CN112881358A - Supermolecule biomolecule nano particle and synthetic method and application thereof - Google Patents
Supermolecule biomolecule nano particle and synthetic method and application thereof Download PDFInfo
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Abstract
The invention discloses a supermolecule biomolecule nano particle, a synthesis method and application thereof. The method comprises the following steps: s1: carrying out a copper-catalysis-free click chemistry method to react azide-modified beta-cyclodextrin with DNA of DBCO modified at the 3' end to obtain homogeneous beta-cyclodextrin-based DNA molecular nanoparticles; s2: mixing the aptamer modified by amino and adamantane containing hydrochloride, and placing the mixture on a shaking table for reaction to obtain adamantane functionalized by the aptamer; s3: self-assembling S1 and S2 to obtain the supermolecular biomolecular nanoparticles; wherein, the steps S1 and S2 are not in sequence. The invention utilizes the supermolecule chemical action with higher combination constant of cyclodextrin and adamantane to upgrade to supermolecule biomolecule nano particles, in addition, cyclodextrin and adamantane are coupled with different functional nucleic acid aptamers, and the combination not only can enter cells for imaging through endocytosis, but also can better perform gene regulation.
Description
Technical Field
The invention relates to the technical field of biomedicine, in particular to a supermolecule nano particle and a synthesis method and application thereof.
Background
Biomolecules such as nucleic acids or aptamers play a major role in the diagnosis or treatment of cancer, and researchers couple them to many synthetic molecules or elements based on their many superior functions, for example: chromophores, lipid organometallic complexes, molecular nanoparticles, and the like. The conjugate has excellent combination of the characteristics of functional biomolecules and synthetic molecules, so that the conjugate has more application possibilities in the aspects of sensing, protein activity regulation, cell behavior regulation, biomedicine and the like. We have previously reported homogeneous biomolecular nanoparticles in which biomolecules (DNA, RNA, etc.) are coupled to molecular nanoparticles. Molecular nanoparticles are a class of molecules with rigid structures, the size of which is on the nanometer scale. The structure of the molecular nano-particle is excellent because the core structure is determined, the functional group sites on the surface are also determined, and the functional groups on the surface can be directionally modified through certain chemical treatment. Compared with the classical inorganic nanoparticles, the molecular nanoparticles have the advantages of precise structure, precise regulation and control of the number, the types and the positions of functional groups and the like. The molecular nano-particles widely researched at present mainly comprise fullerene, polyhedral silsesquioxane, metal heteropoly acid, cyclodextrin and the like.
Compared with other molecular nanoparticles, the cyclodextrin has a unique cavity structure, and the cavity enables host-guest self-assembly of the cyclodextrin and a hydrophobic guest into supramolecules by using supramolecular chemistry. Supramolecular chemistry, also known as "beyond molecular chemistry", has been one of the hot spots of research since the formal proposal of supramolecular concept and related canonical terms by Jean-Marie Lehn in 1978, and unlike the study of covalent bonds by traditional chemistry, supramolecular chemistry has been mainly studied for noncovalent interactions, i.e., intermolecular forces, including hydrophobic interactions, hydrogen bonds, van der waals forces, electrostatic interactions, metal coordination, shape or size matching, etc. Among various non-covalent interactions, the host-guest interaction between β -cyclodextrin (β -CD) and adamantane is widely used to design various functional nanostructures due to its high binding constant (Ka ═ 104-.
Disclosure of Invention
The invention aims to provide a method for synthesizing supermolecular biomolecular nanoparticles, which can enter cells through endocytosis for imaging and can better perform gene regulation, aiming at the defects in the prior art.
The invention relates to a method for synthesizing supermolecule biomolecule nanoparticles, which comprises the following steps:
s1: carrying out a copper-catalysis-free click chemistry method to react azide-modified beta-cyclodextrin with DNA of DBCO modified at the 3' end to obtain homogeneous beta-cyclodextrin-based DNA molecular nanoparticles;
s2: mixing the aptamer modified by amino and adamantane containing hydrochloride, and placing the mixture on a shaking table for reaction to obtain adamantane functionalized by the aptamer;
s3: mixing the homogeneous beta-cyclodextrin-based DNA molecular nanoparticles with the aptamer-functionalized adamantane at room temperature, and vibrating and uniformly mixing to obtain supramolecular biomolecule nanoparticles;
wherein, the steps S1 and S2 are not in sequence.
Further, the nucleic acid aptamer includes, but is not limited to, AS 1411.
Further, in step S1, azide-modified beta-cyclodextrin with a molar ratio of 1:10.5 is reacted with DNA with DBCO modified at the 3' end for 5 hours at 25 ℃ and shaking speed of 1000rpm to obtain the homogeneous beta-cyclodextrin-based DNA molecular nanoparticles.
Further, in step S1, the product is separated by high performance liquid chromatography, and finally the synthesis of the homogeneous β -cyclodextrin-based DNA molecule nanoparticles is determined by mass spectrometry.
Further, the product is separated by high performance liquid chromatography in step S2, and finally the guest aptamer-functionalized adamantane is determined by mass spectrometry.
Further, the molar ratio of the homogeneous β -cyclodextrin-based DNA molecule nanoparticles to the aptamer-functionalized adamantane in step S3 is 1: 1.
The supramolecular biomolecular nanoparticle synthesized by the method for synthesizing the supramolecular biomolecular nanoparticle is disclosed.
The supermolecule biomolecule nano-particles are applied to cell imaging.
According to the invention, by utilizing the supermolecule chemical action with higher binding constant of cyclodextrin and adamantane, on the basis of homogeneous beta-cyclodextrin-based DNA molecular nanoparticles, adamantane with functionalized aptamer is self-assembled and upgraded to supermolecule biomolecule nanoparticles, and in addition, different functional aptamers are coupled with cyclodextrin and adamantane, so that the combination not only can be used for cell imaging through endocytosis, but also can be used for better gene regulation.
Drawings
FIG. 1 is a graph of the results of a liquid chromatographic separation of guest Ada-AS1411 of example 1;
FIG. 2 is a mass spectrum characterization of adamantane for guest Ada-AS1411 of example 1;
FIG. 3a is a graph of a comparative set of host and guest characterization by fluorescence method of example 1;
FIG. 3b is a representation of the subject and guest self-assembly fluorescence method of example 1;
FIG. 4 is an image of the cell of example 1 showing the homogeneous biomolecular nanoparticles and supramolecular nanoparticles;
FIG. 5 is a time-dependent spectrum of cellular uptake of the homogeneous biomolecule nanoparticles of example 1;
fig. 6 is a time-dependent cellular uptake spectrum of supramolecular biomolecular nanoparticles of example 1.
Detailed Description
The following are specific embodiments of the present invention and are further described with reference to the drawings, but the present invention is not limited to these embodiments.
Example 1:
synthesis of guest Ada-AS1411
mu.L of 3.6. mu.M adamantane in DMSO and 100. mu.L of 0.1. mu.M aptamer AS1411 were mixed and reacted at 50 ℃ and shaking speed 1000rpm for 4 hours. The sequence listing for AS1411 is TTT CTC CAT GGT GCT CAC.
Second, HPLC separation of guest Ada-AS1411
1. Preparation of a mobile phase: phase A is an organic phase (80% MeCN (acetonitrile)) + 20% TEAA and phase B is an aqueous phase (TEAA, pH 7.0). The TEAA solution was prepared by mixing 5.6mL of glacial acetic acid with 13.86mL of triethylamine, adding ultrapure water to a volume of 1000mL, and adjusting the pH to about 7.0 with a pH meter;
2. collecting spectrogram of reference sample
3. The product sample is separated and purified by the same conditions
4. Performing spectrogram collection on the purified product
The results show that: the unseparated product had an excessive peak of the starting material and a peak of the objective product on the chromatogram (see FIG. 1).
EIS-MS characterization of object Ada-AS1411
1. Concentrating the HPLC collected product by a concentrator, and removing the mobile phase;
2. the manufacturer carries out mass spectrometry (see the results in FIG. 2).
The results show that: the molecular weights of the target object Ada-AS1411 are 8615.9 respectively, and are consistent with the estimated theoretical molecular weight, so that the successful synthesis of the object part is proved.
Fourth, the self-assembly fluorescence characterization of the host and the guest of the super biomolecule nano particle
1. Preparation of 500nM E33(DNA concentration 7. mu.M): 50. mu.L of E33(DNA concentration 7. mu.M) at a concentration of 1. mu.M was put into a centrifuge tube, and 50. mu.L of ultrapure water was added thereto to dilute it to an E33 concentration of 500nM (DNA concentration 3.5. mu.M)
2. The Cy5 fluorophore-modified guest Ada was UV-fixed at a concentration of 10. mu.M
3. The subject containing the Cy3 modification and the guest containing the Cy5 modification were scanned with a fluorescence spectrometer, and the excitation wavelength and emission wavelength were determined to be Ex: 532nm, Em: 566 nm; ex: 640nm, Em: 661nm
4. Scanning a spectrum of 500nM E33 (subject modified by Cy3) by a fluorescence spectrometer at Ex of 532nM, adding 10 μ M Ada-Cy5 (subject modified by Cy 5) dropwise, and scanning fluorescence spectra of the added subjects to 0.05 μ M, 0.10 μ M, 0.15 μ M, 0.20 μ M, 0.25 μ M, 0.30 μ M, 0.35 μ M, 0.40 μ M, 0.45 μ M, 0.50 μ M, 0.55 μ M, 0.60 μ M, 0.70 μ M, 0.80 μ M, 0.90 μ M and 1.00 μ M respectively to observe whether fluorescence energy is transferred;
5. equal concentrations of equal volumes of starting (single stranded) DNA and guest used on Cy 3-modified hosts were scanned under the same conditions as above for controls to see if there was fluorescence energy transfer in the absence of cyclodextrin cavities.
The product is shown in FIG. 3a, and the comparison group is shown in FIG. 3b, and the results show that: the Cy3 and Cy5 spectrograms in the absence of cyclodextrin have substantially no change with time and concentration, i.e., fluorescence resonance energy transfer cannot occur; in the presence of cyclodextrin, the fluorescence energy of Cy3 was gradually transferred to Cy5 with the addition of guest. The comparison of the two shows that in the presence of cyclodextrin, the adamantane and the cyclodextrin perform host-guest self-assembly of supramolecules to cause the Cy3 and Cy5 to approach each other, thereby triggering resonance transfer of fluorescence energy.
Imaging research of five, beta-cyclodextrin base DNA molecule nano particle and supermolecular biomolecule nano particle cell
1. Synthesizing supermolecule DNA molecule nano particles: beta-cyclodextrin-based DNA molecular nanoparticles and nucleic acid-functionalized adamantane (the sequence number of GGT GGT GGT GGT TGT GGT GGT GGT GG in the example) were mixed at room temperature in a ratio of 1:1(n: n), and the mixture was shaken and mixed uniformly.
2. Culturing MCF-7 cells: after cell passage, the cells were plated, cultured normally (density about 5.0X 105cells/well) in medium at 37 ℃ under 5% CO2 to better adhere.
3. Incubation of sample drug: after cell culture, the medium was aspirated and the cells were incubated for 6h with serum-Free medium containing the same concentration of sample (E33, Free DNA, E33-Ada-aptamer).
4. For the synthetic samples E33 and E33-Ada-aptamer, incubation is carried out for 1h and 3h simultaneously, so as to observe the degree of sample uptake of cells in different time periods and compare the uptake of different samples in the same time period. E33-Ada-aptamer was observed for uptake at 24 h.
5. Measurement of cellular uptake by confocal: after incubation was complete, 5 μ L of viable cell nucleus staining solution Hoechest 33258 was added for 20min, after which the medium was removed, the cells were washed three times with 1ml PBS and immediately imaged on a confocal laser scanning microscope at excitation wavelengths of 405nm (Hoechest) and 543nm (Cy 3). Untreated cells served as large negative controls. The imaging setup remained the same for all samples. (the results are shown in FIGS. 4-6)
The results show that: DMEM as a large negative control without any uptake; free DNA is essentially unable to enter the cell; the beta-cyclodextrin-based DNA molecule nanoparticles and supramolecular DNA molecule nanoparticles can enter cells for cellular imaging.
The degree of uptake by cells increased with increasing incubation time for E33, E33-Ada-aptamer.
The above is not relevant and is applicable to the prior art.
While certain specific embodiments of the present invention have been described in detail by way of illustration, it will be understood by those skilled in the art that the foregoing is illustrative only and is not limiting of the scope of the invention, as various modifications or additions may be made to the specific embodiments described and substituted in a similar manner by those skilled in the art without departing from the scope of the invention as defined in the appending claims. It should be understood by those skilled in the art that any modifications, equivalents, improvements and the like made to the above embodiments in accordance with the technical spirit of the present invention are included in the scope of the present invention.
Claims (8)
1. A method for synthesizing supermolecule biomolecule nano-particles is characterized in that: the method comprises the following steps:
s1: carrying out a copper-catalysis-free click chemistry method, and reacting azide-modified beta-cyclodextrin with DNA of DBCO modified at the 3' end to obtain a main body homogeneous beta-cyclodextrin-based DNA molecular nano particle;
s2: mixing the amino modified aptamer and adamantane containing hydrochloride, and placing the mixture on a shaking table for reaction to obtain the adamantane with functionalized guest aptamer;
s3: mixing host homogeneous beta-cyclodextrin-based DNA molecule nanoparticles with adamantane functionalized by a guest aptamer at room temperature, and oscillating and uniformly mixing to obtain supramolecular biomolecule nanoparticles;
wherein, the steps S1 and S2 are not in sequence.
2. The method for the synthesis of supramolecular biomolecular nanoparticles, as claimed in claim 1, wherein: the nucleic acid aptamer includes, but is not limited to, AS 1411.
3. The method for the synthesis of supramolecular biomolecular nanoparticles, as claimed in claim 1, wherein: in the step S1, azide-modified beta-cyclodextrin with the molar ratio of 1:10.5 and DNA of 3' -end-modified DBCO react for 5 hours at the temperature of 25 ℃ and the shaking speed of a shaking table of 1000rpm to obtain the homogeneous beta-cyclodextrin-based DNA molecular nanoparticles.
4. The method for the synthesis of supramolecular biomolecular nanoparticles, as claimed in claim 1, wherein: and step S1, separating the product by using high performance liquid chromatography, and finally determining the synthesis of the homogeneous beta-cyclodextrin-based DNA molecule nano-particles by mass spectrometry.
5. The method for the synthesis of supramolecular biomolecular nanoparticles, as claimed in claim 1, wherein: in step S2, the product is separated by high performance liquid chromatography, and finally the guest aptamer-functionalized adamantane is determined by mass spectrometry.
6. The method for the synthesis of supramolecular biomolecular nanoparticles, as claimed in claim 1, wherein: in step S3, the molar ratio of the homogeneous β -cyclodextrin-based DNA molecule nanoparticles to the aptamer-functionalized adamantane was 1: 1.
7. Supramolecular biomolecular nanoparticles synthesized by the method for synthesizing supramolecular biomolecular nanoparticles as claimed in any one of claims 1 to 6.
8. The supramolecular biomolecular nanoparticle of claim 7 is used in cellular imaging.
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| CN113281320A (en) * | 2021-06-07 | 2021-08-20 | 江南大学 | Method for detecting aflatoxin B1 based on fluorescent copper nanoparticles |
| CN114773418A (en) * | 2022-03-29 | 2022-07-22 | 国家纳米科学中心 | Aptamer cluster modified nano structure and preparation method and application thereof |
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