CN112683985B - Metal label based on rare earth doped nano metal organic framework material - Google Patents
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Abstract
The invention discloses a metal tag based on a rare earth doped nano metal organic framework material, which is prepared by the following method: 1) Preparing a rare earth metal complex having the structure shown in formula (I):
2) Preparing Ln @ ZIF-8 nano particles with porous structures; 3) Preparation of Ln @ ZIF-8@ SiO 2 (ii) a 4) Preparation of NH 2 ‑Ln@ZIF‑8@SiO 2 (ii) a 5) Preparation of PEG-Ln @ ZIF-8@ SiO 2 . The invention can increase the rare earth content of single particle to 10 5 ‑10 6 And further carrying out SiO on the surface 2 Coating, improving stability, and further modifying surface with PEG to obtain PEG-Ln @ ZIF-8@ SiO 2 The composite nano-particles can be sensitively detected by mass spectrum flow, and simultaneously have good biocompatibility, and the synthesis process is simple to operate.
Description
Technical Field
The invention relates to the technical field of biological imaging, in particular to a metal label based on a rare earth doped nano metal organic framework material.
Background
The mass cytometry combines the traditional flow cytometry analysis method and the mass spectrometry detection method together, and is an emerging high-throughput and multidimensional single-cell biological detection technology. The traditional flow cytometry method adopts a method that cells are stained by an antibody marked by a fluorescent dye, and a fluorescent signal is detected by a fluorescence detector to realize the identification and detection of the cells. The mass cytometry is to couple cells through a stable heavy metal element labeled antibody and further detect a metal signal through inductively coupled plasma mass spectrometry so as to achieve the purpose of cell identification. The technology overcomes the defects of overlapping fluorescence signals and few detection channels in the traditional flow cytometry, can simultaneously detect more than 40 parameters of the same cell at most, and greatly improves the detection efficiency.
Despite the advantages described above, there are still some areas to be improved for the application of current mass flow detection technology, for example, the detection kit used in mass flow is based on commercial Maxpar sizing polymers (MCP) reagents polymer metal chelate tags, each polymer chain can be connected with about 20-30 rare earth metal atoms, and each antibody can be connected with 2-3 polymer chains during the antibody labeling process, so that only about 60-90 rare earth metals can be connected to each antibody. However, mass spectrometry can only detect one of 104 metal signals, so at least a hundred antibodies need to be attached to each cell to achieve the detection effect. On the other hand, the labels on the market are usually imported from foreign countries and are expensive, and the price of a set of standard kits (containing the rare earth coordination polymer 40 x 100 micrograms, which can be subjected to 40 marking experiments) is usually more than 50000 RMB.
Therefore, a more reliable solution is now needed.
Disclosure of Invention
The technical problem to be solved by the present invention is to provide a metal tag based on a rare earth doped nano metal organic framework material, aiming at the defects in the prior art.
In order to solve the technical problems, the invention adopts the technical scheme that: a metal label based on a rare earth doped nano metal organic framework material is prepared by the following steps:
1) Preparing a rare earth metal complex having the structure shown in formula (I):
2) Preparing Ln @ ZIF-8 nano-particles with porous structures by using the rare earth metal coordination compound prepared in the step 1);
3) Coating Ln @ ZIF-8 nano particles with silicon dioxide to obtain Ln @ ZIF-8@ SiO 2 ；
4) For Ln @ ZIF-8@ SiO 2 Carrying out amination modification to prepare NH 2 -Ln@ZIF-8@SiO 2 ；
5) To NH 2 -Ln@ZIF-8@SiO 2 Modifying with PEG to obtain PEG-Ln @ ZIF-8@ SiO 2 I.e. the metal label.
Preferably, the step 1) specifically includes:
1-1) dissolving 2-thenoyltrifluoroacetone in ethanol, and dropwise adding LnCl under the condition of stirring 3 Adding ammonia water after the dropwise addition of the aqueous solution is finished, adjusting the pH value to 9, continuously stirring, adding water, and stirring again; wherein, the rare earth element Ln is any one of Tb, pr, ho and Tm;
1-2) performing rotary evaporation to remove part of ethanol, filtering and drying, dissolving the obtained solid in ethanol, dropwise adding an ethanol solution containing 1, 10-phenanthroline, heating to boiling for concentration after dropwise adding is completed, and recrystallizing the cooled solid with a hot mixed solution of acetone and ethanol to obtain the rare earth metal coordination compound.
Preferably, in the mixed solution of acetone and ethanol, the volume ratio of acetone to ethanol is 1.
Preferably, the step 2) specifically includes:
2-1) preparing two groups of solutions:
dissolving 2-methylimidazole and rare earth complex in methanol to obtain solution A; dissolving zinc nitrate hexahydrate and hexadecyl trimethyl ammonium bromide in methanol to obtain a solution B;
2-2) adding the solution B into the solution A, stirring at normal temperature, and centrifugally cleaning a product by using ethanol; finally, the Ln @ ZIF-8 nano-particles containing the rare earth metal coordination compounds and having the porous structure are obtained.
Preferably, the step 3) specifically includes:
dissolving Ln @ ZIF-8 nanoparticles in ethanol, adding sodium hydroxide aqueous solution, stirring, adding tetraethyl orthosilicate, stirring at room temperature, centrifuging the obtained product, washing with ethanol, and drying to obtain Ln @ ZIF-8@ SiO 2 。
Preferably, the step 4) specifically includes: mixing Ln @ ZIF-8@ SiO 2 Dissolving in ethanol, ultrasonic dispersing, adding APTES, stirring at room temperature, centrifuging, washing with ethanol, and vacuum drying to obtain NH 2 -Ln@ZIF-8@SiO 2 。
Preferably, the step 5) specifically includes: reacting NH 2 -Ln@ZIF-8@SiO 2 Mixing with PEG solution, adding EDC and NHS, stirring at room temperature for reaction, washing the obtained product with ethanol and deionized water, and drying to obtain PEG-Ln @ ZIF-8@ SiO 2 。
The present invention also provides an antibody tag for mass cytometry via PEG-Ln @ ZIF-8@ SiO as described above 2 Coupling with monoclonal antibody.
Preferably, the preparation method of the antibody tag comprises the following steps:
a. taking PEG-Ln @ ZIF-8@ SiO 2 Adding the mixture into borate buffer solution, adding monoclonal antibody, EDC and NHS, and incubating at 37 ℃;
b. and c, centrifuging and washing the product obtained in the step a by using a PBS buffer solution at room temperature to obtain the antibody label.
Preferably, the monoclonal antibody is CD-3, CD-4, CD-8 or CD-45.
The invention has the beneficial effects that:
the invention is different from the existing mass flow polymer metal chelating label, skillfully dopes the rare earth metal into the stable ZIF-8 hollow porous structure, and can improve the rare earth content of a single particle to 10 5 -10 6 And further carrying out SiO on the surface 2 Coating, improving stability, further modifying surface with PEG, and making into PEG-Ln @ ZIF-8@ SiO 2 The composite nano-particles can be sensitively detected by mass spectrum flow, have good biocompatibility, have simple operation of synthesis process and lower cost, and can greatly reduce the use cost of mass spectrum flow detection reagents. After being combined with different antibodies, the PEG-Ln @ ZIF-8@ Sio2 composite nanoparticle can specifically recognize different cell populations, and provides a reliable detection means for mass flow type researches in the aspects of cell biology immunology, hematology, drug screening research and development, clinical diagnosis and the like.
Drawings
FIG. 1 is a synthetic route of a metal tag based on a rare earth doped nanometal organic framework material of the present invention;
FIG. 2 is a TEM image of Tb @ ZIF-8 in an example of the present invention;
FIG. 3 is PEG-Tb @ ZIF-8@ SiO in an embodiment of the present invention 2 -CD4 vs T cell assay results.
Detailed Description
The present invention is further described in detail below with reference to examples so that those skilled in the art can practice the invention with reference to the description.
It will be understood that terms such as "having," "including," and "comprising," as used herein, do not preclude the presence or addition of one or more other elements or combinations thereof.
The invention provides a metal tag based on a rare earth doped nano metal organic framework material, which is prepared by the following method:
1) Preparing a rare earth metal complex having the structure shown in formula (I):
2) Preparing Ln @ ZIF-8 nano-particles with porous structures by using the rare earth metal coordination compound prepared in the step 1), 2-methylimidazole, methanol, zinc nitrate hexahydrate and other raw materials; wherein ZIF-8, namely 2-methylimidazole zinc salt MAF-4, is a porous coordination polymer, also called a metal organic framework, and has the characteristics of high pore volume, high hydrophobicity, high thermal stability, chemical stability and the like;
3) TEOS (tetraethyl orthosilicate) reacts with Ln @ ZIF-8 nano-particles to carry out silicon dioxide coating on the Ln @ ZIF-8 nano-particles to prepare the Ln @ ZIF-8@ SiO 2 ；
4) By APTES (3-aminopropyltriethoxysilane) on Ln @ ZIF-8@ SiO 2 Carrying out amination modification to prepare NH 2 -Ln@ZIF-8@SiO 2 ；
5) To NH 2 -Ln@ZIF-8@SiO 2 Modifying with PEG to obtain PEG-Ln @ ZIF-8@ SiO 2 I.e. the metal label.
The synthesis route of the metal tag is shown in FIG. 1.
The invention also provides an antibody label for mass cytometry, which is prepared by PEG-Ln @ ZIF-8@ SiO 2 Coupling with monoclonal antibody.
More specific examples are provided below to further illustrate the invention.
Example 1
A metal tag based on a rare earth doped nano metal organic framework material is prepared by the following steps:
1. preparation of rare earth metal complexes
In this embodiment, the lanthanide rare-earth element Ln is specifically selected as Tb, and the specific steps are as follows:
1-1, dissolving 440mg of 2-thenoyltrifluoroacetone in 15mL of ethanol, and rapidly stirring;
1-2, 0.05M of TbCl is dripped 3 15mL of aqueous solution, adding a few drops of ammonia water after the dropwise addition is finished, and adjusting the pH value to 9;
1-3, stirring for 1 hour, adding 25mL of water, and stirring for 1 hour;
1-4, removing most ethanol by rotary evaporation, filtering and drying to obtain solid 0.44g;
1-5, dissolving the obtained solid in 15mL of ethanol, dropwise adding 6mL of ethanol solution containing 105mg of 1, 10-phenanthroline, heating to boiling and concentrating after dropwise adding is finished, and recrystallizing the cooled solid with hot acetone/ethanol mixed solution (volume ratio 1: a Tb complex.
2. Tb @ ZIF-8 nano-particle for preparing porous structure
2-1, preparing two groups of solutions:
820mg of 2-methylimidazole and 28mg of Tb complex are dissolved in 40mL of methanol to obtain a solution A; 714mg of zinc nitrate hexahydrate and 72.9mg of cetyltrimethylammonium bromide were dissolved in 40mL of methanol to obtain a solution B;
2-2, quickly adding the solution B into the solution A, and stirring for 24 hours at normal temperature;
2-3, centrifuging at 8000rpm for 15min to remove supernatant
2-4, centrifuging and washing the obtained solid with ethanol, centrifuging at 8000rpm for 15min, repeating for three times, and drying to obtain Tb @ ZIF-8 nanoparticles.
Referring to FIG. 2, it is a transmission electron micrograph of Tb @ ZIF-8, wherein the particle size of Tb @ ZIF-8 is about 50 nm and the size distribution is uniform.
3. Preparation of Tb @ ZIF-8@ SiO 2
3-1, dispersing 40mgTb @ ZIF-8 nanoparticles in 100mL ethanol, and violently stirring;
3-2, adjusting the pH value of the solution obtained in the step to 8 by using a 0.1M NaOH solution;
3-3, adding 20% TEOS (tetraethyl orthosilicate) ethanol solution in three portions, 1.2mL each time, half an hour each time;
3-4, stirring for 18 hours at room temperature, and centrifuging for 15min at the rotating speed of 8000rpm to remove supernatant;
3-5, centrifuging the obtained solid with ethanol at 8000rpm for 15min, repeating for three times to obtain Tb @ ZIF-8@ SiO 2 。
4. Preparation of NH 2 -Tb@ZIF-8@SiO 2
4-1, mixing 50mgTb @ ZIF-8@ SiO 2 Dispersing in 100mL ethanol, and stirring vigorously;
4-2, adding 50 mu L of APTES (3-aminopropyltriethoxysilane), and stirring for 6 hours at room temperature;
4-3, centrifuging at 8000rpm for 15min to remove supernatant;
4-4, centrifuging the obtained solid with ethanol at 8000rpm for 15min, repeating for three times, and vacuum drying to obtain NH2-Tb @ ZIF-8@ SiO 2 。
5. Preparation of EG-Tb @ ZIF-8@ SiO 2
5-1, 50mgNH 2 -Tb@ZIF-8@SiO 2 Dispersing in 100mL of ethanol, and stirring vigorously;
5-2, adding 100mg of PEG (polyethylene glycol) solution (with carboxyl groups at two ends, wt, 6000) and stirring;
5-3, adding EDC and NHS (N-hydroxysuccinimide), and stirring for 12 hours at room temperature;
5-4, centrifuging at 8000rpm for 15min to remove supernatant, washing the obtained solid with ethanol and deionized water, and drying to obtain PEG-Tb @ ZIF-8@ SiO 2 。
Wherein by NH 2 -Tb@ZIF-8@SiO 2 Can be mixed with PEG solutions with different molecular weights according to different proportions (such as 1 2 -Tb@ZIF-8@SiO 2 。
Example 2
The present embodiment provides an antibody tag for mass cytometry, and the preparation method of the antibody tag comprises the following steps:
100ug of PEG-Tb @ ZIF-8@ SiO prepared in example 1 was taken 2 The mixture was added to 50mM borate buffer (pH 8.2), and the monoclonal antibody was added thereto (this example)In the examples, CD-45 was specifically selected) and EDC and NHS (both at a concentration of 150 gL) were used as crosslinking agents -1 ) Incubating at 37 deg.C for a period of time, centrifuging the resultant product with 0.01M PBS (pH 7.4) at room temperature, dispersing into PBS (0.01M, pH 7.4,0.5% BSA), and storing at 4 deg.C to obtain the antibody tag (PEG-Tb @ ZIF-8@ SiO2 @) 2 -CD 4). 1uL antibody tag was applied to human peripheral blood mononuclear cells (10) 6 One) were stained and tested on a mass cytometer.
Referring to FIG. 3, it is PEG-Tb @ ZIF-8@ SiO 2 The results of T cell detection by-CD 4 revealed that PEG-Tb @ ZIF-8@ SiO 2 The CD4 antibody tag enables efficient grouping of T cells (two cell populations, left and right), wherein the CD4 antibody-labelled cells account for 58.36% of the total number of cells. In fig. 3 can be understood as: all cells were uniformly labeled on the ordinate and then used for clustering on the abscissa, with 159TbCD4 on the right and none on the left.
While embodiments of the invention have been disclosed above, it is not intended to be limited to the details shown in the description and the examples, which are set forth, but are fully applicable to various fields of endeavor as are suited to the particular use contemplated, and further modifications will readily occur to those skilled in the art, since the invention is not limited to the details shown and described without departing from the general concept as defined by the appended claims and their equivalents.
Claims (8)
1. A metal label based on a rare earth doped nano metal organic framework material is characterized by being prepared by the following method:
1) Preparing a rare earth metal complex, wherein the structure of the rare earth metal complex is shown as the following formula (I):
2) Preparing Ln @ ZIF-8 nano particles with porous structures by using the rare earth metal coordination compound prepared in the step 1);
3) Silicon dioxide coating is carried out on Ln @ ZIF-8 nano particles to prepare Ln @ ZIF-8@SiO 2 ；
4) For Ln @ ZIF-8@ SiO 2 Carrying out amination modification to prepare NH 2 -Ln@ZIF-8@SiO 2 ；
5) To NH 2 -Ln@ZIF-8@SiO 2 Modifying with PEG to obtain PEG-Ln @ ZIF-8@ SiO 2 I.e. the metal label;
the step 1) specifically comprises the following steps:
1-1) dissolving 2-thenoyltrifluoroacetone in ethanol, and dropwise adding LnCl under the condition of stirring 3 Adding ammonia water after the dropwise addition of the aqueous solution is finished, adjusting the pH value to 9, continuously stirring, adding water, and stirring again; wherein, the rare earth element Ln is any one of Tb, pr, ho and Tm;
1-2) performing rotary evaporation to remove part of ethanol, filtering and drying, dissolving the obtained solid in ethanol, dropwise adding an ethanol solution containing 1, 10-phenanthroline, heating to boiling for concentration after dropwise adding is completed, and recrystallizing the cooled solid with a hot mixed solution of acetone and ethanol to obtain the rare earth metal coordination compound;
the step 2) specifically comprises the following steps:
2-1) preparing two groups of solutions:
dissolving 2-methylimidazole and rare earth complex in methanol to obtain solution A; dissolving zinc nitrate hexahydrate and hexadecyl trimethyl ammonium bromide in methanol to obtain a solution B;
2-2) adding the solution B into the solution A, stirring at normal temperature, and centrifugally cleaning a product by using ethanol; finally, the Ln @ ZIF-8 nano-particles with the porous structure containing the rare earth metal coordination compound are obtained.
2. The metal tag based on the rare earth doped nano metal organic framework material of claim 1, wherein the volume ratio of acetone to ethanol in the mixed solution of acetone and ethanol is 1.
3. The metal tag based on rare earth doped nanometal-organic framework material according to claim 2, characterized in that the step 3) comprises in particular:
dissolving Ln @ ZIF-8 nanoparticles in ethanol, and addingStirring sodium hydroxide water solution uniformly, adding tetraethyl orthosilicate, stirring at room temperature, centrifuging the obtained product, washing with ethanol, and drying to obtain Ln @, ZIF-8@ SiO 2 。
4. The metal tag based on rare earth doped nanometal-organic framework material according to claim 3, characterized in that the step 4) comprises in particular: mixing Ln @ ZIF-8@ SiO 2 Dissolving in ethanol, ultrasonic dispersing, adding APTES, stirring at room temperature, centrifuging, washing with ethanol, and vacuum drying to obtain NH 2 -Ln@ZIF-8@SiO 2 。
5. The metal tag based on a rare earth doped nanometal organic framework material according to claim 4, characterized in that the step 5) comprises in particular: reacting NH 2 -Ln@ZIF-8@SiO 2 Mixing with PEG solution, adding EDC and NHS, stirring at room temperature for reaction, washing the obtained product with ethanol and deionized water, and drying to obtain PEG-Ln @ ZIF-8@ SiO 2 。
6. An antibody tag for mass cytometry, which is prepared by the PEG-Ln @ ZIF-8@ SiO of any one of claims 1 to 5 2 Coupling with monoclonal antibody.
7. The antibody tag for mass cytometry according to claim 6, wherein the antibody tag is prepared by a method comprising the steps of:
a. taking PEG-Ln @ ZIF-8@ SiO 2 Adding into borate buffer solution, adding monoclonal antibody, EDC and NHS, and incubating at 37 deg.C;
b. and c, centrifugally washing the product obtained in the step a by using a PBS (phosphate buffer solution) at room temperature to obtain the antibody label.
8. The antibody tag for mass cytometry of claim 7 wherein said monoclonal antibody is CD-3, CD-4, CD-8 or CD-45.
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