CN115252820B - Preparation method and application of gold-loaded novel MOF composite material with double targeting functions and aggregation-induced emission - Google Patents
Preparation method and application of gold-loaded novel MOF composite material with double targeting functions and aggregation-induced emission Download PDFInfo
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- 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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- 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
- A61K33/242—Gold; Compounds thereof
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- 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
- A61K47/62—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 a protein, peptide or polyamino acid
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- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The invention discloses a preparation method of a nano-gold-loaded novel MOF composite material with double targeting functions and aggregation-induced emission, which comprises the following steps: s01, preparing MOF materials: weighing 0.80-0.90 g of HDBB and 0.45-0.55 g of ceric ammonium nitrate, putting into a tetrafluoroethylene reaction kettle, adding 20-30 mL of DMF and 10-15 mL of formic acid solution, fully stirring until the solution is clear, reacting for at least 24 hours under the constant temperature heating condition of 90-120 ℃, cooling to room temperature after the reaction is completed, washing, and freeze-drying to obtain yellow solid powder, namely MOF material, for later use. The invention also discloses application of the novel MOF composite material obtained by the preparation method in preparing a medicine for treating brain tumor. According to the invention, through the characteristics of high porosity and low cytotoxicity of the MOF material, high-efficiency load and tumor targeting accurate transportation of the nano gold are realized.
Description
Technical Field
The invention relates to a preparation method and application of a nano-gold-loaded novel MOF composite material with double targeting functions and aggregation-induced emission, and belongs to the technical field of medicines.
Background
Traditional MOF drug carriers are mostly modified on common MOFs, so that targeting functions and positioning are achieved. For example, metal organic frame Materials (MOFs) MOF-808 are used as a substrate, organic small molecules 4, 4' - (1E, 1E) -amide-1, 2-di (methylene) di (2-hydroxybenzoic acid) (HDBB) with aggregation-induced luminescence characteristics and cell penetrating peptide Cys-Arg-Glu-Lys-Ala (CREKA) with tumor targeting function are modified on the surface of the MOF-808 material by a post-synthesis modification method, and the characteristics of high porosity of the MOF material are utilized to load antitumor drugs, so that the tumor accurate targeting delivery and sustained release effects are realized.
However, these drug carriers often suffer from poor expression of the corresponding unilateral performance groups due to excessive external modification groups, limiting the possibilities of multifunctional applications of the drug carrier.
In addition, in an acidic medium, since HDBB contains a large hydrophobic group, it is difficult to dissolve, and molecules aggregate to emit light in an acidic solution. Theoretically, the more acidic the orange fluorescence of HDBB is, the more pronounced. As the pH increases, the HDBB deprotonates to a salt and fluoresces green, but an increase in pH affects the solubility of the HDBB and affects the aggregate luminescence. That is, in the prior art, as the pH becomes higher, the higher the alkalinity becomes, the weaker the fluorescence properties of HDBB become. The normal pH value of the body fluid at different parts of the human body is different, for example, the pH value of arterial blood is 7.35-7.45, and the average pH value is 7.40, and the body fluid belongs to weak alkalinity. The pH value of gastric juice is 1.0-3.0, the pH value of urine is 5.0-6.0, the pH value of cerebrospinal fluid is 7.31-7.34, and the pH value of pancreatic juice produced by pancreas is 7.8-8.0. That is, the existing HDBB cannot realize aggregation-induced emission in alkaline environments (such as arterial blood, cerebrospinal fluid and pancreatic juice), thereby limiting the possibility of multi-functional application of the drug carrier.
Disclosure of Invention
The invention aims to solve the technical problem of providing a preparation method of a nano-gold loaded novel MOF composite material with double targeting functions and aggregation-induced emission, wherein the stronger the alkalinity is and the stronger the HDBB fluorescence is in a certain range.
Meanwhile, the invention provides an application of the nano-gold-loaded novel MOF composite material with double targeting functions and aggregation-induced emission, which is obtained by the preparation method, in preparing a medicine for treating brain tumor.
In order to solve the technical problems, the invention adopts the following technical scheme:
a preparation method of a nano-gold-loaded novel MOF composite material with double targeting functions and aggregation-induced emission comprises the following steps:
s01, preparing MOF materials: weighing 0.80-0.90 g of HDBB and 0.45-0.55 g of ceric ammonium nitrate, putting into a tetrafluoroethylene reaction kettle, adding 20-30 mL of DMF and 10-15 mL of formic acid solution, fully stirring until the solution is clear, reacting for at least 24 hours under the constant temperature heating condition of 90-120 ℃, cooling to room temperature after the reaction is completed, washing, and freeze-drying to obtain yellow solid powder, namely MOF material for later use;
preparation of a MOF@T7@Angiopep-2 composite material: weighing 10-20 mg of T7 peptide and 10-20 mg of Angiopep-2 brain peptide, placing the obtained mixture in a round bottom flask filled with 5-10 mL of DMF, stirring the obtained mixture at 80-120 r/min until the obtained mixture is completely dissolved, adding 200-350 mg of MOF material prepared by S01, adding 300-350 mg of hexafluorophosphate and 0.3-0.5 mL of diisopropylethylamine, sealing and keeping out of the sun, and stirring the obtained mixture at room temperature for 24-30 h; after the reaction is finished, washing and freeze-drying are carried out to obtain the MOF@T7@Angiopep-2 composite material;
s03, preparing MOF@T7@Angiopep-2 composite material loaded nano gold: weighing 6-8 mg of HAuCl 4 ·4H 2 O is dissolved in 20-30 mL of deionized water, stirred until the O is completely dissolved, a bright yellow chloroauric acid solution is obtained, 20-25 mg of MOF@T7@Angiopep-2 composite material prepared by S02 is put into a round bottom flask, then 20-25 mL of chloroauric acid solution is added, stirring is carried out at room temperature for at least 1h, then 9-11 mg of sodium citrate is added, stirring is carried out at 35-40 ℃ for 3-5 h, and a light purple turbid liquid is obtained; after the reaction is completed, washing and freeze-drying are carried out, and the MOF@T7@Angiopep-2@Au composite material is obtained.
In S01, the washing method comprises the following steps: washing with 20-30 mL of DMF at least 3 times, and washing with 20-30 mL of absolute ethyl alcohol at least 3 times; the freeze-drying method comprises the following steps: vacuum drying at-50 deg.c in freeze drier for 10-15 hr.
In S02, the method of washing is: washing thoroughly with DMF at least 3 times; the freeze-drying method comprises the following steps: transferring the mixture into a freeze dryer, and vacuum drying the mixture for 12 to 18 hours at the temperature of minus 50 ℃.
In S03, the washing method comprises the following steps: washing thoroughly with deionized water at least 3 times; the freeze-drying method comprises the following steps: transferring to a freeze dryer, and vacuum drying at-50deg.C for at least 12 hr.
In S01, the MOF material is of a three-dimensional structure, cerium ions and fluorescent micromolecules HDBB are connected through metal coordination bonds, so that the stronger the alkalinity of the MOF material is, the stronger the fluorescence of the HDBB is.
The pH is in the range of 5.5 to 7.5.
The novel nano-gold-loaded MOF composite material with double targeting functions and aggregation-induced emission is obtained by the preparation method.
An application of a gold-loaded novel MOF composite material with double targeting functions and aggregation-induced emission in preparing a medicine for treating brain tumor.
The preparation principle of the MOF material comprises the following steps: the principle of the Daff reaction is adopted, namely, hexamethylenetetramine is used for formylating the aromatic compound. Preparing 4-aldehyde-3-hydroxybenzoic acid. Then the Schiff base reaction is used, namely, the nucleophilic addition reaction of aldehyde and primary amine is carried out under certain conditions, and then a molecule of water is eliminated to generate a product with the general formula RCH=NR 1 It was shown that HDBB with aggregation-induced emission was prepared.
According to the invention, terephthalic acid and transition metal cerium are used for synthesizing the MOF material, and the transition metal cerium ions and HDBB are connected through metal coordination bonds. In an acidic medium, the HDBB contains large hydrophobic groups, is difficult to dissolve, and molecules are concentrated in the solution to emit light. Theoretically, the more acidic the more pronounced the orange fluorescence. As the pH increases, HDBB deprotonates to salt and fluoresces green, but a high pH affects HDBB solubility and aggregation luminescence. Therefore, the invention constructs the MOF three-dimensional structure, uses metal ion connection points to connect fluorescent small molecules, so that the fluorescent small molecules are fixed at a certain position (the crystal form is shown by XRD patterns), and the intermolecular activities are limited, namely, the fluorescent small molecules can be aggregated and luminescent in alkaline medium, thus obtaining the novel porous composite material with stronger alkalinity and stronger fluorescence within a certain range.
The modification principle of the MOF composite material comprises the following steps: the surface layer of the synthesized porous material (namely MOF material) has partially unreacted exposed carboxyl, and a certain amount of catalyst is added to promote the exposed carboxyl and the amino of the target polypeptide to form amide, so that the targeting function of the MOF composite material is realized.
According to the invention, gold ions in chloroauric acid solution are fully adsorbed through high porosity and large pore diameter of a porous material (namely MOF material), and then a catalyst is added to reduce the porous material gold ions into nano gold, so that the purpose of loading the nano gold is achieved.
The aggregation-induced emission principle of the invention: the fluorescence is enhanced by blocking the rotation of the molecule, which is the mechanism of aggregation-induced emission, and by preventing the molecule from consuming the excited state energy. Synthesizing a long chain molecule of a rotatable diphenyl ring in the molecule, and aggregating the molecules together through a metal coordination bond to realize aggregation-induced luminescence.
The polypeptide targeting principle of the invention: targeting functional polypeptides T7 and Angiopep-2 synthesized by taking endogenous polypeptides as templates are firstly mediated by the Angiopep-2 polypeptides and a low density lipoprotein receptor LRP1 to realize the crossing of a blood brain barrier; then, the T7 peptide is utilized to highly affine with a transferrin receptor TfR which is highly expressed in brain capillary endothelial, and accurate brain targeting is further realized through receptor mediated endocytosis. Bifunctional targeting guides generally have higher target affinity in humans with less risk of off-target.
The invention has the following beneficial effects:
the invention provides a preparation method and application of a gold-loaded novel MOF composite material with double targeting functions and aggregation-induced emission, and the high-efficiency load and tumor targeting accurate transportation of gold nanoparticles are realized through the characteristics of high porosity and low cytotoxicity of the MOF material. The invention not only endows the MOF material with a certain function (within a certain range, the stronger the alkalinity is, the stronger the fluorescence of HDBB is), but also increases the space which can be modified on the surface of the material, so that the single function is easier to express or the material can be modified more. The invention further aims to provide a visual accurate positioning method for in-vivo nano-gold targeted therapy, which is characterized in that the method for synthesizing the MOF material by taking organic micromolecules with specific functions as connectors is adopted, and the method for synthesizing the MOF material by taking organic micromolecules HDBB with aggregation-induced emission characteristics as raw materials is adopted, so that the visual accurate positioning process of tumor cells of a drug carrier is realized.
Drawings
FIG. 1 is a schematic diagram showing the synthesis of HDBB in the present invention;
FIG. 2 is an infrared spectrum of HDBB and MOF materials of the present invention;
FIG. 3 is a graph showing nitrogen adsorption isotherms of MOF materials of the present invention;
FIG. 4 shows fluorescence spectra of HDBB of the present invention under 415.0nm excitation in phosphate buffer solutions of different pH concentrations;
FIG. 5 is a fluorescence spectrum of MOF@T7@Angiopep-2 composite material according to the invention under 415nm excitation in phosphate buffer solutions with different pH concentrations;
FIG. 6 is an amino acid analysis of a MOF@T7@Angiopep-2 composite material according to the invention;
FIG. 7 is a graph comparing the UV-visible absorption spectra of the gold nanoparticle, MOF@T7@Angiopep-2 composite material and MOF@T7@Angiopep-2@Au composite material of the invention;
FIG. 8 is an XRD pattern for a MOF@T7@Angiopep-2 composite material and a MOF@T7@Angiopep-2@Au composite material according to the present invention;
FIG. 9 is a graph of the cellular activity of MOF@T7@Angiopep-2 composite materials of the invention tested by the CCK-8 method;
FIG. 10 is a plot of a cell-targeted laser scanning confocal microscope of the MOF@T7@Angiopep-2 composite material of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more clear, the present invention will be described in further detail with reference to the accompanying drawings and examples. The specific embodiments described herein are to be considered in an illustrative sense only and are not intended to limit the invention.
Example 1:
a preparation method of a nano-gold-loaded novel MOF composite material with double targeting functions and aggregation-induced emission comprises the following steps:
1. preparation of aggregation-induced emission small organic molecules:
(1) 2.0g of m-hydroxybenzoic acid was weighed, 15mL of methanesulfonic acid was added thereto, and stirring was carried out at 150 r/min. Weighing 3.0-3.5 g of hexamethylenetetramine (urotropine), adding about 0.1g of hexamethylenetetramine each time, stirring uniformly in 150r/min water bath at the temperature of 80 ℃, and refluxing and stirring for 3 hours. The reaction was monitored using thin layer chromatography, and until the starting material was consumed, the temperature was reduced to 50 ℃ and 10mL of deionized water was added. Stopping heating, continuing stirring, and stopping stirring after the temperature of the solution reaches the room temperature for 1 h. The product was extracted 6 times with a mixture of ethyl acetate and methanol (5:1, v/v) and the upper organic phases were combined and washed 3 times with 3mL of saturated sodium chloride solution. Extracting with 10% (V/W) sodium hydroxide solution, washing with 5mL for several times until the added sodium hydroxide is not discolored, and adjusting pH of the obtained water phase to 3 with concentrated hydrochloric acid. Filtering, and vacuum freeze drying to obtain pale yellow solid powder 4-aldehyde-3-hydroxybenzoic acid.
(2) The resulting pale yellow solid powder of 4-formyl-3-hydroxybenzoic acid was weighed 0.8g at room temperature, placed in a three-necked flask, 15mL of methanol was added, 0.25g of hydrazine sulfate was slowly added using an addition funnel, stirred well at 100r/min and heated for 1h, and then washed well with methanol. Vacuum freeze drying, and transferring into ethanol solution for one-time recrystallization. Vacuum drying at-50deg.C to obtain yellow solid powder HDBB, the synthetic route of which is shown in figure 1. Since HDBB contains large hydrophobic groups, it is difficult to dissolve, and molecules aggregate to emit light in an acidic solution. As shown in fig. 4, the stronger the acidity, the more pronounced the fluorescence of HDBB. As the pH increases, the weaker the HDBB fluorescence affects the aggregate luminescence.
2. Preparation of MOF material:
0.80g of HDBB and were weighed out0.45g of ceric ammonium nitrate is put into a clean tetrafluoroethylene reaction kettle, 20mL of N, N-Dimethylformamide (DMF) and 10mL of formic acid solution are added, and the mixture is fully stirred until the solution is clear and then reacted for 24 hours under the condition of constant temperature heating at 90 ℃. After the reaction is cooled to room temperature, washing with 20mL of DMF solution for 3 times, washing with 20mL of absolute ethanol solution for 3 times, transferring into a freeze dryer, and vacuum drying for 10 hours at-50 ℃ to obtain yellow solid powder MOF material for later use; as can be seen from FIG. 2, at 780cm -1 The absorption peak of the metal hydroxide bond appears, proving that the HDBB is connected with the cerium ion. Through testing, the specific surface area is 27.5031m 2 Per g, average adsorption pore diameter of
I.e. the MOF material is a porous material. As shown in fig. 3, the results of the nitrogen adsorption isotherm of the MOF material are shown, and it can be seen that the MOF material has adsorptivity.
3. Preparation of MOF@T7@Angiopep-2 composite material:
10mg of T7 peptide and 10mg of Angiopep-2 brain peptide were weighed, placed in a round bottom flask containing 5-mL of N, N-Dimethylformamide (DMF), stirred at 80r/min until complete dissolution, then 200mg of the prepared porous MOF material was added, 300mg of hexafluorophosphate and 0.3mL of diisopropylethylamine were added, and the mixture was stirred under sealed light-shielding conditions at room temperature for 24 hours. After the reaction is completed, the mixture is fully washed for 3 times by using N, N-Dimethylformamide (DMF), and then transferred to a freeze dryer for vacuum drying for 12 hours at the temperature of minus 50 ℃ to obtain the MOF@T7@Angiopep-2 composite material. As shown in FIG. 5, the MOF@T7@Angiopep-2 composite material obtained in the embodiment still has good fluorescence under an alkaline condition, and in the embodiment, by constructing a MOF three-dimensional structure and connecting fluorescent small molecules HDBB by using cerium metal ion connection points, the MOF material is fixed at a certain position (the MOF material has a crystal form as seen by an XRD chart of FIG. 8) and intermolecular activities are limited, so that the MOF material can gather and emit light even in an alkaline medium, and a novel porous composite material with stronger alkalinity and stronger fluorescence in a certain range is obtained. As shown in FIG. 6, the analysis result contains the specific amino acids of two polypeptides, which proves that the T7 and Angiopep-2 polypeptides are connected on the surface of the composite material.
4. Preparation of MOF@T7@Angiopep-2 composite material supported nano gold:
weighing 6mg of HAuCl 4 ·4H 2 O is dissolved in 20mL of deionized water, stirred until the O is completely dissolved, bright yellow chloroauric acid solutions with the concentration of 1mM are obtained, 20mg of MOF@T7@Angiopep-2 composite material is added into a round bottom flask, 20mL of chloroauric acid solution is added, stirring is carried out for 1h at room temperature, 9mg of sodium citrate is added, and stirring is carried out for 3h at 35 ℃ to obtain light purple turbid liquid. And after the reaction is finished, fully washing for 3 times by using deionized water, transferring to a freeze dryer, and vacuum drying for 12 hours at the temperature of minus 50 ℃ to obtain the MOF@T7@Angiopep-2@Au composite material. As shown in fig. 7, the absorption peak position of the gold nanoparticles is at 520nm, which proves that the composite material is loaded with nano gold. As shown in FIG. 8, the diffraction peak positions are mainly concentrated in the range of 10-30 degrees, and after the diffraction peak positions are compounded with the Au nanoparticles, obvious characteristic diffraction peaks belonging to the Au particles appear, wherein 38.2 degrees, 44.4 degrees and 64.6 degrees respectively correspond to (111), (200) and (220) crystal faces of the Au. Meanwhile, after the Au particles are compounded, the characteristic peak attributed to the MOF is extremely weak, because the model of the MOF is weakened under the influence of the strong characteristic peak of the Au.
The embodiment provides a novel nano-gold-loaded MOF composite material with double targeting functions and aggregation-induced emission, which is obtained by adopting the preparation method. As shown in FIG. 9, the MOF@T7@Angiopep-2 composite material was tested for cell activity by the CCK-8 method, and the result showed low toxicity of the MOF@T7@Angiopep-2 composite material.
The embodiment provides an application of a gold-loaded novel MOF composite material with double targeting functions and aggregation-induced emission in preparing a medicine for treating brain tumor. As shown in fig. 10, the cell-targeting laser scanning confocal microscopy of the mof@t7@angiopep-2 composite material illustrates that the mof@t7@angiopep-2 composite material has targeting property. Targeting functional polypeptides T7 and Angiopep-2 synthesized by taking endogenous polypeptides as templates are firstly mediated by the Angiopep-2 polypeptides and a low density lipoprotein receptor LRP1 to realize the crossing of a blood brain barrier; then, the T7 peptide is utilized to highly affine with a transferrin receptor TfR which is highly expressed in brain capillary endothelial, and accurate brain targeting is further realized through receptor mediated endocytosis.
Example 2:
a preparation method of a nano-gold-loaded novel MOF composite material with double targeting functions and aggregation-induced emission comprises the following steps:
1. preparation of aggregation-induced emission small organic molecules:
(1) 3.0g of m-hydroxybenzoic acid was weighed, and 20mL of methanesulfonic acid was added thereto and stirred at 200 r/min. 3.5g of hexamethylenetetramine (urotropin) is weighed and added in multiple times, about 0.1g of hexamethylenetetramine is added each time, and the mixture is stirred uniformly in a water bath at 200r/min and the temperature is up to 80 ℃, and the mixture is stirred under reflux for 5 hours. The reaction was monitored using thin layer chromatography, and until the starting material was consumed, the temperature was reduced to 50 ℃ and 20mL of deionized water was added. Stopping heating, continuing stirring, and stopping stirring after the temperature of the solution reaches the room temperature for 1 h. The product was extracted 8 times with a mixture of ethyl acetate and methanol (5:1, v/v) and the upper organic phases were combined and washed 3 times with 4mL of saturated sodium chloride solution. 10mL of the aqueous phase is extracted and washed for a plurality of times by using a 10% (V/W) sodium hydroxide solution until the added sodium hydroxide does not change color, and the pH of the aqueous phase is adjusted to 4 by using concentrated hydrochloric acid. Filtering, and vacuum freeze drying to obtain pale yellow solid powder 4-aldehyde-3-hydroxybenzoic acid.
(2) 1.0g of the pale yellow solid powder of the obtained 4-aldehyde-3-hydroxybenzoic acid was weighed into a three-necked flask at room temperature, 20mL of methanol was added, 0.45g of hydrazine sulfate was slowly added using an addition funnel, and the mixture was sufficiently stirred and heated at 150r/min for 2 hours, followed by sufficient washing with methanol. Vacuum freeze drying, and transferring into ethanol solution for one time of recrystallization. Vacuum drying is carried out again at the temperature of minus 50 ℃ to obtain yellow solid powder HDBB.
2. Preparation of MOF material:
0.90g of HDBB and 0.55g of ceric ammonium nitrate are weighed and put into a clean tetrafluoroethylene reaction kettle, 30mL of N, N-Dimethylformamide (DMF) and 15mL of formic acid solution are added, and the mixture is fully stirred until the solution is clear and then reacted for 30 hours under the condition of constant temperature heating at 120 ℃. After the reaction is cooled to room temperature, washing with 30mL of DMF solution for 4 times, washing with 30mL of absolute ethanol solution for 4 times, transferring into a freeze dryer, and vacuum drying for 15h at-50 ℃ to obtain yellow solid powder of the novel MOF material for later use.
3. Preparation of MOF@T7@Angiopep-2 composite material:
20mg of T7 peptide and 20mg of Angiopep-2 brain peptide were weighed into a round bottom flask containing 10mL of N, N-Dimethylformamide (DMF), and after 120r/min stirring to complete dissolution, 350mg of the prepared novel porous (i.e., MOF material) was added, 350mg of hexafluorophosphate and 0.5mL of diisopropylethylamine were added, and the mixture was stirred under sealed light-shielding conditions at room temperature for 30 hours. After the reaction is completed, the mixture is fully washed for 4 times by using N, N-Dimethylformamide (DMF), and then transferred to a freeze dryer for vacuum drying for 18 hours at the temperature of minus 50 ℃ to obtain the MOF@T7@Angiopep-2 composite material.
4. Preparation of MOF@T7@Angiopep-2 composite material supported nano gold:
weigh 8mg of HAuCl 4 ·4H 2 O is dissolved in 30mL of deionized water, stirred until the O is completely dissolved, a bright yellow chloroauric acid solution is obtained, 25mg of MOF@T7@Angiopep-2 composite material is added, the mixture is placed into a round bottom flask, 25mL of the chloroauric acid solution is added, stirring is carried out for 2 hours at room temperature, 11mg of sodium citrate is added, and stirring is carried out for 5 hours at 40 ℃ to obtain a light purple turbid liquid. And after the reaction is finished, fully washing for 4 times by using deionized water, transferring to a freeze dryer, and vacuum drying for 18 hours at the temperature of minus 50 ℃ to obtain the MOF@T7@Angiopep-2@Au composite material.
Example 3:
a preparation method of a nano-gold-loaded novel MOF composite material with double targeting functions and aggregation-induced emission comprises the following steps:
1. preparation of aggregation-induced emission small organic molecules:
(1) 2.5g of m-hydroxybenzoic acid was weighed, 18mL of methanesulfonic acid was added thereto and stirred at 180 r/min. 3.2g of hexamethylenetetramine (urotropin) is weighed and added in multiple times, about 0.1g of hexamethylenetetramine is added each time, and the mixture is stirred uniformly in a water bath at 180r/min and the temperature is up to 80 ℃, and the mixture is stirred under reflux for 4 hours. The reaction was monitored using thin layer chromatography, and until the starting material was consumed, the temperature was reduced to 50 ℃ and 15mL of deionized water was added. Stopping heating, continuing stirring, and stopping stirring after the temperature of the solution reaches the room temperature for 1 h. The product was extracted 7 times with a mixture of ethyl acetate and methanol (5:1, v/v) and the upper organic phases were combined and washed 3 times with 3.5mL of saturated sodium chloride solution. 8mL of the aqueous phase was extracted and washed with 10% (V/W) sodium hydroxide solution for a plurality of times until the added sodium hydroxide was not discolored, and the pH of the aqueous phase was adjusted to 3.5 with concentrated hydrochloric acid. Filtering, and vacuum freeze drying to obtain pale yellow solid powder 4-aldehyde-3-hydroxybenzoic acid.
(2) The resulting pale yellow solid powder of 4-formyl-3-hydroxybenzoic acid, 0.9g, was weighed into a three-necked flask at room temperature, 17mL of methanol was added, 0.35g of hydrazine sulfate was slowly added using an addition funnel, and the mixture was stirred well at 120r/min and heated for 1.5 hours, followed by thorough washing with methanol. Vacuum freeze drying, and transferring into ethanol solution for one time of recrystallization. Vacuum drying is carried out again at the temperature of minus 50 ℃ to obtain yellow solid powder HDBB.
2. Preparation of MOF material:
0.85g of HDBB and 0.50g of ceric ammonium nitrate are weighed and put into a clean tetrafluoroethylene reaction kettle, 25mL of N, N-Dimethylformamide (DMF) and 12mL of formic acid solution are added, and the mixture is fully stirred until the solution is clear and then reacted for 24 hours under the condition of constant temperature heating at 105 ℃. After the reaction is cooled to room temperature, washing 3 times by 25mL of DMF solution and 3 times by 25mL of absolute ethanol solution, transferring into a freeze dryer, and vacuum drying for 12 hours at-50 ℃ to obtain yellow solid powder novel MOF material for later use.
3. Preparation of MOF@T7@Angiopep-2 composite material:
15mg of T7 peptide and 15mg of Angiopep-2 brain peptide were weighed into a round bottom flask containing 8mL of N, N-Dimethylformamide (DMF), and after stirring at 100r/min until complete dissolution, 280mg of the prepared novel porous (i.e., MOF material) was added, 320mg of hexafluorophosphate and 0.4mL of diisopropylethylamine were added, and stirring was performed under sealed light-shielding conditions at room temperature for 27h. After the reaction is completed, the mixture is fully washed for 3 times by using N, N-Dimethylformamide (DMF), and then transferred to a freeze dryer for vacuum drying for 15 hours at the temperature of minus 50 ℃ to obtain the MOF@T7@Angiopep-2 composite material.
4. Preparation of MOF@T7@Angiopep-2 composite material supported nano gold:
weigh 7mg of HAuCl 4 ·4H 2 O is dissolved in 25mL of deionized water, stirred until the O is completely dissolved, a bright yellow chloroauric acid solution is obtained, 22mg of MOF@T7@Angiopep-2 composite material is added, the mixture is placed into a round bottom flask, 22mL of the chloroauric acid solution is added, stirring is carried out for 1.5h at room temperature, 10mg of sodium citrate is added, and stirring is carried out for 4h at 37 ℃ to obtain a light purple turbid liquid. And after the reaction is finished, fully washing for 3 times by using deionized water, transferring to a freeze dryer, and vacuum drying for 15 hours at the temperature of minus 50 ℃ to obtain the MOF@T7@Angiopep-2@Au composite material.
The foregoing has shown and described the basic principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that the above embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the spirit and scope of the invention, which is defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (7)
1. A preparation method of a nano-gold-loaded MOF composite material with double targeting functions and aggregation-induced emission is characterized by comprising the following steps: the method comprises the following steps:
s01, preparing MOF materials: weighing 0.80-0.90 g of HDBB and 0.45-0.55 g of ceric ammonium nitrate, putting into a tetrafluoroethylene reaction kettle, adding 20-30 mL of DMF and 10-15 mL of formic acid solution, fully stirring until the solution is clear, reacting for at least 24 hours under the constant temperature heating condition of 90-120 ℃, cooling to room temperature after the reaction is completed, washing, and freeze-drying to obtain yellow solid powder, namely MOF material for later use;
preparation of a MOF@T7@Angiopep-2 composite material: weighing 10-20 mg of T7 peptide and 10-20 mg of Angiopep-2 brain peptide, placing the obtained mixture in a round-bottomed flask filled with 5-10 mL of DMF, stirring the obtained mixture at 80-120 r/min until the obtained mixture is completely dissolved, adding 200-350 mg of MOF material prepared by S01, adding 300-350 mg of hexafluorophosphate and 0.3-0.5 mL of diisopropylethylamine, and stirring the obtained mixture for 24-30 hours at room temperature in a sealed light-proof manner; after the reaction is finished, washing and freeze-drying are carried out to obtain the MOF@T7@Angiopep-2 composite material;
s03, preparing MOF@T7@Angiopep-2 composite material loaded nano gold: weighing 6-8 mg of HAuCl 4 ·4H 2 O is dissolved in 20-30 mL of deionized water, stirred until the O is completely dissolved, a bright yellow chloroauric acid solution is obtained, 20-25 mg of MOF@T7@Angiopep-2 composite material prepared by S02 is put into a round bottom flask, then 20-25 mL of chloroauric acid solution is added, stirring is carried out at room temperature for at least 1h, then 9-11 mg of sodium citrate is added, stirring is carried out at 35-40 ℃ for 3-5 h, and a light purple turbid liquid is obtained; after the reaction is completed, washing and freeze-drying are carried out, and the MOF@T7@Angiopep-2@Au composite material is obtained.
2. The method of manufacturing according to claim 1, characterized in that: in S01, the washing method comprises the following steps: washing with 20-30 mL of DMF for at least 3 times, and washing with 20-30 mL of absolute ethyl alcohol for at least 3 times; the freeze-drying method comprises the following steps: transferring the mixture into a freeze dryer, and vacuum drying the mixture for 10-15 h at the temperature of minus 50 ℃.
3. The method of manufacturing according to claim 1, characterized in that: in S02, the method of washing is: washing thoroughly with DMF at least 3 times; the freeze-drying method comprises the following steps: transferring the mixture into a freeze dryer, and vacuum drying the mixture for 12-18 h at the temperature of minus 50 ℃.
4. The method of manufacturing according to claim 1, characterized in that: in S03, the washing method comprises the following steps: washing thoroughly with deionized water at least 3 times; the freeze-drying method comprises the following steps: transferring to a freeze dryer, and vacuum drying at-50deg.C for at least 12 hr.
5. The method of manufacturing according to claim 1, characterized in that: in S01, the MOF material is of a three-dimensional structure, cerium ions are connected with fluorescent micromolecules HDBB through metal coordination bonds, so that the MOF material has stronger alkalinity and stronger HDBB fluorescence within the pH range of 5.5-7.5.
6. The nano-gold-loaded MOF composite material with double targeting functions and aggregation-induced emission, which is obtained by the preparation method according to any one of claims 1-5.
7. The application of the gold-loaded MOF composite material with double targeting functions and aggregation-induced emission in preparing a medicine for treating brain tumor according to claim 6.
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