good dispersibility, and surface modification does not cause a significant increase in the hydrated particle size of the material.
TABLE 1 surface potential and hydrated particle size of the samples
Figure BDA0002410922300000081
Example 5
The compounds of example 1 (Au) were weighed out separately0)500.1mg each of-G5-CD, Au CSTDs, RGD-Gd @ Au CSTDs-PS and Gd @ Au CSTDs-PS in comparative example 1 was dissolved in 1m L ultra pure water to conduct UV-VIS absorption spectrum test, as shown in FIG. 6, (Au)0)50The aqueous solutions of the four nanoparticles of-G5-CD, Au CSTDs (a), Gd @ Au CSTDs-PS and RGD-Gd @ Au CSTDs-PS (b) all show obvious characteristic absorption peaks in the wavelength range of 500-550nm, particularly show surface plasma resonance absorption peaks of the gold nanoparticles at about 520nm, and the two synthesized carrier materials are both successfully wrapped by the gold nanoparticles.
Example 6
0.5mg of each of RGD-Gd @ Au CSTDS-PS in example 1 and Gd @ Au CSTDS-PS in comparative example 1 was weighed and dissolved in 1m L ultra-pure water respectively for TEM test, as shown in FIG. 7, the gold core particle diameters of Gd @ Au CSTDS-PS (FIG. 7a) and RGD-Gd @ Au CSTDS-PS (FIG. 7b) were 2.2nm and 2.4nm respectively, and the analysis results show that there is no great difference between the sizes of the gold cores of the two materials, the distribution is narrow, and the gold cores have good monodispersity.
Example 7
G3-Ad and (Au) in example 1 were weighed respectively0)500.5mg each of-G5-CD, Au CSTDs, RGD-Gd @ Au CSTDs-PS and Gd @ Au CSTDs-PS in comparative example 1 were dissolved in 1m L ultrapure water, and dropwise added to a silicon wafer to conduct AFM test, as shown in FIG. 8, G3-Ad (a), (Au) and (Au) were prepared0)50-G5-CD(b)、Au CSTDs(c) Gd @ Au CSTDs-PS (d), RGD-Gd @ Au CSTDs-PS (e) are nearly spherical in shape and have particle diameters of 4.20nm, 5.78nm, 10.75nm, 11.13nm and 11.61nm, respectively, whereby G3-Ad and (Au) can be further demonstrated0)50the-G5-CD forms core-shell structure dendrimer Au CSTDs with larger particle size through the self-assembly of the host and the guest.
Example 8
0.5mg of each of RGD-Gd @ Au CSTDs-PS in example 1 and Gd @ Au CSTDs-PS in comparative example 1 was weighed and dissolved in 1m L ultra pure water respectively for hydrodynamic size test, as shown in FIG. 9, the hydrated particle size of the two materials did not change significantly within 10 days of standing in the aqueous solution, indicating that the materials had good stability.
Example 9
The method comprises the steps of weighing 1mg of Bovine Serum Albumin (BSA) and dissolving the RGD-Gd @ Au CSTDs and the RGD-Gd @ Au CSTDs-PS prepared in the embodiment 1 into PBS, scanning the PBS by using an ultraviolet absorption spectrometer to obtain a result as shown in a graph 10(a), wherein the BSA has an absorption peak at 278nm, weighing 2mg of the RGD-Gd @ Au CSTDs and the RGD-Gd @ AuCSTDs-PS prepared in the embodiment 1, preparing into 2mg/m L-concentration solutions, respectively diluting the solutions into 1mg/m L, 0.5mg/m L and 0.25mg/m L-weighing 2mg of the PBS, preparing into 1mg/m L-concentration solutions, absorbing the 0.5m L-concentration BSA solutions, respectively adding the prepared solutions into the prepared solutions, fully adding the prepared Gd-CSTDS and RGD-CSTDS-PS into the PBS-75 nm-RGD-Ag-10-CSTDS-PS, respectively adding the Gd-Gd @ Au-DS-CSTDS-PS-concentration to the PBS solutions, and uniformly mixing the PBS solutions to obtain a supernatant, wherein the RGD-Au-Ag modified PBS-PS-10-CS-PS-10-PBS-concentration is reduced, the RGD-Ag-CSTDS-PS is obtained after the supernatant is well mixed, the supernatant is uniformly mixed, the supernatant is obtained after the supernatant is well absorbed by centrifugal culture solution, the centrifugal culture solution is well, the centrifugal culture solution is added, the ultraviolet absorption of the RGD-Ag.
Example 10
Taking in example 1The prepared targeting RGD-Gd @ Au CSTDs-PS material and the non-targeting Gd @ AuCSTDs-PS material prepared in the comparative example 1 take ultrapure water as a solvent, nanoparticle aqueous solutions with Gd concentrations of 0.64mM, 0.32mM, 0.16mM, 0.08mM and 0.04mM are prepared, T1 relaxation times of the two materials are measured by a T1 magnetic resonance imager, and MR imaging pictures are scanned. The test result is shown in FIG. 11, the reciprocal relaxation time of the prepared RGD-Gd @ Au CSTDS-PS particles is increased along with the increase of Gd concentration, a good linear relation is shown, and the relaxation rate of the RGD-Gd @ Au CSTDS-PS particles is 9.414mM through calculation-1s-1The relaxation rate of the Gd @ Au CSTDs-PS particles obtained in comparative example 1 was 8.795mM-1s-1. Experimental results show that the two prepared nanoparticles have good MR imaging contrast functions.
Example 11
In vitro CT imaging effects of the RGD-Gd @ Au CSTDS-PS prepared in example 1, the Gd @ Au CSTDS-PS prepared in comparative example 1 and the medical contrast agent Omnipaque were observed and compared by a medical CT scanner, wherein the RGD-Gd @ Au CSTDS-PS sample prepared in example 1 and the Gd @ Au CSTDS-PS prepared in comparative example 1 were weighed to prepare solutions having an Au concentration of 0.08M in ultrapure water, and then diluted to 100. mu. L each in the solutions of 0.04M, 0.02M, 0.01M and 0.005M, respectively, Omnipaque having the same iodine concentration gradient was prepared in the same manner, and CT values of the respective samples were measured by a CT tester to obtain linear relationships between X-ray attenuation and gold concentration, as shown in FIG. 12, the Omnipaque fitted curve had a greater RGD-Gd @ Au-PS and Gd @ CSTU-PS, indicating that the material had a greater Omnipaque imaging effect than that of Omnipaque CT used clinically.
Example 12
The effect of RGD-Gd @ AuCSTDs-PS prepared in example 1 and Gd @ Au CSTDs-PS prepared in comparative example 1 on cell survival was evaluated by CCK8 colorimetric method using 4T1 cells as model cells, RGD-Gd @ Au CSTDs-PS was dispersed in sterile PBS buffer to prepare a mother solution with gold concentration of 2000. mu.M, and was sterilized overnight by ultraviolet irradiation, a sample solution of non-targeted @ Gd Au CSTDs-PS prepared in comparative example 1 was prepared in the same manner, cultured 4T1 cells were seeded in a 96-well plate, and was seeded at a density of 1 ten thousand cells/well with 100. mu. L per well volume, after overnight culture, samples of respective dilution gradients were added, with respective Au concentrations of 10, 25, 50, 100, 200. mu.M per well, co-cultured for 24h with cells, 5 parallel wells per gradient were made with PBS buffer as a control, and cell viability was checked by CCK-8 method, with each well as a CCK-8 solution, after incubation for 4 hours at 37 ℃ and with a cell viability measured by an MR-85% MR material, which had a high survival rate as indicated by a high as shown in the above-85% MR test results of the cell viability test chart indicated by using an MR-85.
Example 13
The method comprises the steps of preparing a mother solution with an Au concentration of 2000 mu M from targeting RGD-Gd @ Au CSTDs-PS prepared in example 1 by using a sterile PBS buffer solution, irradiating overnight by ultraviolet, inoculating cultured 4T1 cells into a 12-pore plate, inoculating the cells according to the density of 20 ten thousand cells/pore, wherein each pore volume is 1M L, diluting the mother solution to a solution with Au concentrations of 10, 25, 50, 100 and 200 mu M by 1640 culture medium, adding the diluted sample and 4T1 cells, co-culturing for 4h at 37 ℃, washing the cells for three times by PBS, removing pancreatin, digesting and centrifuging, phagocytosing supernatant, digesting the obtained precipitate with 1M L aqua regia for 24h, adding 1M L pg ultrapure water after complete digestion, detecting the Gd concentration in the sample by ICP-OES, detecting the Gd concentration of the Gd @ PS and 4T cells by using a sterile PBS buffer solution with a Gd @ PS buffer solution with a Gd @ 5 @ PBS buffer solution, and a sterile PBS buffer solution with a Gd @ 5 RGD @ 5 @ PS @ 5 @ RGD @ 5 @ PS @ 5 @ RGD @ 5 RGD @ PS @ 5 RGD @ PS @ 5, and a sterile PBS buffer solution with a sterile PBS buffer solution, and a sterile PBS buffer solution with a sterile medium for a concentration of a sterile medium for supplementing a concentration of 5 RGD @ 5 RGD @ 5 RGD @ 5 for supplementing a sterile medium, and a sterile medium for supplementing a sterile PBS for supplementing a sterile medium for supplementing a sterile PBS for supplementing a sterile medium for supplementing RGD @ 5 for supplementing a sterile medium.
Example 14
The RGD-Gd @ Au CSTDs-PS prepared in example 1 and Gd @ Au CSTDs-PS prepared in comparative example 1 are prepared into 0.1M L saline solution with gadolinium concentration of 0.01M, after anesthesia is injected into the abdominal cavity of a mouse, two different saline solutions with 100 mu L of each mouse are respectively injected through tail veins, and MR scanning is carried out at different time before and after injection to evaluate the MR imaging effect of the material, as shown in fig. 14(a) and (c), after 30min of injection, the signal enhancement effect of a tumor part of the mouse is enhanced, the signal enhancement effect of the tumor part corresponding to the Gd @ CSTAU-PS and the RGD @ Gd @ CSTAU-PS reaches the peak value within 1h, the signal to noise ratio of the tumor part is respectively 65 and 52, at the same time point, the signal enhancement effect of the RGD-Gd @ CSTAU-PS is obviously higher than that of the Gd @ CSTAU-PS, and the material can be specifically targeted to the tumor tissue after RGD modification is fully proved, and the imaging effect is enhanced.
Example 15
After anesthesia of the abdominal cavity of the mouse by injecting anesthetic, 100 mu L of two different physiological saline solutions of each mouse are respectively injected through the tail vein, and CT scanning is carried out at different times before and after injection, so as to evaluate the CT imaging effect of the material, as shown in fig. 14(b) and (d), after 30min of injection, the signal enhancement effect of the tumor part of the mouse reaches the peak value at 1h, the CT values of the tumor parts corresponding to Gd @ CSTAU-PS and RGD-Gd-CSTAU-PS are respectively 60.8HU and 51.1 HU. at the same time point, and the signal enhancement effect of the RGD-Gd @ CSTAU-PS is higher than that of the Gd @ CSTAU-PS, which shows that the material has the enhanced imaging effect.
Example 16
The RGD-Gd @ Au CSTDs-PS material prepared in example 1 and Gd @ Au CSTDs-PS prepared in comparative example 1 were configured as 0.1M L saline solution with gold concentration of 0.1M after anesthesia of intraperitoneal injection of the mice, two different saline solutions with gold concentration of 0.1M per mouse were injected through caudal vein, respectively, the mice were sacrificed at different time points (1, 6, 12, 24h) after injection, the major organs (heart, liver, spleen, lung, kidney and tumor) were taken out and weighed and subjected to ICP-OES digestion for one week, and then the Au content in each organ was measured by ICP-OES, the uninjected mice were taken as a control group for 0h, three mice were made in parallel at each time point, the results are shown in FIGS. 15(a) and (b), after the caudal vein injection of each group of material for 24 hours, the gold element content of each organ (heart, liver, spleen, lung, kidney) was first increased after the preparation of the two groups of the material RGD @ Au-PS material, and the targeted Gd @ Au-PS material was metabolized at the same time point, and the tumor-RGD-PS material was found to be decreased in vivo as the targeted RGD-PS material was also confirmed.

Claims (8)

1. A method for preparing a core-shell structure dendrimer CT/MR imaging contrast agent comprises the following steps:
(1) dissolving β -cyclodextrin β -CD, N' -carbonyldiimidazole CDI and fifth generation polyamidoamine dendrimer G5 in dimethyl sulfoxide DMSO solution respectively, mixing β -CD and CDI solution, stirring and reacting for 6-8h to obtain reaction liquid, dripping the reaction liquid into G5 solution, stirring and reacting for 70-80h at room temperature, dialyzing, freeze-drying to obtain G5-CD, dropwise adding chloroauric acid aqueous solution into G5-CD aqueous solution, stirring and reacting for 15-30min, then adding precooled sodium borohydride aqueous solution, stirring and reacting for 3-4h in ice bath, dialyzing, freeze-drying to obtain a main molecule (Au)0)50-G5-CD；
(2) Respectively dissolving 1-adamantane acetic acid Ad-COOH, EDC and NHS in a DMSO solution, adding EDC into the Ad-COOH solution, stirring and reacting at room temperature for 30-40min, adding NHS, and stirring and reacting at room temperature for 3-4h to obtain an activated Ad-COOH solution; dropwise adding the mixture into a DMSO solution in which third-generation polyamide-amine dendrimer G3 is dissolved, stirring at room temperature for reaction for 3-4 days, dialyzing, and freeze-drying to obtain an object molecule G3-Ad;
(3) the host molecule (Au)0)50Respectively dissolving G5-CD and a guest molecule G3-Ad in ultrapure water, mixing at room temperature, stirring, reacting for 20-30h, and obtaining the core-shell structure dendrimer (Au) through the action of a supramolecular host and a guest0)50-G5-CD/Ad-G3 solution, dialyzed, lyophilized to obtain (Au)0)50-G5-CD/Ad-G3, denoted as Au CSTDs;
(4) dissolving COOH-PEG-RGD in DMSO, adding EDC and NHS for activation to obtain an activated COOH-PEG-RGD solution; then dropwise adding the mixture into DMSO solution of Au CSTDs, and stirring and reacting for 3-4 days at room temperature; finally dialyzing, and freeze-drying to obtain (Au)0)50-G5-CD/Ad-G3-PEG-RGD；
(5) Will (Au)0)50Respectively dissolving-G5-CD/Ad-G3-PEG-RGD and chelating agent diethylene pentaacetate DTPA in ultrapure water, mixing at room temperature, stirring for reaction for 24-30h, dialyzing, and freeze-drying to obtain (Au)0)50-G5-CD/Ad-G3-PEG-RGD-DTPA；
(6) Will (Au)0)50Respectively dissolving-G5-CD/Ad-G3-PEG-RGD-DTPA and gadolinium nitrate in ultrapure water, mixing at room temperature, stirring for reaction for 24-30h, then dropwise adding 1,3-PS solution, stirring for reaction for 24-30h, dialyzing, and freeze-drying to obtain (Au)0)50G5-CD/Ad-G3-PEG-RGD-DTPA (Gd) -PS, marked as RGD-Gd @ Au CSTDs-PS, namely the core-shell structure dendrimer CT/MR imaging contrast agent.
2. The method according to claim 1, wherein the molar ratio of CDI to β -CD in step (1) is 10-15:1, and the molar ratio of β -CD to G5 is 18-20: 1.
3. The method of claim 1, wherein: the molar ratio of G5-CD to chloroauric acid in the step (1) is 1: 50-52; the molar ratio of the sodium borohydride to the chloroauric acid is 3-4: 1.
4. The method of claim 1, wherein: the molar ratio of EDC, NHS and Ad-COOH in the step (2) is 10-15:10-15: 1; the molar ratio of G3 to Ad-COOH was 1: 1.3-1.5.
5. The method of claim 1, wherein: (Au) in the step (3)0)50The molar ratio of G5-CD to G3-Ad was 1: 10.
6. The method of claim 1, wherein: the molar ratio of COOH-PEG-RGD to AuCSTDs in the step (4) is 10-12: 1; the molar ratio of EDC, NHS and COOH-PEG-RGD is 10-15:10-15: 1.
7. The method of claim 1, wherein: (Au) in the step (5)0)50The molar ratio of the-G5-CD/Ad-G3-PEG-RGD to DTPA is 1: 28-30.
8. The method of claim 1, wherein: (Au) in the step (6)0)50The molar ratio of the-G5-CD/Ad-G3-PEG-RGD-DTPA to the gadolinium nitrate to the 1,3-PS is 1:28-30: 90-100.
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