CN115581777A - Preparation method and application of AuNC @ ZIF-8 drug carrier - Google Patents
Preparation method and application of AuNC @ ZIF-8 drug carrier Download PDFInfo
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- CN115581777A CN115581777A CN202211274451.5A CN202211274451A CN115581777A CN 115581777 A CN115581777 A CN 115581777A CN 202211274451 A CN202211274451 A CN 202211274451A CN 115581777 A CN115581777 A CN 115581777A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 46
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- 239000003814 drug Substances 0.000 claims abstract description 68
- 108010024636 Glutathione Proteins 0.000 claims abstract description 43
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- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
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- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
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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
- A61K47/69—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
- A61K47/6949—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 inclusion complexes, e.g. clathrates, cavitates or fullerenes
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- 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
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- 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
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
- C08G83/008—Supramolecular polymers
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- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
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Abstract
The invention discloses a preparation method and application of an AuNC @ ZIF-8 drug carrier. The preparation method comprises the steps of synthesizing AuNCs with a certain particle size and structure through chloroauric acid and glutathione with a specific proportion and concentration, purifying, and then mixing with Zn (NO) with a specific volume 3 ) 2 Reacting with 2-methylimidazole, and preparing the AuNCs @ ZIF-8 medicament carrier by a one-step methodAnd (3) a body. The invention solves the problems that the existing photodegradation MOFs fluorescence quantum has low yield and slow light response, and can not track the release of the photo-triggered drugs in real time; and poor stability and certain cytotoxicity. The drug carrier prepared by the method has high fluorescence quantum yield, good stability and light response performance, simple preparation method and mild conditions; can be used for preparing photoresponse medicines and/or preparing cancer treatment medicines and medicine light imaging analysis.
Description
Technical Field
The invention belongs to the technical field of analytical chemistry, and particularly relates to a preparation method and application of an AuNC @ ZIF-8 drug carrier.
Background
In recent years, cancer has become one of the major diseases that endanger human health. In cancer therapy, there is increasing interest in designing diverse on-demand dosing regimens to minimize side effects and improve therapeutic efficacy. The nano-scale drug delivery system has great application potential in cancer treatment. Metal-organic frameworks (MOFs) are an ideal nano-carrier, and have attracted much attention because of their large surface area, high porosity, high loading capacity, multi-functionalization, and controllable release capability of stimuli-responsive drugs with various morphologies and chemical properties.
The photodegradable material can react to external light stimulation and has great advantage in controllable drug release. Currently, some studies on photodegradable MOFs have been reported. These studies can be divided into two categories: one is to utilize a ligand which can be cracked by light to react with coordination metal ions to generate photodegradable MOFs; another class is the use of photoresponsive materials that can generate MOFs degradation factors. The photodegradable MOFs have high fluorescence activity, high fluorescence quantum yield and high and low light response speed, and directly influence the timeliness of tracking the release of the light-triggered drugs in real time. Gold nanoclusters (AuNCs) are often applied to preparation of light control drugs or carriers due to unique optical properties, but the stability of the gold nanoclusters is poor, auNCs and zeolite imidazolate framework materials (ZIF-8) are respectively prepared and then combined to form a core-shell structure in the prior art, auNCs are located on the surface of ZIF-8 and are used for detecting specific metal ions, MOFs carrying anti-cancer drugs are synthesized in the prior art, and then the anti-cancer drugs are physically adsorbed, so that the stability of the AuNCs carrying anti-cancer drugs is poor, the drug combination is not stable enough, and the AuNCs have certain cytotoxicity. Therefore, there is a need to develop photodegradable MOFs with higher fluorescence activity and stability and safety.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a preparation method of an AuNC @ ZIF-8 drug carrier, the AuNC @ ZIF-8 drug carrier prepared by the method, and the application of the drug carrier in the preparation of photoresponse drugs and/or the preparation of cancer treatment drugs and the application of the drug carrier in the aspect of drug light imaging analysis.
In order to realize the purpose, the invention adopts the following technical scheme:
a preparation method of an AuNC @ ZIF-8 drug carrier comprises the following steps:
s1, synthesizing AuNCs: preparing chloroauric acid and glutathione into a mixed solution and reacting to obtain an AuNCs aqueous solution A, wherein the mass concentration of the chloroauric acid is not lower than 0.5mg/mL, and the mass concentration of the glutathione is not lower than 0.5mg/mL; trapping the component with the molecular weight of more than 1kDa in the AuNCs aqueous solution A, wherein the component is purified AuNCs;
s2, synthesizing AuNCs @ ZIF-8: separately preparing Zn 2+ And (2) mixing the zinc nitrate solution with the substance amount concentration of 60-100 mmol/L and the 2-methylimidazole solution with the 2-methylimidazole substance amount concentration of 1.5-2.5 mol/L with the AuNCs purified in the step S1 to obtain a mixed solution B, carrying out ultrasonic treatment on the mixed solution B, then centrifuging, washing and centrifuging to obtain a precipitate, namely the AuNCs @ ZIF-8 drug carrier.
The preparation method of the drug carrier comprises the steps of firstly synthesizing AuNCs with specific particle size and structure by chloroauric acid and glutathione with specific proportion and concentration, purifying the AuNCs, and then mixing the AuNCs with Zn (NO) with a certain volume 3 ) 2 And 2-methylimidazole reaction, the AuNCs @ ZIF-8 is prepared by a one-step method, the AuNCs @ ZIF-8 and the ZIF-8 are not prepared respectively, the prepared AuNCs @ ZIF-8 drug carrier has high fluorescence quantum yield and high stability, photolysis occurs under a specific illumination condition, and the AuNCs @ ZIF-8 drug carrier can be applied to preparation of light-controlled release drugs.
Furthermore, the mass concentration of the chloroauric acid in the mixed liquid in the step S1 is 0.5-1.0 mg/mL.
Further, the mass concentration of glutathione in the mixed solution of step S1 is 0.5 to 1.5mg/mL.
The research discovers that the concentrations of chloroauric acid and glutathione can influence the amount of gold clusters AuNCs, and further influence the yield of fluorescence quantum; the content of the chloroauric acid is less than 0.5mg/mL, which can cause the quantum yield to be reduced, but the content of the chloroauric acid is more than 1mg/mL, which can not further improve the actual quantum yield, and the concentration of the chloroauric acid is preferably 0.5-1.0 mg/mL in consideration of economic cost; the gold clusters can be better wrapped by a proper amount of glutathione, and if the concentration of the glutathione is too low and is less than 0.5mg/mL, the gold clusters cannot be wrapped well, so that the fluorescence quantum yield is low due to the concentration of the gold clusters; if the concentration of glutathione is too high, the glutathione will be dialyzed out without affecting the protocol, but the mass concentration of glutathione is preferably 0.5 to 1.5mg/mL in view of economic factors.
Further, the mixing reaction in step S1 is carried out at 60 to 80 ℃.
Further, the mixing reaction in step S1 is stirring at 500rpm for 24 hours.
Further, the time of the ultrasonic treatment in the step S2 is 5min.
Further, the centrifugation in step S2 is centrifugation at 8000rpm for 10min after the ultrasound.
Further, in the step S2, the sediment obtained by centrifugation is washed 3 times by water and ethanol respectively to obtain the AuNCs @ ZIF-8 drug carrier.
The invention also provides the AuNC @ ZIF-8 drug carrier prepared by the method.
Further, the AuNC @ ZIF-8 pharmaceutical carrier comprises ZIF-8 and AuNCs wrapped inside and monodispersed.
The AuNC @ ZIF-8 drug carrier AuNCs is wrapped by ZIF-8, and is measured to be monodisperse in ZIF-8 through imaging by a high-angle annular dark field-scanning transmission electron microscope (HAADF-STEM), wherein monodisperse means that the AuNCs have consistent particle size and are uniformly distributed in ZIF-8.
Further, the average particle size of the AuNC @ ZIF-8 pharmaceutical carrier is 235. + -. 26.4nm.
Further, the fluorescence quantum yield of the AuNC @ ZIF-8 drug carrier is higher than 50%.
Preferably, the AuNC @ ZIF-8 drug carrier has a fluorescence quantum yield of 52.96%.
Further, the AuNC @ ZIF-8 drug carrier described above is photolyzed under light conditions.
Preferably, the light irradiation conditions are light wavelength of 405nm and light intensity of 0.1W/cm 2 。
Special properties of AuNC @ ZIF-8 derive from Zn of 2-methylimidazole 2+ Zn of-N and glutathione and AuNCs 2+ -O/N competitive coordination interactions. Under irradiation with light, on the one hand, the Au-S bond of AuNCs is broken, resulting in Zn 2+ Enhanced and reduced Zn carboxyl/amino interactions with AuNCs 2+ The ability to coordinate to the 2-methylimidazole nitrogen atom, the collapse of ZIF-8 and the release of AuNCs, resulting in reduced fluorescence emission; on the other hand, the Au-S bond cleavage of AuNCs was accompanied by the conversion of Au (I) to Au (0), resulting in a decrease in fluorescence emission. In the two-step synthesis of ZIF-8@ AuNCs, zn is present on the outer surface of ZIF-8 2+ In conjunction with the carboxyl/amino groups on AuNCs, the intramolecular rotation of AuNCs surface was partially restricted, resulting in a slight enhancement of the fluorescence emission of ZIF-8@ AuNCs. Under light irradiation, the Au-S bond in AuNCs is broken, while the ZIF-8 structure is not changed, resulting in the separation of AuNCs from ZIF-8. Therefore, no competitive coordination occurred in ZIF-8@ AuNCs.
The invention also provides application of the AuNC @ ZIF-8 drug carrier in preparation of photoresponse drugs and/or preparation of cancer treatment drugs.
The invention also provides application of the AuNC @ ZIF-8 medicament carrier in the aspect of medicament photoimaging analysis.
The invention also provides a preparation method of the light-controlled release medicine, which comprises the following steps:
s3, synthesizing AuNCs: preparing chloroauric acid and glutathione into a mixed solution and reacting to obtain an AuNCs aqueous solution A, wherein the mass concentration of chloroauric acid is not lower than 0.5mg/mL, and the mass concentration of glutathione is not lower than 0.5mg/mL; retaining the component with the molecular weight of more than 1kDa in the AuNCs aqueous solution A, wherein the component is purified AuNCs;
s4, respectively preparing Zn 2+ The mass concentration of the substance is 60-100 mmol/LZinc nitrate solution and 2-methylimidazole solution with the amount concentration of 1.5-2.5 mol/L of 2-methylimidazole substance are mixed with AuNCs purified in the step S1 to obtain mixed solution B, a medicine is added into the mixed solution B to enable the volume concentration of the medicine to be 0.2-0.8 mg/mL to obtain mixed solution C, the mixed solution C is subjected to ultrasonic treatment and then is subjected to centrifugation to obtain precipitate, and the precipitate after the centrifugation is washed to obtain the light-operated release medicine.
Furthermore, in the mixed liquid in the step S3, the mass concentration of the chloroauric acid is not less than 0.5-1.0 mg/mL.
Furthermore, in the mixed liquid in the step S3, the mass concentration of the glutathione is 0.5-1.5 mg/mL.
Further, the mixing reaction in step S3 is carried out at 60 to 80 ℃.
Further, the mixing reaction in step S3 is stirring at 500rpm for 24 hours.
Further, the time of the ultrasonic treatment in step S4 is 5min.
Further, the centrifugation in step S4 is centrifugation at 8000rpm for 10min after the ultrasound.
Further, in the step S4, the washing is to wash the precipitate obtained by centrifugation with ethanol until the supernatant is transparent, so as to obtain the light-controlled release drug.
Preferably, the number of washing in step S4 is 5.
Further, the drug in step S4 is one of cisplatin DDP, docetaxel DTX, and doxorubicin DOX.
The invention also provides the light-controlled release medicament prepared by the preparation method.
The invention also provides application of the light-controlled release medicament in the aspect of reducing cytotoxicity of the medicament.
Compared with the prior art, the invention has the following beneficial effects:
(1) The AuNC @ ZIF-8 fluorescence quantum prepared by the one-step method has the advantages of high yield, good stability and photoresponse, simple preparation method and mild conditions.
(2) The AuNC @ ZIF-8 prepared by the invention can be used as a nano carrier for drug coating, and the formed drug-AuNC @ ZIF-8 has small cytotoxicity and quick photoresponse.
(3) The drug carrier prepared by the invention can be used for preparing photoresponse drugs and/or preparing cancer treatment drugs and drug light imaging analysis.
(4) The medicine prepared by the invention can be used for rapid real-time monitoring of medicine release in HeLa cells with high space-time resolution.
Drawings
FIG. 1 is a graph showing the morphological characteristics of AuNC @ ZIF-8, a sample of example 1 in Experimental example 1.
The drawing is marked with: A. b is a TEM image, C is dynamic light scattering, and D-F is an elemental mapping image of HAADF-STEM imaging.
FIG. 2 is a graph showing the morphological characterization of AuNC/ZIF-8, a sample of comparative example 3 in Experimental example 1.
The figure is marked with: A. b is a TEM image, C is dynamic light scattering, and D-F is an elemental mapping image of HAADF-STEM imaging.
FIG. 3 is a graph of the topographical characterization of the comparative example 4, comparative example 8, and comparative example 9 samples.
The figure is marked with: A. b, C, D are TEM images of comparative example 4, comparative example 8, and comparative example 9 samples, respectively.
FIG. 4 is SEM images of example 1 sample AuNC @ ZIF-8 and comparative example 3 sample AuNC/ZIF-8 in Experimental example 2 and after storage of different dispersants.
The figure is marked with: A. b and C show SEM images of the newly prepared sample of example 1, the sample dispersed in an aqueous solution and the sample dispersed in a DMEM cell culture solution, respectively.
FIG. 5 is XRD patterns of AuNC @ ZIF-8 as a sample of example 1 and ZIF-8 as a sample of comparative example 2 in Experimental example 3.
FIG. 6 is samples of example 1 of Experimental example 4, auNC @ ZIF-8 andcomparative example 1 sampleUltraviolet-visible absorption spectra and fluorescence spectra of AuNCs.
The drawing is marked with: curves a and b are respectively the ultraviolet visible absorption spectrum diagrams of AuNCs and AuNC @ ZIF-8, curves c and d are respectively the fluorescence emission diagrams of AuNCs and AuNC @ ZIF-8, an interpolation diagram a and an interpolation diagram b are respectively the photos of AuNCs and AuNC @ ZIF-8 under a daylight lamp, and an interpolation diagram c and an interpolation diagram d are respectively the photos of AuNCs and AuNC @ ZIF-8 under an ultraviolet lamp.
FIG. 7 is a graph showing fluorescence spectra of AuNCs, a sample of comparative example 1, and AuNC/ZIF-8, a sample of comparative example 3 in Experimental example 4.
The figure is marked with: curve a is the AuNCs fluorescence spectrum of the sample of comparative example 1; curve b is the fluorescence spectrum of AuNC/ZIF-8 sample of comparative example 3.
FIG. 8 is a graph of relative fluorescence intensity at different illumination times and TEM of example 1 sample AuNC @ ZIF-8 in Experimental example 5.
FIG. 9 is a TEM image of the sample ZIF-8 of comparative example 2 in Experimental example 5 before and after the light irradiation.
The figure is marked with: a represents a TEM image before illumination; b represents a TEM image after the light irradiation.
FIG. 10 is a fluorescence spectrum before and after light irradiation and a TEM image after light irradiation of AuNC/ZIF-8 sample of comparative example 3 in Experimental example 5.
The figure is marked with: a represents the fluorescence spectra of the sample of comparative example 3 before and after the illumination; b represents a TEM image of the sample of comparative example 3.
FIG. 11 is a HAADF-STEM map and an element mapping map of example 7 sample DDP-AuNC @ ZIF-8 in Experimental example 6.
The drawing is marked with: a represents a HAADF-STEM map of a sample of example 7; B. c and D respectively represent mapping graphs of Zn, au and Pt as metal elements.
FIG. 12 is a graph showing the relationship between AuNC @ ZIF-8 carrier, ZIF-8 and AuNC @ ZIF-8 drugs and HeLa cell activities in Experimental example 7.
The figure is marked with: a represents the activity of HeLa cells under the action of samples with different concentrations under the condition of no illumination; b represents the activity of HeLa cells under the condition of illumination and the action of a sample with a specific concentration along with the change of time.
FIG. 13 is a photograph showing the cytograms of DOX-AuNC @ ZIF-8 sample of example 8 before and after the light irradiation at different times in Experimental example 8.
The drawing is marked with: a represents a cell fluorescence imaging graph after the sample of the example 8 is used for treating the HeLa cells for 30min under the condition of no illumination; b represents a cell fluorescence imaging graph at different times after illumination for 5min.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated. The term "one-step method" means that the AuNC @ ZIF-8 drug carrier is prepared in one step after AuNCs is prepared, rather than preparing AuNCs and ZIF-8 separately and then preparing AuNC @ ZIF-8. The preparation method is characterized in that the preparation method is mild in condition, namely, the step does not involve the reaction at the temperature higher than 100 ℃ or the temperature higher than the atmospheric pressure or the reaction containing strong acid and strong base; to distinguish the supports prepared in example 1 from comparative example 3, example 1 was designated AuNCs @ ZIF-8, and comparative example 3 was designated AuNCs/ZIF-8; in the embodiment, the steps S1-S2 and the steps S3-S4 belong to two different methods respectively, and no sequence relation exists.
EXAMPLE 1 preparation of drug Carrier AuNCs @ ZIF-8
The preparation method of the drug carrier AuNCs @ ZIF-8 comprises the following steps:
s1, synthesizing AuNCs: adding chloroauric acid and glutathione into water to form chloroauric acid with mass concentration of 0.7mg/mL and glutathione aqueous solution with mass concentration of 0.9mg/mL, stirring for 24h at 70 ℃ and rotation speed of 500rpm to obtain AuNCs aqueous solution A, and then intercepting components with molecular weight of more than 1kDa by using a dialysis bag, wherein the components are purified AuNCs; preparing a purified AuNCs aqueous solution to make the volume of the purified AuNCs aqueous solution consistent with the volume of the purified AuNCs aqueous solution before interception by a dialysis bag;
s2, synthesizing AuNCs @ ZIF-8: adding Zn (NO) 3 ) 2 And 2-methylimidazole in water to form Zn in a concentration of 80mmol/L 2+ And 2-methylimidazole with the mass concentration of 2mol/L, mixing the mixture with 0.9mL of water, adding 1.2mL of the aqueous solution of AuNCs purified in S1, uniformly mixing to obtain a mixed solution B, carrying out ultrasonic treatment for 5min, centrifuging at 8000rpm for 10min, washing precipitates obtained by centrifuging with water and ethanol for 3 times respectively to obtain a drug carrier AuNCs @ ZIF-8, which is recorded as a sample in example 1.
Example 2 preparation of drug Carrier AuNCs @ ZIF-8
The preparation method of the drug carrier AuNCs @ ZIF-8 comprises the following steps:
s1, synthesizing AuNCs: adding chloroauric acid and glutathione into water to form chloroauric acid with the mass concentration of 0.5mg/mL and glutathione aqueous solution with the mass concentration of 0.5mg/mL, stirring for 24 hours under the conditions that the temperature is 60 ℃ and the rotating speed is 500rpm to obtain AuNCs aqueous solution A, and then intercepting components with the molecular weight of more than 1kDa by using a dialysis bag, wherein the components are purified AuNCs; preparing a purified AuNCs aqueous solution to make the volume of the purified AuNCs aqueous solution consistent with the volume before interception by a dialysis bag;
s2, synthesizing AuNCs @ ZIF-8: adding Zn (NO) 3 ) 2 And 2-methylimidazole in water to form Zn in a concentration of 60mmol/L 2+ And 2-methylimidazole with the mass concentration of 1.5mol/L are mixed in 0.8mL of water, 1.0mL of aqueous solution of AuNCs purified in S1 is added, the mixture is uniformly mixed to obtain a mixed solution B, ultrasonic treatment is carried out for 5min, then centrifugation is carried out for 10min at 8000rpm, and precipitates obtained by the centrifugation are washed by water and ethanol for 3 times respectively to obtain a drug carrier AuNCs @ ZIF-8 which is recorded as a sample of example 2.
EXAMPLE 3 preparation of drug Carrier AuNCs @ ZIF-8
The preparation method of the drug carrier AuNCs @ ZIF-8 comprises the following steps:
s1, synthesizing AuNCs: adding chloroauric acid and glutathione into water to form chloroauric acid with the mass concentration of 1.0mg/mL and glutathione aqueous solution with the mass concentration of 1.5mg/mL, stirring for 24 hours under the conditions that the temperature is 80 ℃ and the rotating speed is 500rpm to obtain AuNCs aqueous solution A, and then intercepting components with the molecular weight of more than 1kDa by using a dialysis bag, wherein the components are purified AuNCs; preparing a purified AuNCs aqueous solution to make the volume of the purified AuNCs aqueous solution consistent with the volume before interception by a dialysis bag;
s2, synthesizing AuNCs @ ZIF-8: zn (NO) 3 ) 2 And 2-methylimidazole in water to form Zn in a concentration of 100mmol/L 2+ Mixing with 2-methylimidazole with substance amount concentration of 2.5mol/L in 1.0mL of water, adding 1.5mL of aqueous solution of AuNCs purified in S1, mixing well to obtain mixed solution B, ultrasonic treating for 5min, centrifuging at 8000rpm for 10min, washing precipitate obtained by centrifuging with water and ethanol for 3 times respectivelyThe drug carrier AuNCs @ ZIF-8 was obtained and recorded as the sample of example 3.
Example 4 preparation of drug Carrier AuNCs @ ZIF-8
The preparation was carried out according to the method described in example 1, except that 1.5mg/mL of chloroauric acid was used in the step S1, and other steps and parameters were the same as those in example 1, to prepare the sample of example 4.
EXAMPLE 5 preparation of drug Carrier AuNCs @ ZIF-8
The preparation was carried out according to the method in example 1 except that 2mg/mL of glutathione was used in the step S1 and other steps and parameters were kept the same as in example 1 to prepare the sample of example 5.
EXAMPLE 6 preparation of the drug DDP-AuNCs @ ZIF-8
The preparation method of the drug DDP-AuNCs @ ZIF-8 with light-operated release comprises the following steps:
s3, synthesizing AuNCs: adding chloroauric acid and glutathione into water to form chloroauric acid with mass concentration of 0.7mg/mL and glutathione aqueous solution with mass concentration of 0.9mg/mL, stirring for 24h at the temperature of 70 ℃ and the rotation speed of 500rpm to obtain AuNCs aqueous solution A, and then using a dialysis bag to intercept a component with molecular weight of more than 1kDa, wherein the component is purified AuNCs; preparing a purified AuNCs aqueous solution to make the volume of the purified AuNCs aqueous solution consistent with the volume of the purified AuNCs aqueous solution before interception by a dialysis bag;
s4, synthesizing DDP-AuNCs @ ZIF-8: adding Zn (NO) 3 ) 2 And 2-methylimidazole in water to form Zn in a concentration of 80mmol/L 2+ And 2-methylimidazole with the amount concentration of 2mol/L of substance are mixed in 0.9mL of water, then 1.2mL of AuNCs aqueous solution purified in S3 is added to obtain mixed solution B, then medicine DDP is added to the mixed solution B to ensure that the volume concentration of the medicine is 0.5mg/mL and is uniformly mixed to obtain mixed solution C, ultrasonic treatment is carried out for 5min, then centrifugation is carried out for 10min at 8000rpm, precipitates obtained by the centrifugation are respectively washed for 5 times by ethanol to obtain the light-controlled release medicine DDP-AuNCs @ ZIF-8, and the sample is marked as example 6.
EXAMPLE 7 preparation of the drug DTX-AuNC @ ZIF-8
The preparation method of the light-operated release medicament DTX-AuNC @ ZIF-8 comprises the following steps:
s3, synthesizing AuNCs: adding chloroauric acid and glutathione into water to form chloroauric acid with the mass concentration of 0.7mg/mL and glutathione aqueous solution with the mass concentration of 0.9mg/mL, stirring for 24 hours under the conditions that the temperature is 75 ℃ and the rotating speed is 500rpm to obtain AuNCs aqueous solution A, and then intercepting a component with the molecular weight of more than 1kDa by using a dialysis bag, wherein the component is purified AuNCs. Preparing a purified AuNCs aqueous solution to make the volume of the purified AuNCs aqueous solution consistent with the volume of the purified AuNCs aqueous solution before interception by a dialysis bag;
s4, synthesizing DTX-AuNCs @ ZIF-8: zn (NO) 3 ) 2 And 2-methylimidazole in water to form Zn in a concentration of 80mmol/L 2+ And 2-methylimidazole with the mass concentration of 2mol/L is mixed in 0.9mL of water, then 1.2mL of AuNCs aqueous solution purified in S3 is added to obtain mixed solution B, then medicine DTX is added to the mixed solution B to ensure that the volume concentration of the medicine is 0.5mg/mL, the mixed solution C is uniformly mixed to obtain mixed solution C, ultrasonic treatment is carried out for 5min, then centrifugation is carried out for 10min at 8000rpm, precipitates obtained by centrifugation are respectively washed for 5 times by ethanol to obtain light-controlled release medicine DTX-AuNCs @ ZIF-8, and the sample is marked as example 7.
EXAMPLE 8 preparation of the drug DOX-AuNCs @ ZIF-8
The preparation method of the optically controlled release medicament DOX-AuNCs @ ZIF-8 comprises the following steps:
s3, synthesizing AuNCs: adding chloroauric acid and glutathione into water to form chloroauric acid with mass concentration of 0.7mg/mL and glutathione aqueous solution with mass concentration of 0.9mg/mL, stirring for 24h at 65 ℃ and 500rpm to obtain AuNCs aqueous solution A, and then using a dialysis bag to intercept a component with molecular weight of more than 1kDa, wherein the component is purified AuNCs. Preparing a purified AuNCs aqueous solution to make the volume of the purified AuNCs aqueous solution consistent with the volume of the purified AuNCs aqueous solution before interception by a dialysis bag;
s4, synthesizing DOX-AuNCs @ ZIF-8: adding Zn (NO) 3 ) 2 And 2-methylimidazole in water to form Zn in a concentration of 80mmol/L 2+ Mixing 2-methylimidazole with the amount concentration of 2mol/L in 0.9mL of water, adding 1.2mL of aqueous solution of AuNCs purified in S3 to obtain mixed solution B, and adding DOX to the mixed solution B to obtain medicinal compositionVolume concentration is 0.5mg/mL, mixed evenly to obtain a mixed solution C, ultrasonic treatment is carried out for 5min, then centrifugation is carried out for 10min at 8000rpm, precipitates obtained by centrifugation are respectively washed for 5 times by ethanol, and the photo-controlled release pharmaceutical composition DOX-AuNCs @ ZIF-8 is obtained and recorded as a sample of example 8.
Comparative example 1 preparation of AuNCs
AuNCs synthesized by performing only step S1 in example 1 were used as comparative example 1, and the specific steps were as follows:
synthesis of AuNCs: adding chloroauric acid and glutathione into water to form chloroauric acid with mass concentration of 0.7mg/mL and glutathione aqueous solution with mass concentration of 0.9mg/mL, stirring for 24h at 70 ℃ and rotation speed of 500rpm to obtain AuNCs aqueous solution A, and then intercepting a component with molecular weight of more than 1kDa by using a dialysis bag, wherein the component is purified AuNCs; preparing a purified AuNCs aqueous solution to make the volume of the purified AuNCs aqueous solution consistent with the volume before interception by a dialysis bag; sample designated comparative example 1;
comparative example 2ZIF-8 preparation
As comparative example 2, ZIF-8 synthesized by performing only step S2 (without performing the operation of step S1) in example 1 was specifically prepared as follows:
synthesizing ZIF-8: adding Zn (NO) 3 ) 2 And 2-methylimidazole in water to form Zn in a concentration of 80mmol/L 2+ And 2-methylimidazole with the amount concentration of 2mol/L of the substance in 0.9mL of water, carrying out ultrasonic treatment for 5min, then centrifuging at 8000rpm for 10min, and washing precipitates obtained by centrifuging with water and ethanol for 3 times respectively to obtain ZIF-8 which is marked as a sample of comparative example 2.
Comparative example 3AuNCs/ZIF-8 preparation
The procedure of example 1 for synthesizing AuNCs @ ZIF-8 was followed by resolution, i.e., ZIF-8 was synthesized in step S2 and then mixed with AuNCs. The method comprises the following specific steps:
s1, synthesizing AuNCs: adding chloroauric acid and glutathione into water to form chloroauric acid with mass concentration of 0.7mg/mL and glutathione aqueous solution with mass concentration of 0.9mg/mL, stirring for 24h at 70 ℃ and rotation speed of 500rpm to obtain AuNCs aqueous solution A, and then intercepting components with molecular weight of more than 1kDa by using a dialysis bag, wherein the components are purified AuNCs; preparing a purified AuNCs aqueous solution to make the volume of the purified AuNCs aqueous solution consistent with the volume before interception by a dialysis bag;
s2, synthesizing ZIF-8: zn (NO) 3 ) 2 And 2-methylimidazole in water to form Zn in a concentration of 80mmol/L 2+ Mixing the ZIF-8 with 2-methylimidazole with the mass concentration of 2mol/L in 0.9mL of water, performing ultrasonic treatment for 5min, then centrifuging at 8000rpm for 10min, and washing precipitates obtained by centrifuging for 3 times with water and ethanol respectively to obtain ZIF-8;
s3, adding 1.2mL of purified AuNCs aqueous solution into the ZIF-8 prepared in the S2, uniformly mixing, carrying out ultrasonic treatment for 30min, then centrifuging at 8000rpm for 10min, washing precipitates obtained by centrifuging for 3 times by using water and ethanol respectively, and distinguishing the precipitates from the medicament carrier obtained in the example 1 to obtain a sample which is represented by AuNCs/ZIF-8 and is marked as a comparative example 3 sample.
Comparative example 4
Comparative example 4 was prepared according to the method of example 1, except that 0.3mg/mL of chloroauric acid was used in step S1, and the other steps and parameters were the same as in example 1.
Comparative example 5
The preparation was carried out according to the method in example 1 except that 0.3mg/mL of glutathione was used in the step S1 and the other steps and parameters were kept the same as in example 1 to prepare a sample of comparative example 5.
Comparative example 6
Preparation was carried out according to the method in example 1, with the difference that Zn in step S2 2+ The amount of substance(s) of (2) was 40mmol/L, and the other steps and parameters were kept the same as in example 1, to prepare a sample of comparative example 6.
Comparative example 7
Preparation was carried out according to the method in example 1, with the difference that Zn in step S2 2+ The amount of substance(s) of (1) was 200mmol/L, and the other steps and parameters were kept the same as in example 1, to prepare a sample of comparative example 7.
Comparative example 8
The preparation was carried out in accordance with the method in example 1 except that the amount concentration of the substance of 2-methylimidazole in step S2 was 0.5mol/L and the other steps and parameters were kept the same as in example 1 to prepare a sample of comparative example 8.
Comparative example 9
Comparative example 9 was prepared according to the method of example 1, except that the amount concentration of the substance of 2-methylimidazole in step S2 was 3mol/L and the other steps and parameters were kept the same as example 1.
Comparative example 10
Comparative example 10 was prepared according to the method of example 1, except that no dialysis bag purification was used in step S1 and the other steps and parameters were the same as in example 1.
Experimental examples 1 to 8 are related experiments to test the above examples and comparative examples
Experimental example 1 morphological characterization of samples AuNCs @ ZIF-8 from examples 1-3 and samples from comparative examples 1-10
(1) Experimental methods
The morphological characteristics (under scales of 200nm and 50 nm) of the sample AuNCs @ ZIF-8 in example 1 under different magnifications were characterized by using a Transmission Electron Microscope (TEM), and the sample in comparative example 3 was used as a control to characterize the morphological characteristics, and the particle size of the sample was analyzed by using a dynamic light scattering nanometer particle size analyzer; a high-angle annular dark-field scanning transmission electron microscope (HAADF-STEM) was used to analyze the elemental distribution of the sample image and the internal structure of the drug carrier, while recording the morphological features of the other examples 1-5 and comparative examples 3-10.
(2) Results of the experiment
Example 1 the experimental results are shown in fig. 1, fig. 1A is a TEM image of the sample aunc @ zif-8 of example 1, and it can be seen from fig. 1A that aunc @ zif-8 has a uniform spherical structure. FIG. 1B is an enlarged TEM image of the edge portion of AuNC @ ZIF-8, and it can be seen from the image that there are many black dots, i.e., gold clusters (as indicated by the blue dotted circles in FIG. 1B) uniformly distributed on the edge of AuNC @ ZIF-8, indicating that AuNCs are uniformly distributed on AuNC @ ZIF-8. FIG. 1C shows the dynamic light scattering of AuNC @ ZIF-8, indicating that AuNC @ ZIF-8 has an average diameter of 235. + -. 26.4nm. FIGS. 1D-F are element mapping plots for HAADF-STEM imaging by AuNC @ ZIF-8. It can be seen that the Au and Zn elements are uniformly distributed in the whole AuNC @ ZIF-8 region, which indicates that AuNCs are monodisperse, rather than aggregated, in the AuNC @ ZIF-8 region.
Comparative example 3 the experimental results are shown in fig. 2, and fig. 2A is a TEM image of the comparative example 3 sample, from which it can be seen that the comparative example 3 sample shows good corner-cut cubic crystals. FIG. 2B is an enlarged TEM image of the edge portion of the sample of comparative example 3, with a purple dotted line to mark the outer surface of ZIF-8 in the sample of comparative example 3, and a blue dotted line to indicate gold clusters. It can be seen that many gold clusters are distributed on the outer surface of ZIF-8. FIG. 2C shows the dynamic light scattering of the sample, indicating that the average diameter of the comparative example 3 sample is 176.9. + -. 3.1nm. FIGS. 2D-F are elemental mapping plots of HAADF-STEM imaging of the sample. Both Au and Zn elements were contained in the entire sample. The content of Au element is obviously less than that of Zn element, and the Au element is mainly distributed on the edge of ZIF-8. The above results indicate that AuNCs are uniformly modified on the outer surface of ZIF-8, rather than being embedded within the ZIF-8 crystal.
For better comparison, other examples and comparative examples were also characterized, wherein the characterization results of comparative example 4, comparative example 8 and comparative example 9 are shown in fig. 3. Fig. 3A and 3B are TEM images of comparative example 4 and example 4, respectively. As can be seen in fig. 3A, when the chloroauric acid concentration was lower, the sample exhibited uniform corner-cut cubic crystals, indicating that less AuNCs did not change the morphology of ZIF-8; however, when the chloroauric acid concentration was greater, the sample exhibited a uniform spherical structure, indicating that the AuNCs were successfully embedded in the ZIF-8 crystals. Fig. 3C and 3D are TEM images of comparative example 8 and comparative example 9, respectively. As can be seen from fig. 3C, when the concentration of 2-methylimidazole is small, the sample exhibits a polyhedral configuration; however, when the concentration of 2-methylimidazole is higher, the sample shows irregular aggregation morphology. After observing the morphologies of examples 1 to 5 and comparative examples 3 to 10, the morphological characteristics were recorded, and the results are shown in table 1, and it can be seen from table 1 that the samples 1 to 5 of the present examples all have a uniform spherical structure, but not the samples prepared within the scope of the method of the present invention (comparative example 3), and the cut-angle cubic crystals having a non-spherical structure were prepared if the chloroauric acid content was too low (comparative example 4); too high or too low contents of zinc ions and imidazole (comparative examples 6 to 9) lead to non-uniform structures; if dialysis is not performed, coordination of glutathione to zinc ions, imidazole, etc. is caused, resulting in structural and morphological changes, and a uniform spherical drug carrier structure cannot be prepared (comparative example 10).
TABLE 1 characterization of sample morphology
| Sample numbering | Topographic features | Sample numbering | Topographic features |
| Example 1 | Uniform spherical structure | Comparative example 5 | Uniform spherical structure |
| Example 2 | Uniform spherical structure | Comparative example 6 | Irregularity |
| Example 3 | Uniform spherical structure | Comparative example 7 | Irregularity |
| Example 4 | Uniform spherical shapeStructure of the product | Comparative example 8 | Irregularity |
| Example 5 | Uniform spherical structure | Comparative example 9 | Irregularity |
| Comparative example 3 | Homogeneous corner-cut cubic crystal | Comparative example 10 | Irregularity |
| Comparative example 4 | Homogeneous corner-cut cubic crystal | / | / |
Experimental example 2 sample stability characterization
(1) Experimental method
The morphological Structure (SEM) of the sample prepared newly in example 1 and the sample stored in aqueous solution and DMEM cell culture solution in the dark at 4 ℃ for 30 days are respectively characterized by a scanning electron microscope, and the morphological change and the stability of the sample AuNC @ ZIF-8 in different liquids in example 1 are analyzed for a certain time. The morphological changes of the samples of example 1 were also recorded.
(2) Results of the experiment
As shown in FIG. 4, among these, FIGS. 4A, 4B and 4℃ are the newly prepared AuNC @ ZIF-8 and SEM pictures of the AuNC @ ZIF-8 dispersed in an aqueous solution and a DMEM cell culture solution after storing at 4 ℃ for 30 days, respectively, and it can be seen from FIG. 4 that the AuNC @ ZIF-8 dispersed in an aqueous solution and a DMEM cell culture solution for 30 days has no change in morphology, indicating that AuNC @ ZIF-8 has good stability.
Experimental example 3 characterization of crystal structure
(1) Experimental methods
The X-ray diffractometer was used to plot the X-ray diffraction (XRD) patterns of the drug carrier sample aunc @ ZIF-8 in example 1 and the sample ZIF-8 in comparative example 2 (as a control), and the crystal structures of ZIF-8 and aunc @ ZIF-8 were analyzed.
(2) Results of the experiment
As can be seen from the XRD pattern in FIG. 5, auNC @ ZIF-8 is consistent with the theoretical peak of ZIF-8, indicating that intercalation of AuNCs has little effect on the crystal lattice of ZIF-8.
Experimental example 4 optical Properties characterization
(1) Experimental methods
Measuring the ultraviolet-visible absorption spectra of the sample AuNCs in comparative example 1, the sample in comparative example 3 and the sample AuNC @ ZIF-8 in example 1 using an ultraviolet-visible spectrophotometer, measuring the fluorescence spectra of the sample AuNCs in comparative example 1, the sample in comparative example 3 and the sample AuNC @ ZIF-8 in example 1 using a fluorescence spectrometer, and measuring the fluorescence quantum yield of the samples; the fluorescence quantum yields of the samples of example 4 and comparative examples 3 to 5 were determined simultaneously.
(2) Results of the experiment
The UV-visible absorption spectrum and fluorescence spectrum of AuNC @ ZIF-8 in example 1 and AuNCs in comparative example 1 are shown in FIG. 6. Curves a and b in FIG. 6 are the UV-visible absorption spectra of AuNCs and AuNC @ ZIF-8, respectively, both of which absorb at 400nm as seen in FIG. 6, and the inset graphs a and b are photographs under fluorescent lamps corresponding to AuNCs and AuNC @ ZIF-8, respectively, in which AuNCs are yellow transparent solutions and AuNC @ ZIF-8 is a pale yellow turbid solution, respectively. Curves c, d are fluorescence emission plots of AuNCs and AuNC @ ZIF-8, respectively, interpolated plot c, d are photographs of AuNCs and AuNC @ ZIF-8 under a UV lamp, respectively. As can be seen from the figure, auNCs has a maximum fluorescence emission wavelength of 638nm and weak fluorescence (interpolated graph c), while AuNC @ ZIF-8 has a blue shift from 638nm to 618nm with a significant increase in fluorescence intensity (curve d) and emits bright orange-yellow fluorescence (interpolated graph d). The fluorescence quantum yield of AuNC @ ZIF-8 (52.96% as shown in Table 2) was 12.8 times that of AuNCs (4.13% as shown in Table 2). The AuNC @ ZIF-8 is proved to have extremely high fluorescence quantum yield.
The fluorescence spectra of the AuNCs sample of comparative example 1 and the AuNCs sample of comparative example 3 are shown in FIG. 7. The curves a and b in FIG. 7 are the fluorescence spectra thereof, respectively. It can be seen from FIG. 7 that the maximum emission wavelength of the comparative example 3 sample is at 618nm, which is consistent with the fluorescence wavelength of AuNC @ ZIF-8 obtained in the one-step method of example 1. Shows that ZIF-8 can promote blue shift of the fluorescence spectrum of AuNCs, and is irrelevant to the dosage and usage of AuNCs and ZIF-8. In addition, the fluorescence quantum yield of the sample of comparative example 3 is only 15.29%, as shown in Table 2, which is significantly less than that of AuNC @ ZIF-8 in example 1. The low fluorescence quantum yield of AuNC/ZIF-8 is demonstrated (Table 2).
TABLE 2 fluorescence quantum yield of samples
| Sample numbering | Fluorescence quantum yield (%) | Sample numbering | Fluorescence quantum yield (%) |
| Example 1 | 52.96 | Comparative example 1 | 4.13 |
| Example 3 | 52.36 | Comparative example 3 | 15.29 |
| Example 4 | 52.08 | Comparative example 4 | 19.31 |
| Example 5 | 52.79 | Comparative example 5 | 33.35 |
Through the appearance characterization of the samples and the results in table 2, the content of chloroauric acid is less than 0.5mg/mL (comparative example 4), which results in the decrease of quantum yield, but is more than 1mg/mL (example 4), which does not further improve the actual quantum yield, and the concentration of chloroauric acid in the range of the invention can improve the fluorescence quantum yield and is economical and practical in consideration of economic cost factors. Glutathione in the range can better wrap the gold clusters, and if the concentration of the glutathione is too small (comparative example 5), the gold clusters cannot be wrapped well, so that the fluorescence quantum yield is low due to the concentration of the gold clusters; after the glutathione concentration was increased to a certain level, excess glutathione was removed by dialysis (example 5), and the protocol was not affected.
Experimental example 5 photolysis Performance test
(1) Experimental methods
The fluorescence intensity of AuNC @ ZIF-8 in example 1 was measured by a fluorescence spectrometer and the structure was characterized by TEM, specifically, auNC @ ZIF-8 was dispersed in water at a wavelength of 405nm and a light intensity of 0.1W/cm in 0.5mg/mL 2 The light is respectively irradiated for 0, 2, 5, 10, 15 and 20min, the fluorescence intensity of AuNC @ ZIF-8 at the wavelength of 618nm under different illumination times is recorded by a fluorescence spectrometer, and the morphology of the light is characterized by TEM. Simultaneously measuring the light wavelength at 405nm and the light intensity at 0.1W/cm 2 TEM images of ZIF-8 in comparative example 2 before and 20min after light irradiation were used as a control. For comparison, the fluorescence intensity of the sample of comparative example 3 before and after 20min of light irradiation was measured at the same time, andthe morphology of the sample in comparative example 3 was characterized by TEM.
(2) Results of the experiment
Example 1 the relative fluorescence intensity of the sample AuNC @ ZIF-8 at different illumination times is shown in FIG. 8. As can be seen from FIG. 8, as the light irradiation time increased from 0min to 20min, the fluorescence intensity of AuNC @ ZIF-8 gradually decreased, and after light irradiation for 20min, the fluorescence intensity of AuNC @ ZIF-8 decreased to 12.7% of the initial fluorescence intensity. From the corresponding TEM image, auNC @ ZIF-8 was seen to degrade gradually, from the initial solid sphere along the edges towards the center of the sphere and finally almost completely. To further illustrate the photolytic properties of AuNC @ ZIF-8, ZIF-8 was characterized after illumination. TEM images before and after ZIF-8 irradiation are shown in FIG. 9, and it can be seen that the light wavelength is 405nm and the light intensity is 0.1W/cm 2 After irradiating ZIF-8 with light for 20min (FIG. 8B), the structure of ZIF-8 did not change significantly (compared to FIG. 8A before irradiation with light). It is demonstrated that AuNC @ ZIF-8 exhibits significant photolytic properties under light irradiation. Comparative example 3 the sample had a light wavelength of 405nm and a light intensity of 0.1W/cm 2 The fluorescence spectrum before (curve a) and after (curve b) 20min after light irradiation is shown in FIG. 10. It can be seen that the fluorescence intensity of the sample in comparative example 3 was reduced by about 71.23% after the light irradiation (FIG. 10A), and from the TEM image of AuNC/ZIF-8 after the light irradiation (FIG. 10B), it can be seen that AuNCs on the edge surface of ZIF-8 disappeared and the cubic crystal shape of ZIF-8@ AuNCs did not change after the light irradiation, so that the sample in comparative example 3 did not have photolysis.
Experimental example 6AuNC @ ZIF-8 drug carrier coating behavior characterization
(1) Experimental methods
The element distribution of the DDP-AuNC @ ZIF-8 image of the sample of example 7 and the internal structure of the present drug carrier were analyzed using HAADF-STEM according to DDP-AuNC @ ZIF-8 prepared in example 7.
(2) Results of the experiment
See FIG. 11 for HAADF-STEM diagram of DDP-AuNC @ ZIF-8 and mapping diagram of Zn, au, pt. The HAADF-STEM was characterized by using DDP-AuNC @ ZIF-8 as a model (FIG. 10A), and FIGS. 11B, 10C, and 10D are mapping graphs in which metal elements are Zn, au, and Pt, respectively. As can be seen from the figure, the DDP-AuNC @ ZIF-8 material contains three elements, namely Zn (FIG. 11B), au (FIG. 11C) and Pt (FIG. 11D). Wherein Zn and Au elements are from AuNC @ ZIF-8, and Pt elements are from encapsulated DDP, thus proving that DDP is encapsulated in AuNC @ ZIF-8 to form DDP-AuNC @ ZIF-8 nano composite material.
Experimental example 7 cytotoxicity test
(1) Experimental method
Commercially available HeLa cells were cultured under non-light conditions, randomly divided into 5 groups, and treated with ZIF-8, auNC @ ZIF-8, DDP-AuNC @ ZIF-8, DTX-AuNC @ ZIF-8, and DOX-AuNC @ ZIF-8 at different concentrations using the samples of comparative example 2, example 1, and examples 6-8, respectively, each of the 5 groups was further divided into 6 groups according to the concentration, and the HeLa cells were treated with 6 treatments (total of 30 concentrations of 6 samples of 5 groups) at concentrations of 0. Mu.g/mL (blank), 5. Mu.g/mL, 10. Mu.g/mL, 25. Mu.g/mL, 50. Mu.g/mL, and 75. Mu.g/mL), incubated for 24 hours under the light conditions, and then treated with HeLa cells subjected to the cell activity after incubation under non-light conditions (unit% represents the percentage of the cell activity before incubation) by the cell count CCK-8 method, and then subjected to the drug-induced cell toxicity statistics.
Commercially available HeLa cells were cultured under light conditions, randomly divided into 5 groups, and subjected to blank control (no drug treatment) and drug treatment at a concentration of 50. Mu.g/mL, respectively, using the samples of example 1 and the samples of examples 6 to 8, specifically AuNC @ ZIF-8, DDP-AuNC @ ZIF-8, DTX-AuNC @ ZIF-8 and DOX-AuNC @ ZIF-8, respectively, for each group, and the HeLa cell activities at 0, 2, 5, 10, 15, and 20min were recorded, respectively. The characteristic of the carrier that the HeLa cell toxicity and biocompatibility of each drug processing under the condition of illumination and the characteristic of the carrier can be used as the drug carrier is characterized.
(2) Results of the experiment
FIG. 12 is a graph showing the toxicity of ZIF-8, auNC @ ZIF-8, DDP-AuNC @ ZIF-8, DTX-AuNC @ ZIF-8 and DOX-AuNC @ ZIF-8 against HeLa cells at different concentrations under the non-light condition (A) and the light condition (B). As can be seen from FIG. 12A, in the absence of light, the activity of HeLa cells treated with 75. Mu.g/mL ZIF-8 drug was less than 80% after incubation for 24h, while the activity of HeLa cells treated with the same concentrations of AuNC @ ZIF-8, DDP-AuNC @ ZIF-8, DTX-AuNC @ ZIF-8 and DOX-AuNC @ ZIF-8 carriers or drugs, respectively, did not change significantly, indicating that the above drugs have no significant cytotoxicity.
As can be seen from FIG. 12B, the light intensity was 0.1W/cm at a light wavelength of 405nm 2 Under the illumination condition, after 50 mu g/mL AuNC @ ZIF-8 and HeLa cells are nurtured for 20min, the cell activity is hardly changed compared with that under the condition of no illumination. The AuNC @ ZIF-8 is shown to have good biocompatibility. However, after 50 μ g/mL of drugs-AuNC @ ZIF-8 (referred to as drugs DDP-AuNC @ ZIF-8, DTX-AuNC @ ZIF-8 and DOX-AuNC @ ZIF-8) and HeLa are respectively used for cell nurturing for 0min, 2 min, 5min, 10min, 15 min and 20min, the cell survival rate is gradually reduced along with the increase of time, which indicates that AuNC @ ZIF-8 can be used as a carrier of the drug, is rapidly degraded under the irradiation of light and effectively releases the drug to kill cells.
Experimental example 8 real-time tracking imaging of photo-drug release
(1) Experimental method
Commercially available HeLa cells were cultured in the absence of light, the HeLa cells were randomly divided into two groups, and the HeLa cells were treated with 0.5mg/mL DOX-AuNC @ ZIF-8 (example 8) for 30min and then irradiated with light for 5min (light conditions: 488nm wavelength and 0.1W/cm light intensity: light conditions: light intensity: 0.1W/cm) 2 ) Under the condition, a confocal laser scanning microscope is adopted to carry out in-situ real-time imaging on two groups of HeLa cells, the imaging of the HeLa cells is recorded in 0min, 10min, 20min and 30min respectively, and no light is used as a contrast.
(2) Results of the experiment
FIG. 13 is a graph of the fluorescence images of the sample of example 8, after incubating the HeLa cells treated with the drug DOX-AuNC @ ZIF-8 for 30min, under the no-light condition (A) and after 5min (B), at different times, it can be seen from FIG. 13 that under the light condition, at 0min, the red fluorescence is mainly concentrated in the cytoplasm, and no significant red fluorescence is present in the nucleus; at 20min, each nucleus had a small amount of red fluorescence; at 30min, red fluorescence was enhanced for each nucleus. In contrast to the control group without light, the red fluorescence was always present in the cytoplasm and not in the nucleus. The results show that under the condition of the light, DOX-AuNC @ ZIF-8 releases the drug DOX, and the drug DOX migrates from cytoplasm to nucleus.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such modifications are intended to be included in the scope of the present invention.
Claims (10)
1. A preparation method of an AuNC @ ZIF-8 drug carrier is characterized by comprising the following steps:
s1, synthesizing AuNCs: preparing chloroauric acid and glutathione into a mixed solution and reacting to obtain an AuNCs aqueous solution A, wherein the mass concentration of the chloroauric acid is not lower than 0.5mg/mL, and the mass concentration of the glutathione is not lower than 0.5mg/mL; retaining the component with the molecular weight of more than 1kDa in the AuNCs aqueous solution A, wherein the component is purified AuNCs;
s2, synthesizing AuNCs @ ZIF-8: separately preparing Zn 2+ And (2) mixing the zinc nitrate solution with the substance amount concentration of 60-100 mmol/L and the 2-methylimidazole solution with the 2-methylimidazole substance amount concentration of 1.5-2.5 mol/L with the AuNCs purified in the step S1 to obtain a mixed solution B, carrying out ultrasonic treatment on the mixed solution B, then centrifuging, washing and centrifuging to obtain a precipitate, namely the AuNCs @ ZIF-8 drug carrier.
2. The method according to claim 1, wherein the mixed solution in the step S1 contains chloroauric acid at a mass concentration of 0.5 to 1.0mg/mL.
3. The method according to claim 1, wherein the mixed solution in step S1 contains glutathione at a mass concentration of 0.5 to 1.5mg/mL.
4. AuNC @ ZIF-8 pharmaceutical carrier prepared according to any one of claims 1 to 3.
5. The AuNC @ ZIF-8 pharmaceutical carrier of claim 4, wherein the AuNC @ ZIF-8 pharmaceutical carrier has an average particle size of 235 ± 26.4nm.
6. The AuNC @ ZIF-8 drug carrier of claim 4, wherein the AuNC @ ZIF-8 drug carrier has a fluorescence quantum yield of more than 50%.
7. The use of an AuNC @ ZIF-8 pharmaceutical carrier as claimed in claim 4 in the manufacture of a photoresponsive medicament and/or in the manufacture of a medicament for the treatment of cancer.
8. The use of an AuNC @ ZIF-8 drug carrier as claimed in claim 4 in drug photoimaging assays.
9. A preparation method of a light-controlled release medicine comprises the following steps:
s3, synthesizing AuNCs: preparing chloroauric acid and glutathione into a mixed solution and reacting to obtain an AuNCs aqueous solution A, wherein the mass concentration of the chloroauric acid is not lower than 0.5mg/mL, and the mass concentration of the glutathione is not lower than 0.5mg/mL; retaining the component with the molecular weight of more than 1kDa in the AuNCs aqueous solution A, wherein the component is purified AuNCs;
s4, respectively preparing Zn 2+ Zinc nitrate solution with the substance quantity concentration of 60-100 mmol/L and 2-methylimidazole solution with the substance quantity concentration of 1.5-2.5 mol/L are mixed with the AuNCs purified in the step S1 to obtain mixed solution B, a medicine is added into the mixed solution B to ensure that the volume concentration of the medicine is 0.2-0.8 mg/mL to obtain mixed solution C, the mixed solution C is subjected to ultrasonic treatment and then is centrifuged to obtain precipitate, and the precipitate after centrifugation is washed to obtain the light-controlled release medicine.
10. A light-controlled release drug prepared by the preparation method of claim 9.
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