CN113797356A - Carbon nano composite biological preparation, preparation method and application - Google Patents
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- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
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- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/13—Tumour cells, irrespective of tissue of origin
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/38—Albumins
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- A61K38/385—Serum albumin
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/52—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
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Abstract
The invention relates to the field of nano materials and biomedicine, in particular to a carbon nano composite biological agent and a preparation method and application thereof, wherein the carbon nano composite biological agent comprises carbon nano particles, the surfaces of the carbon nano particles comprise a plurality of functional groups, and the functional groups are one or more of hydroxyl, carboxyl, sulfydryl or amino; by the thermal complexing action, the surface of the carbon nano particle is wound with a composite biological material, and the functional group on the surface of the carbon nano particle is a binding site of the carbon nano particle and the biological material; the biological material comprises one or more of a biological macromolecule, a cell or cell debris, a bacterium or bacterial debris, a virus or virus debris. The coating of the biological material on the surfaces of the carbon nano particles can stably coat the biological material on the surfaces of the carbon nano particles. Greatly improves the luminescence property of the carbon nano-particle, improves the immunogenicity of the biological material coated on the surface of the carbon nano-particle, further has better immune activation characteristic, and can be applied to the diagnosis and treatment of cancers.
Description
Technical Field
The invention relates to the field of nano materials and biomedicine, in particular to a carbon nano composite biological agent, a preparation method and application thereof.
Technical Field
Carbon Nanoparticles (CNPs) are spheroidal, prismoid, or other irregularly shaped Carbon-based nanoparticles having three dimensions less than 100 nm. CNPs have the characteristics of good fluorescence characteristic, no toxicity, good biocompatibility, easy absorption and discharge by organisms and the like. CNPs as nano-materials have great application prospects in the biomedical field.
Pure carbon nanoparticles are easy to aggregate in an aqueous solvent, so that potential risks exist in application in organisms, and the application of the pure carbon nanoparticles in the biomedical fields such as drug carriers, imaging reagents, tumor immune activation and the like is limited.
Disclosure of Invention
The invention aims to overcome the technical problems that carbon nano particles are easy to agglomerate in an aqueous solvent, a stable carbon nano composite biological material cannot be obtained, the application in the field of biomedicine is limited and the like in the prior art, and provides a carbon nano composite biological preparation.
Another object of the present invention is to provide a method for preparing a carbon nanocomposite biological agent.
Another object of the present invention is to provide an application of the carbon nanocomposite biological agent.
The purpose of the invention is realized by the following technical scheme:
a carbon nano composite biological agent comprises carbon nano particles, wherein the surface of each carbon nano particle comprises a plurality of functional groups, and each functional group is one or more of hydroxyl, carboxyl, sulfydryl or amino; by the thermal complexing effect, the surface of the carbon nano particle is wound with a composite biological material, and the functional group on the surface of the carbon nano particle is a binding site of the carbon nano particle and the biological material; the biological material comprises one or more of a biological macromolecule, a cell or cell debris, a bacterium or bacterial debris, a virus or virus debris.
Mixing the carbon nano-particles and the biological material, and under the action of external energy, enabling one or more groups of hydroxyl, sulfydryl, carboxyl and amino on the surfaces of the carbon nano-particles to interact with the biological material through a thermal process, so that the biological material is wound on the surfaces of the carbon nano-particles. Biological materials mainly include biological macromolecules, cells or cell debris, bacteria or bacteria debris, viruses or virus debris. The interaction between the biomacromolecule and the functional group on the surface of the carbon nano particle leads the biomacromolecule to be wound on the surface of the carbon nano particle under the thermal process. The surfaces of cells, bacteria and viruses contain abundant substances such as proteins, so the cells, the bacteria, the viruses and fragments thereof can be compounded with the carbon nanoparticles through biological macromolecules such as proteins on the surfaces. The biological material is compounded on the surface of the carbon nano-particles, so that the dispersibility of the carbon nano-particles in an aqueous solution is improved, the carbon nano-particles are prevented from agglomerating in the water, a stable carbon nano-composite biological material is formed, the immunogenicity of the biological material coated on the surfaces of the carbon nano-particles is improved, the biological material has better immune activation characteristics, and the effectiveness of the application of the carbon nano-composite biological material in the fields of tumor immune activation, drug carriers, biological imaging agents and the like is improved.
Preferably, the biomacromolecule comprises one or more of a protein, polypeptide, nucleic acid, polynucleotide, carbohydrate, dextran, polysaccharide or lipid.
Preferably, the cells or cell fragments are cancer cells or cancer cell fragments.
A preparation method of the carbon nano composite biological agent comprises the following steps:
s1, preparing carbon nano particles;
s2, mixing the carbon nanoparticles obtained in the step S1 with the biological material according to the mass ratio of 1 (0.1-10000), reacting for 2-30 min at the temperature of 25-100 ℃, and purifying to obtain the nano-carbon particles.
The preparation of the carbon nanoparticles in the step S1 specifically comprises: mixing citric acid and urea, dissolving in dimethyl sulfoxide or dimethylformamide, placing in a high-pressure reaction kettle, heating and reacting for 2-10 h at 110-220 ℃, and then centrifugally cleaning the obtained carbon nanoparticles by using methanol or ethanol, wherein the centrifugal rotation speed is preferably 6000-10000 rpm.
Or the preparation of the carbon nano-particles is specifically as follows: mixing citric acid and disperse blue-1 in deionized water or ultrapure water, placing the mixture into a high-pressure reaction kettle, heating and reacting for 2-10 hours at the temperature of 110-220 ℃, and then carrying out centrifugal cleaning on the obtained carbon nanoparticles by using methanol or ethanol, wherein the centrifugal rotation speed is preferably 6000-10000 rpm.
Of course, the nanoparticles of the present invention are not limited to the above-described method.
The heating method used in step S2 includes one of heat conduction, heat radiation, photo-heat, magneto-heat, or microwave heating.
The carbon nano composite biological agent is applied as a biological imaging agent.
The carbon nano composite biological preparation is applied as a drug carrier.
The carbon nano composite biological agent is applied as a tumor immunity medicine.
Compared with the prior art, the invention has the following technical effects:
the biological composite preparation of the carbon nano particles, provided by the invention, is prepared by the following steps that the biological material reacts with active groups (one or more of hydroxyl, sulfydryl, carboxyl and amino) on the surfaces of the carbon nano particles, and the active groups are wound on the surfaces of the carbon nano particles under the action of heat generated by external energy, so that the biological composite preparation of the carbon nano particles and the biological material is formed. The coating of the biological material on the surfaces of the carbon nano particles can effectively improve the dispersibility of the carbon nano particles in the aqueous solution and prevent the carbon nano particles from agglomerating in the water. The method has the effects of greatly improving the luminous intensity and luminous stability of the carbon nanoparticles, improving the immunogenicity of the biological material coated on the surfaces of the carbon nanoparticles, further having better immune activation characteristic, and improving the application of the carbon nano composite biological material in the fields of tumor immune activation, drug carriers, biological imaging agents and the like.
Drawings
FIG. 1 shows fluorescence spectra of carbon nanoparticles and bovine serum albumin complex;
FIG. 2 shows absorption spectra of carbon nanoparticles and their mixtures with biological compounds before and after dialysis;
FIG. 3 shows fluorescence spectra of carbon nanoparticles and bovine serum albumin complex formulations thereof at different reaction temperatures;
FIG. 4 shows absorption spectra of carbon nanoparticles and their dialyzed bovine serum albumin complex preparations at different reaction temperatures;
FIG. 5 shows the change of the absorption spectrum of the carbon nanoparticles and the bovine serum albumin complex after the carbon nanoparticles and the bovine serum albumin complex are stored at room temperature for 1 month;
FIG. 6 shows the change of fluorescence spectrum of the carbon nanoparticles and the bovine serum albumin complex after the carbon nanoparticles and the bovine serum albumin complex are stored at room temperature for 1 month;
FIG. 7 is a fluorescence spectrum of carbon nanoparticles and their complex preparations with cells;
FIG. 8 is an absorption spectrum of carbon nanoparticles and their complex preparations with cells;
FIG. 9 shows absorption spectra of carbon nanoparticles and their complex preparations with cells before and after dialysis at different reaction temperatures;
FIG. 10 tumor growth curves of tumor immune activator-injected mice and control mice;
FIG. 11 is a schematic structural diagram of the interaction between the carbon nanoparticles of the present invention and biomaterials (a-hydroxy, b-carboxy, c-mercapto, d-amino; 1-biomaterial, 2-carbon nanoparticles).
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below with reference to specific examples and comparative examples. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the examples given herein without any inventive step, are within the scope of the present invention.
Unless otherwise specified, the devices used in this example are all conventional experimental devices, the materials and reagents used are commercially available, and the experimental method without specific description is also a conventional experimental method.
Example 1
Dissolving citric acid and urea in a DMSO solvent according to a mass ratio of 1:3 to obtain a transparent solution, placing the transparent solution in a 50ml polytetrafluoroethylene high-pressure reaction kettle, reacting for 4 hours at 160 ℃, adding a large amount of ethanol into the solution after reaction, washing to obtain a black solid, washing the solid with water, centrifuging (8000rpm, 5min), and drying to obtain dark blue powder. The diameter of the obtained carbon nano-particles is measured to be 3-10 nm. The mass ratios of C, N, O, S elements of the carbon nanoparticles were 50.1%, 29.3%, 19.1%, and 1.5%, respectively.
Dissolving the obtained carbon nanoparticles in deionized water, preparing a solution with the concentration of (0.1-1.5) mg/mL, mixing the carbon nanoparticles and the bovine serum albumin according to the mass ratio of 1:10, heating to 25-100 ℃ by adopting heating modes such as illumination heating, hot plate heating, water bath (oil bath) heating, oven heating or ultrasonic heating, reacting for 2-30 min, and stirring at the rotating speed of 40-250 rpm. Thus obtaining the bovine serum albumin (CQD-BSA) composite preparation of the carbon nano particles.
Example 2
Dissolving citric acid and disperse blue-1 in water (or ultrapure water, PBS buffer solution, etc.) according to a mass ratio of 1:3 to obtain a transparent solution, placing the transparent solution in a 50ml polytetrafluoroethylene high-pressure reaction kettle, and reacting for 3 hours at 200 ℃. Adding a large amount of ethanol into the reacted solution to obtain black solid, washing the solid with water, centrifuging (8000rpm, 5min), and drying to obtain dark blue powder.
Dissolving the carbon nanoparticles in deionized water to prepare a solution with a concentration of (0.1-1.2) mg/mL, and adding 1x10 to each milliliter of the solution4～1x10104T1 breast cancer cells. Heating to 25-100 ℃ by adopting heating modes such as illumination heating, hot plate heating, water bath (oil bath) heating, oven heating or ultrasonic heating, reacting for 2-30 min, and stirring at the rotating speed of 40-500 rpm. Obtaining the carbon nano particle breast cancer cell (CQD-cell) composite preparation.
Example 3
Carbon nanoparticles were prepared as in example 1.
Dissolving the obtained carbon nanoparticles in deionized water, preparing a solution with the concentration of (0.1-1.5) mg/mL, mixing the carbon nanoparticles and the lactobacillus according to the mass ratio of 1.0:10, heating to 25-100 ℃ by adopting heating modes such as illumination heating, hot plate heating, water bath (oil bath) heating, oven heating or ultrasonic heating, reacting for 2-30 min, and stirring at the rotating speed of 40-250 rpm. Thus obtaining the lactobacillus composite preparation of carbon nano particles.
Example 4
Carbon nanoparticles were prepared as in example 1.
Dissolving the obtained carbon nanoparticles in deionized water to prepare a solution with the concentration of (0.1-1.5) mg/mL, mixing the carbon nanoparticles and African Swine Fever Virus (ASFV) according to the mass ratio of 1.0:10, heating to 25-100 ℃ by adopting heating modes such as illumination heating, hot plate heating, water bath (oil bath) heating, oven heating or ultrasonic heating, reacting for 2-30 min, and stirring at the rotating speed of 40-250 rpm. Thus obtaining the African swine fever virus (CQD-ASFV) composite preparation of the carbon nano particles.
Experimental example 1
The fluorescence of the carbon nanoparticles (CQD) obtained in the examples and bovine serum albumin (CQD-BSA) complex preparations of the obtained carbon nanoparticles was measured, and the results are shown in fig. 1. The CQD-BSA obtained after the compounding increases the dispersibility of the carbon nano particles, and particularly shows that the PL emission intensity is obviously enhanced.
Experimental example 2
The carbon nanoparticles (CQD) obtained in example 1 and bovine serum albumin (CQD-BSA) complex preparations of carbon nanoparticles were placed in dialysis bags, respectively, and dialyzed for 2 days. By measuring carbon nanodiamond before (CQD) and after dialysis (CQD diays); and absorption spectra of the carbon nanoparticle bovine serum albumin complex preparation before (CAD-BSA) and after (CQD-BSA diays) dialysis. As shown in fig. 2, the absorption of the dialyzed pure carbon nanoparticle solution was close to 0, and almost all of the solution was eluted. And the absorption spectrum line of the compound preparation is basically unchanged, which shows that the carbon nano particles and the bovine serum albumin are effectively compounded.
Experimental example 3
The carbon nanoparticles obtained in example 1 and bovine serum albumin were dissolved in deionized water at a mass ratio of 1:10, and the mixture was stirred and heated for 10min at reaction temperatures of 25 ℃, 40 ℃, 60 ℃, 80 ℃ and 90 ℃. Fluorescence tests were performed on CQD-BSA obtained at different reaction temperatures, and the results are shown in FIG. 3, where the fluorescence intensity of the complex formulation was significantly increased with increasing complexing temperature. The CQD-BSA obtained at different temperatures was dialyzed for 2 days, and the absorption spectra before and after dialysis were measured, and as a result, as shown in FIG. 4, the amount of carbon quantum particles dialyzed out gradually decreased with the increase of the composite temperature.
Experimental example 4
The carbon nanoparticles (CQD) obtained in example 1 and a bovine serum albumin (CQD-BSA) complex preparation of carbon nanoparticles were dispersed in an aqueous solution to prepare a solution of 1 mg/mL. The solution was stored at room temperature and left to stand for 30 days. The absorption spectra of CQD and CQD-BSA before and after standing were measured, and the results are shown in FIG. 5, after standing, the absorption peak near 600nm of the red wavelength band of the carbon nanodots disappeared, only the ultraviolet absorption peak near 350nm remained, while the absorption line of the composite preparation remained basically unchanged, which indicates that the structure of the pure carbon nanoparticles was changed after standing for 30 days, while the composite preparation was slightly affected. As a result of measuring fluorescence spectra of CQD and CQD-BSA before and after standing, pure carbon nanodots aggregated and the peak value of PL decreased after standing for a long period of time as shown in FIG. 6. The composite preparation is very stable and the spectrum is basically unchanged.
Experimental example 5
The fluorescence characteristics of the breast cancer (CQD-cell) complex formulation of the carbon nanoparticles and the carbon nanoparticles obtained in example 2 were observed by fluorescence spectroscopy, and the results are shown in fig. 7. After the compounding, the dispersibility of the carbon nano particles is increased, and the emission peak intensity is enhanced, and the blue shift of the emission peak position is accompanied. From the absorption spectra of CQD and CQD-cell, as shown in FIG. 8, it can be found that the absorption spectra of the carbon nanoparticles before and after the compounding are not substantially changed.
Experimental example 6
The carbon nanoparticles obtained in example 2 were combined with 4T1 breast cancer cells, and 1mL of the carbon nanoparticles having a mass concentration of 0.2mg/mL and the number of the carbon nanoparticles was 1X1064T1 cells (Takara Shuzo), and stirringThe reaction temperature is set to be 25 ℃, 40 ℃, 70 ℃ and 90 ℃ respectively for 10 min. The change of absorption spectra of the complex preparation before and after dialysis proves the complex stability of the carbon nanoparticles and the 4T1 cells under the applied energy, and the result is shown in FIG. 9. From fig. 9, it is found that as the recombination temperature increases, the dialyzed carbon nanoparticles gradually decrease, the absorption intensity gradually increases, and the shape of the absorption spectrum curve remains substantially unchanged.
Experimental example 7
A certain amount of the CQD-cell preparation compounded at 80 ℃ in Experimental example 6 was injected into mice bearing 4T1 breast cancer tumor. Preferably, the injection is metered to 200ul and the method of injection is one of intravenous injection, subcutaneous injection and ascites injection, preferably subcutaneous injection.
Tumor growth curves of the mice were measured, and the results are shown in fig. 10. Fig. 10 shows that the tumor growth of the experimental group a is significantly inhibited and cured, while the tumor of the control group b is gradually increased. The CQD-cell preparation is proved to effectively activate the tumor immune function of the mice, and inhibit and kill the tumors in the mice.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (8)
1. The carbon nano composite biological preparation is characterized by comprising carbon nano particles, wherein the surfaces of the carbon nano particles comprise a plurality of functional groups, and the functional groups are one or more of hydroxyl, carboxyl, sulfydryl or amino; by the thermal complexing effect, the surface of the carbon nano particle is wound with a composite biological material, and the functional group on the surface of the carbon nano particle is a binding site of the carbon nano particle and the biological material; the biological material comprises one or more of a biological macromolecule, a cell or cell debris, a bacterium or bacterial debris, a virus or virus debris.
2. The carbon nanocomposite biologic according to claim 1, wherein said biologic macromolecules comprise one or more of a protein, a polypeptide, a nucleic acid, a polynucleotide, a carbohydrate, a glucan, a polysaccharide, or a lipid.
3. The carbon nanocomposite biologic according to claim 1, wherein said cells or cell fragments comprise cancer cells or cancer cell fragments.
4. A method for preparing the carbon nanocomposite biologicals of any one of claims 1 to 3, comprising the steps of:
s1, preparing carbon nano particles;
s2, mixing the carbon nanoparticles obtained in the step S1 with the biological material according to the mass ratio of 1 (0.10-10000), reacting for 2-30 min at the temperature of 25-100 ℃, and purifying to obtain the nano-carbon particles.
5. The method for preparing a carbon nano composite biological agent according to claim 4, wherein the preparation of the carbon nano particles in the step S1 specifically comprises: citric acid and urea or disperse blue-1 are mixed according to the mass ratio of 1: (1-6) mixing and dissolving in a solvent, and reacting for 2-10 h under the condition of solvothermal reaction at 110-220 ℃.
6. Use of the carbon nanocomposite biologics of any one of claims 1 to 3 as bioimaging agents.
7. Use of the carbon nanocomposite biologics of any one of claims 1 to 3 as a pharmaceutical carrier.
8. Use of the carbon nanocomposite biologics of any one of claims 1 to 3 as tumor immune activators.
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