CN108635588B - Drug small molecule modified noble metal nano particle and preparation method and application thereof - Google Patents

Drug small molecule modified noble metal nano particle and preparation method and application thereof Download PDF

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CN108635588B
CN108635588B CN201810425895.1A CN201810425895A CN108635588B CN 108635588 B CN108635588 B CN 108635588B CN 201810425895 A CN201810425895 A CN 201810425895A CN 108635588 B CN108635588 B CN 108635588B
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drug
noble metal
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small molecule
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CN108635588A (en
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杨蓉
张雨飞
韩秋森
刘学良
王新环
王琛
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National Center for Nanosccience and Technology China
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6923—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B22—CASTING; POWDER METALLURGY
    • B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
    • B22F1/00—Metallic powder; Treatment of metallic powder, e.g. to facilitate working or to improve properties
    • B22F1/05—Metallic powder characterised by the size or surface area of the particles
    • B22F1/054—Nanosized particles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B22—CASTING; POWDER METALLURGY
    • B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
    • B22F9/00—Making metallic powder or suspensions thereof
    • B22F9/02—Making metallic powder or suspensions thereof using physical processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures

Abstract

The invention discloses a noble metal nano particle modified by drug micromolecules and a preparation method and application thereof, wherein the preparation method comprises the steps of placing a noble metal target material into a drug micromolecule solution, and ablating the noble metal target material by adopting pulse laser to prepare the drug micromolecule modified noble metal nano particle; the particle size of the prepared drug micromolecule modified noble metal nano particle is 2-10nm, and the modification amount of the drug micromolecule is 0.05-0.8 wt%; can be applied to the preparation of the medicine for treating or preventing neurodegenerative diseases Alzheimer's disease. The preparation method provided by the invention is simple to operate and quick in reaction, and the prepared precious metal nanoparticles modified by the drug micromolecules have the effect of remarkably inhibiting amyloid A beta aggregation, and have wide application prospects in research and development of drugs for treating Alzheimer's disease.

Description

Drug small molecule modified noble metal nano particle and preparation method and application thereof
Technical Field
The invention belongs to the technical field of nano materials, and relates to a precious metal nano particle modified by drug micromolecules, and a preparation method and application thereof.
Background
The noble metal nanoparticles are various in types and wide in sources, comprise gold nanoparticles, silver nanoparticles, platinum nanoparticles and the like, and have the advantages of stable performance, easiness in preparation and the like; in addition, some noble metal nanoparticles can pass through the blood brain barrier and are widely applied to the aspect of biomedicine. However, due to the limitation of poor biocompatibility, the noble metal nanoparticles have certain limitations in the application field of nano-drugs.
The small molecules of the medicine for inhibiting polypeptide aggregation comprise epigallocatechin gallate, pentagalloyl glucose, procyanidine B, baicalein, oleuropein and the like, can be extracted from plants, have rich sources and are easy to purify; however, due to the small molecular weight, in the field of neurodegenerative diseases caused by amyloid, the treatment effect of the small drug molecules is influenced to a certain extent due to the large action area of protein-protein interaction and the small action area between the small drug molecules and the target; on the other hand, the small drug molecules are not easy to pass through the blood brain barrier, so that the practical application of the small drug molecules is limited.
The combination of the small drug molecules and the noble metal nanoparticles can improve the biocompatibility of the noble metal nanoparticles and possibly improve the probability of the small drug molecules passing through the blood brain barrier, so that the advantages of the small drug molecules and the noble metal nanoparticles can exert a synergistic effect. Research shows that the noble metal nano-particle modified by the drug micromolecule has good application in the aspects of antibiosis, formation inhibition of biological membrane and polypeptide aggregation inhibition.
In the prior art, the preparation of the noble metal nanoparticles modified by drug small molecules usually adopts a chemical synthesis method, and has the defects of complex reaction, need of adding a surfactant, complex post-treatment of the prepared product and the like.
In conclusion, on the basis of the existing research, how to research and develop a preparation method of the precious metal nanoparticles modified by the drug micromolecules, which is green, pollution-free, simple and controllable in reaction, high in preparation efficiency, uniform in product size and good in dispersibility, has important theoretical and practical significance.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a precious metal nanoparticle modified by drug micromolecules and a preparation method and application thereof.
According to one aspect of the invention, the preparation method of the noble metal nanoparticles modified by the drug micromolecules comprises the steps of placing a noble metal target material in a drug micromolecule solution, and ablating the noble metal target material by adopting pulsed laser to prepare the noble metal nanoparticles modified by the drug micromolecules.
In the reaction process, the pulse laser ablates the noble metal target to form a plasma plume which contains atoms, molecules, ions and the like, the plasma plume is in a high-temperature, high-pressure and high-density state after absorbing laser energy to form cavitation bubbles, the temperature and the pressure in the plasma plume can be rapidly reduced from the peak value along with the attenuation of each pulse, the process can lead the cluster to reach the critical nucleation radius, then nucleation is carried out, the cavitation bubbles are broken due to the gradually reduced temperature and pressure, the nucleation sites enter the solvent after the cavitation bubbles are broken to react with the drug small molecules in situ, and the drug small molecule modified noble metal nanoparticles are further grown.
In the technical scheme, the preparation method further comprises the steps of stirring the drug micromolecule solution in a uniform state by adopting magnetic force in the pulse laser ablation process, and preparing the obtained drug micromolecule modified noble metal nanoparticles through dialysis and purification.
Further, in the above technical solution, the wavelength of the pulse laser is 266-1064nm, preferably 450-550 nm. Preferably, the wavelength range of the pulsed laser is in the visible range, safe to operate, and sufficient to facilitate the laser liquid phase ablation process to occur.
Preferably, in the above technical solution, the pulse frequency of the pulsed laser is 5 to 100 Hz. The lower the pulse frequency of the laser, the stronger the single pulse energy, and in order to obtain a higher pulse energy under the same conditions, the pulse laser frequency is preferably 10 to 20 Hz.
Preferably, in the above technical solution, the input voltage of the pulse laser is 500-600V, preferably 540-550V, and correspondingly, the pulse energy of the pulse laser is 10-400mJ, preferably 50-100 mJ. The preferred input voltage range may provide a corresponding preferred pulsed laser energy. The laser energy is preferably selected, so that the successful synthesis of the metal nanoparticles modified by the drug micromolecules with uniform particle size and good dispersibility can be ensured, and the property of the micromolecules can be ensured not to be damaged in the process of the laser liquid phase ablation reaction method.
Preferably, in the above technical solution, the focal length of the pulse laser is 5-25cm, preferably 17.5 cm. The preferred focal length of the pulsed laser reduces the energy loss of the pulsed laser due to transmission before reaching the target.
Further, in the above technical solution, the ablation time of the pulsed laser is 5-60min, preferably 8-12 min. The optimized laser ablation time can ensure that the properties of the drug micromolecules are not damaged on the basis of ensuring that the synthesized metal nanoparticles modified by the drug micromolecules have enough yield, and meanwhile, the metal nanoparticles modified by the drug micromolecules with better appearance can be obtained within the optimized time range.
Further, in the technical scheme, the concentration of the drug small molecule solution is 10-200 mug/mL, preferably 80-120 mug/mL. The optimal concentration of the small drug molecules can ensure the modification amount of the small drug molecules on the surfaces of the noble metal nanoparticles, and meanwhile, the small drug molecule modified noble metal nanoparticles with good dispersity and uniform particle size distribution can be formed by regulation.
Preferably, in the above technical solution, the solvent of the drug small molecule solution is one or more of water, ethanol, acetone, and DMSO, and is preferably water. The preferred solvent has no toxicity, better biocompatibility, low price and easy obtainment, and can be used in the field of biological medicine.
Still further, in the above technical solution, the noble metal is one or more of gold, silver, platinum, rhodium and iridium, and is preferably gold, silver and platinum. The preferred noble metals are stable in performance, more widely available and relatively less expensive than all noble metals.
Preferably, in the above technical scheme, the drug small molecule is one or more of epigallocatechin gallate, pentagalloylglucose, procyanidin B, baicalein and oleuropein, preferably epigallocatechin gallate and/or oleuropein. The preferable drug small molecules are soluble in water or ethanol, and also soluble in organic solvents, and have wide sources and easy extraction.
Further, in the above technical solution, the rotation speed of the magnetic stirring is 200-1750rpm, preferably 1500 rpm. The preferred magnetic stirring speed maximizes the homogeneous solution obtained during the reaction.
According to another aspect of the invention, the precious metal nanoparticles modified by the drug micromolecules obtained by the preparation method are provided.
Specifically, the particle size of the nano particles is 2-10nm, and the modification amount of the drug micromolecules is 0.05-0.8 wt%. The nano particles in the particle size range have small size effect and quantum tunneling effect, have excellent solubility and biocompatibility, have the possibility of passing through a blood brain barrier, and can be widely applied to the field of biomedicine. The modification amount range can effectively link the properties of the drug small molecules and the properties of the noble metal nanoparticles together, so that the drug small molecules and the noble metal nanoparticles have synergistic effect.
According to another aspect of the present invention, there is provided an application of the above-mentioned preparation method or the above-mentioned noble metal nanoparticle modified by a small drug molecule in the preparation of a drug for treating or preventing neurodegenerative diseases.
In particular, the disease is alzheimer's disease. Misfolding of a β 42 is one of the causes of alzheimer's disease. The noble metal nanoparticles are combined with the drug small molecules, so that the biocompatibility of the noble metal nanoparticles is improved, the targeting property of the noble metal nanoparticles is enhanced, the action area of the drug molecules and the Abeta 42 is increased, the drug small molecules and the nanoparticles have the effect of synergistically inhibiting the aggregation of the Abeta 42, and the application prospect in the treatment and prevention of the Alzheimer's disease is good.
The invention has the advantages that:
(1) the noble metal target material is ablated in the drug micromolecule solution by adopting a laser liquid phase ablation method to prepare the drug micromolecule modified noble metal nanoparticles, the operation is simple, the reaction is rapid, and the drug micromolecules can be modified on the surfaces of the noble metal nanoparticles in situ without post-treatment;
(2) the prepared precious metal nanoparticles modified by the drug micromolecules have good dispersibility, single particle size distribution, stable performance and good biocompatibility, combines the advantages of the drug micromolecules and the precious metal nanoparticles, and has good application prospect in the aspect of inhibiting biomedicine;
(3) the noble metal nanoparticles modified by the drug micromolecules prepared by the laser liquid phase method improve the biocompatibility and the targeting property of the noble metal nanoparticles, increase the interaction area between the drug molecules and the polypeptide, and are beneficial to improving the probability of the drug micromolecules passing through the blood brain barrier, so that the drug micromolecules can effectively inhibit the aggregation of amyloid protein, and have good application prospect in the research and development of drugs for treating neurodegenerative diseases such as Alzheimer's disease and the like.
Drawings
FIG. 1 is a TEM image of epigallocatechin gallate modified gold nanoparticles prepared in example 1 of the present invention;
FIG. 2 shows the results of UV-VIS (a) and Fourier transform IR (b) tests on EGCG-modified gold nanoparticles prepared in example 1;
FIG. 3 is a TEM image of EGCG-modified silver nanoparticles prepared in example 2 of the present invention;
FIG. 4 is a TEM image of epigallocatechin gallate modified platinum nanoparticles prepared in example 3 of the present invention;
FIG. 5 is a TEM image of oleuropein-modified gold nanoparticles prepared in example 4 of the present invention;
FIG. 6 is a TEM image of EGCG-modified gold nanoparticles prepared under different pulsed laser energies according to example 5 of the present invention;
FIG. 7 is a TEM image of epigallocatechin gallate modified gold nanoparticles prepared by different pulse laser ablation times prepared in example 6 of the present invention;
FIG. 8 is a TEM image of epigallocatechin gallate modified gold nanoparticles prepared in example 7 according to the present invention at different epigallocatechin gallate concentrations;
FIG. 9 is the thioflavin T fluorescence curve of the gold nanoparticles modified by epigallocatechin gallate prepared in example 1 of the present invention acting on amyloid A beta;
FIG. 10 is a TEM image of the gold nanoparticles modified with epigallocatechin gallate prepared in example 1 of the present invention after acting on amyloid Abeta 42.
Detailed Description
The following detailed description of embodiments of the present invention is provided in connection with the accompanying drawings and examples. The following examples are intended to illustrate the present invention, but not to limit the scope of the invention, which is defined by the claims.
Unless otherwise specified, experimental reagents and materials used in the examples of the present invention are commercially available, and unless otherwise specified, technical means used in the examples of the present invention are conventional means well known to those skilled in the art.
Example 1
The embodiment of the invention provides a precious metal nanoparticle modified by drug micromolecules, and the specific preparation method comprises the following steps: placing the noble metal target material in 7mL of 100 μ g/mL epigallocatechin gallate aqueous solution, ablating the gold target material for 10min under the energy of 100mJ by using laser with the focal length of 17.5cm, obtaining uniform solution by adopting magnetic stirring at 1500rpm, and dialyzing the obtained solution for 48 h.
FIG. 1 is a TEM image of epigallocatechin gallate modified gold nanoparticles prepared in example 1 of the present invention.
As can be seen from the results in FIG. 1, the prepared epigallocatechin gallate modified gold nanoparticles have single particle size distribution and good dispersibility, and the particle size is about 2.78 +/-0.51 nm.
In addition, the ultraviolet-visible absorption spectrum of the obtained precious metal nanoparticles modified by the drug micromolecules is detected according to the following method: 400 mu L of gold nanoparticle solution modified by epigallocatechin gallate, gold nanoparticle solution and epigallocatechin gallate aqueous solution are respectively contained in a standard cuvette, and an ultraviolet spectrophotometer is used for testing the absorptivity of the sample in the range of 200-900nm, so as to obtain the ultraviolet-visible absorption spectrum of the sample.
Fig. 2a shows the uv-vis absorption spectrum result of the gold nanoparticle modified with epigallocatechin gallate prepared in example 1 of the present invention.
As can be seen from the results in FIG. 2a, the gold nanoparticles modified by epigallocatechin gallate have three distinct absorption peaks at 214nm, 262nm and 532 nm. The absorption peaks at 214nm and 262nm correspond to the absorption peaks at 226nm and 273nm of epigallocatechin gallate; the absorption peak at 532nm corresponds to the absorption peak at 530nm of the gold nanoparticles, and the results show that the epigallocatechin gallate is modified on the gold nanoparticles.
Meanwhile, the Fourier transform infrared spectrum of the obtained precious metal nanoparticles modified by the drug micromolecules is detected according to the following method: respectively dripping a certain volume of gold nanoparticle solution modified by epigallocatechin gallate and epigallocatechin gallate aqueous solution to CaF2On the chip, after drying, the sample is tested to 4000cm by using a Fourier transform infrared spectrometer-1-500cm-1Transmittance in the range, resulting in a fourier transform infrared spectrum of the sample.
FIG. 2b shows the Fourier transform infrared spectrum of the gold nanoparticles modified by epigallocatechin gallate prepared in example 1 of the present invention.
As can be seen from the results in FIG. 2b, the tableThe infrared spectrogram of the gold nanoparticles modified by the gallocatechin gallate has a plurality of absorption peaks: 3633cm-1Has a peak of vO-HStretching vibration of 1697cm-1Has a peak of vC＝O1452cm-1The peak is nu on benzene ringC＝C1229cm of telescopic vibration-1、1148cm-1And 1066cm-1Has a peak of v＝C-O-CThe asymmetric stretching vibration of the gold nanoparticles corresponds to an infrared peak of the epigallocatechin gallate, which indicates that the epigallocatechin gallate is successfully modified on the gold nanoparticles.
The results of the combined graphs 2a and 2b show that the epigallocatechin gallate obtained in the example 1 of the invention is modified on the surface of the gold nanoparticles.
Example 2
Embodiment 2 of the present invention provides a precious metal nanoparticle modified by a small drug molecule, which differs from embodiment 1 only in that: the noble metal target used was silver, and the laser energy was 50 mJ.
Fig. 3 is a TEM image of the silver nanoparticle modified with epigallocatechin gallate prepared in example 2 of the present invention. As can be seen from the figure, the obtained nanoparticles have relatively uniform size distribution, about 9.24 +/-2.91 nm, and have larger particle size compared with the gold nanoparticles modified by epigallocatechin gallate.
The ultraviolet-absorption spectrum and infrared spectrum of the product obtained in example 2 of the present invention were evaluated in the same manner as in example 1 of the present invention. As a result, it was found that epigallocatechin gallate was modified on the silver nanoparticles.
Example 3
Embodiment 3 of the present invention provides a precious metal nanoparticle modified by a small drug molecule, which differs from embodiment 1 only in that: the noble metal target used is platinum.
FIG. 4 is a TEM image of epigallocatechin gallate modified platinum nanoparticles prepared in example 3 of the present invention. As can be seen from the figure, the obtained nanoparticles have relatively uniform size distribution, about 1.69 +/-0.42 nm, and the particle size is smaller than that of the gold nanoparticles modified by epigallocatechin gallate.
The ultraviolet-absorption spectrum and infrared spectrum of the product obtained in example 3 of the present invention were evaluated in the same manner as in example 1 of the present invention. As a result, it was found that epigallocatechin gallate was modified on the platinum nanoparticles.
Example 4
Embodiment 4 of the present invention provides a precious metal nanoparticle modified by a small drug molecule, which differs from embodiment 1 only in that: the small molecule used is oleuropein, and the laser energy is 50 mJ.
FIG. 5 is a TEM image of oleuropein-modified gold nanoparticles prepared in example 4 of the present invention. As can be seen from the figure, the obtained nanoparticles have relatively uniform size distribution, about 5.34 +/-1.21 nm, and have larger particle size compared with the gold nanoparticles modified by epigallocatechin gallate.
The ultraviolet-absorption spectrum and infrared spectrum of the product obtained in example 4 of the present invention were evaluated in the same manner as in example 1 of the present invention. From the results, oleuropein was modified on the gold nanoparticles.
Example 5
Embodiment 5 of the present invention provides a method for preparing a drug small molecule modified noble metal nanoparticle by using pulsed lasers with different pulse energies, and compared with embodiment 1, the method is different only in that: the pulse energy of the pulse laser is 10mJ, 50mJ, 80mJ and 100mJ respectively.
FIG. 6 is a TEM image of epigallocatechin gallate modified gold nanoparticles prepared in example 5 of the present invention.
As can be seen from the figure, the size of the nanoparticles decreased with the increase of the laser energy, and the particle size distribution of the product tended to be uniform and the dispersibility was better when the pulse energy was 50-100 mJ.
Example 6
Embodiment 6 of the present invention provides a noble metal nanoparticle modified by a drug small molecule prepared by using different ablation times, and compared with embodiment 1, the difference is only that: the ablation time of the pulse laser is respectively 5min, 10min, 20min and 30 min.
FIG. 7 is a TEM image of epigallocatechin gallate modified gold nanoparticles prepared in example 6 of the present invention.
As can be seen from the figure, when the ablation time is 5min, the particle size distribution of the prepared gold nanoparticles modified by the drug micromolecules is not uniform, and nanoparticles with larger particle sizes exist; when the ablation time is increased to 10min, the particle size distribution tends to be uniform; as the ablation time is further increased to 20-30min, the dispersibility and the particle size uniformity of the obtained product are always better, and the particle size of the product is increased along with the increase of the burning time.
Example 7
Embodiment 7 of the present invention provides a noble metal nanoparticle modified with small drug molecules, which is prepared from small drug molecule solutions with different concentrations, and compared with embodiment 1, the differences are only that: the concentrations of epigallocatechin gallate solutions were 10. mu.g/mL, 50. mu.g/mL, 100. mu.g/mL and 200. mu.g/mL, respectively.
FIG. 8 is a TEM image of epigallocatechin gallate modified gold nanoparticles prepared in example 7 of the present invention.
As can be seen from the figure, the particle size of the gold nanoparticles modified with epigallocatechin gallate decreased with the increase of the concentration of epigallocatechin gallate; when the concentration of the epigallocatechin gallate is lower (10 mu g/mL-50 mu g/mL), nanoparticles with larger particle sizes exist, the epigallocatechin gallate is not enough to completely coat the gold nanoparticles, and the morphology of the gold nanoparticles cannot be well regulated; when the concentration of the epigallocatechin gallate is 100 mu g/mL, the epigallocatechin gallate can regulate the morphology of the gold nanoparticles to form the gold nanoparticles modified by the epigallocatechin gallate with good dispersibility and uniform particle size distribution; when the concentration of epigallocatechin gallate is further increased, nanoparticles with good dispersibility and uniform particle size distribution can still be obtained.
Test example 1
The test example of the invention provides application of precious metal nanoparticles modified by drug small molecules in inhibiting amyloid A beta aggregation. The specific operation method comprises the following steps: the gold nanoparticles modified by epigallocatechin gallate prepared in the embodiment 1 of the invention with a certain volume of 15 mug/mL are mixed with Abeta 42, the final volume is 20 muL, then the mixture is mixed with 10 muM and 180 muL of thioflavin T, and the emission peak intensity at 485nm under the excitation of light with the wavelength of 450nm within 0-48h is measured. Diluting 10 mu L of mixed solution of gold nanoparticles modified by epigallocatechin gallate and Abeta 42 for 7 days by three times, then dripping the diluted solution onto a TEM copper mesh, dyeing by using phosphotungstic acid, and observing the appearance of Abeta 42 under the influence of the noble metal nanoparticles modified by epigallocatechin gallate by using TEM.
FIG. 9 is the thioflavin T fluorescence spectrum of A β 42 under the action of the gold nanoparticles modified by epigallocatechin gallate prepared in example 1 of the present invention.
The aggregation kinetic curve shows that the aggregation capability of Abeta 42 is obviously inhibited after the gold nanoparticles modified by the epigallocatechin gallate are added.
Fig. 10 is a TEM image of a β 42 morphology after gold nanoparticles were reacted with epigallocatechin gallate modified gold nanoparticles prepared in example 1 of the present invention.
The aggregation morphology shows that Abeta 42 can be aggregated to form a net structure (figure 10a), the fiber forming capability is inhibited after the gold nanoparticles are added (figure 10b), the fiber forming capability is obviously inhibited after the gold nanoparticles modified by epigallocatechin gallate are added, and the net-shaped fiber structure is changed into a short, spot-shaped or amorphous polypeptide structure (figure 10 c).
Finally, while the invention has been described in detail by way of general description and specific embodiments, it will be apparent to those skilled in the art that certain changes and modifications may be made thereto without departing from the scope of the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.

Claims (15)

1. A preparation method of noble metal nanoparticles modified by drug micromolecules is characterized by comprising the steps of placing a noble metal target material in a drug micromolecule solution, and ablating the noble metal target material by adopting pulsed laser to prepare the noble metal nanoparticles modified by the drug micromolecules;
wherein the pulse frequency of the pulse laser is 5-100Hz, the pulse energy of the pulse laser is 50-100mJ, the wavelength of the pulse laser is 450-550nm, the ablation time of the pulse laser is 8-12min, and the concentration of the drug micromolecule solution is 80-120 mu g/mL.
2. The preparation method according to claim 1, further comprising assisting the drug small molecule solution in a uniform state by magnetic stirring during the pulsed laser ablation, and purifying the obtained drug small molecule-modified noble metal nanoparticles by dialysis.
3. The production method according to claim 1 or 2, wherein the pulse frequency of the pulsed laser is 10 to 20 Hz;
and/or the input voltage of the pulse laser is 500-600V;
and/or the focal length of the pulse laser is 5-25 cm.
4. The method as claimed in claim 3, wherein the input voltage of the pulsed laser is 540-550V.
5. The method of claim 3, wherein the pulsed laser has a focal length of 17.5 cm.
6. The preparation method according to claim 1 or 2, wherein the solvent of the drug small molecule solution is one or more of water, ethanol, acetone and DMSO.
7. The preparation method according to claim 6, wherein the solvent of the drug small molecule solution is water.
8. The production method according to claim 1 or 2, wherein the noble metal is one or more of gold, silver, platinum, rhodium, and iridium;
and/or the drug small molecule is one or more of epigallocatechin gallate, pentagalloyl glucose, procyanidine B, baicalein and oleuropein.
9. The preparation method of claim 8, wherein the small drug molecules are epigallocatechin gallate and/or oleuropein.
10. The method as claimed in claim 2, wherein the magnetic stirring is performed at a rotation speed of 200-1750 rpm.
11. The method of claim 10, wherein the magnetic stirring is performed at 1500 rpm.
12. A pharmaceutical small molecule modified noble metal nanoparticle obtained by the method of any one of claims 1 to 11.
13. The drug small-molecule modified noble metal nanoparticle of claim 12, wherein the particle size of the nanoparticle is 2-10nm, and the modification amount of the drug small molecule is 0.05-0.8 wt%.
14. Use of the noble metal nanoparticles prepared by the preparation method of any one of claims 1-11 or modified by the drug small molecules of claim 12 or 13 in the preparation of a drug for treating or preventing neurodegenerative diseases.
15. The use according to claim 14, wherein the disease is alzheimer's disease.
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