CN113171454B - Degradable bismuth-based microwave diagnosis and treatment reagent and preparation method and application thereof - Google Patents

Degradable bismuth-based microwave diagnosis and treatment reagent and preparation method and application thereof Download PDF

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CN113171454B
CN113171454B CN202110378042.9A CN202110378042A CN113171454B CN 113171454 B CN113171454 B CN 113171454B CN 202110378042 A CN202110378042 A CN 202110378042A CN 113171454 B CN113171454 B CN 113171454B
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bismuth
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shell structure
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CN113171454A (en
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李世美
孟宪伟
谭龙飞
任湘菱
吴琼
付长慧
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Technical Institute of Physics and Chemistry of CAS
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Abstract

The invention discloses a degradable bismuth-based microwave diagnosis and treatment reagent and a preparation method and application thereof. The main chemical bond required for forming the nano complex-based porous core-shell structure is an amido bond, and the bond can be selectively degraded in a tumor weak acid environment; meanwhile, in the porous core-shell structure, the core nano complex and the shell COF have large pi electron groups, so that an effective pi-pi conjugation effect exists between the core nano complex and the shell COF, and the obtained COF shell is more compact and the core-shell structure is more stable. The nano-complex-based porous core-shell structure has efficient microwave thermal conversion, microwave generation of active oxygen, CT/MR/X-ray fluorescence imaging performance and tumor microenvironment responsive degradation performance, and can be used as a microwave diagnosis and treatment reagent to realize tumor diagnosis and treatment integration.

Description

Degradable bismuth-based microwave diagnosis and treatment reagent and preparation method and application thereof
Technical Field
The invention relates to a microwave diagnosis and treatment reagent, in particular to a preparation method of a degradable bismuth-based microwave diagnosis and treatment reagent and application of the degradable bismuth-based microwave diagnosis and treatment reagent in microwave diagnosis and treatment.
Background
The thermotherapy technology, as an ablation therapy which can not only avoid large-area tissue damage to a patient caused by surgical operation, but also avoid toxic and side effects caused by a large amount of medicines in vivo, has gradually become a research hotspot in the current tumor micro/noninvasive therapy. The microwave has the advantages of good biological safety, high heat conversion efficiency, deep tissue penetration depth, no interference of bones and gas and the like, and is widely applied to clinical treatment of various diseases. Along with this, the microwave thermotherapy technology for tumor is also attracting more and more interest. However, because the microwave ablation apparatus is limited by the problems that the heating efficiency of the existing microwave apparatus is insufficient, the normal tissue around the focus is easily damaged due to larger microwave radiation power, the tumor ablation is incomplete due to the microwave ablation, the heat transfer caused by the ablation is easily carbonized is blocked, and the like, the heat conversion efficiency of the microwave radiation energy at the tumor is specifically improved, the microwave ablation precision is improved, and the microwave ablation apparatus is combined with other novel effective therapies (such as dynamic therapy), and has great research significance for the synergistic effect of the microwave ablation.
The nanometer microwave sensitizer can specifically absorb and convert microwave radiation energy due to the existence of a special structural confinement effect so as to obviously enhance the heat conversion efficiency of microwaves, thereby realizing excellent microwave heat ablation effect at lower microwave radiation frequency. Under the action of an external microwave magnetic field, the nanoscale microwave sensitizer gathered at the tumor can specifically cause the microwave heating of tumor tissues, so that the damage of microwave radiation to normal tissues is weakened, and the application prospect of the microwave ablation technology is greatly expanded. At present, the successfully prepared microwave sensitizer mainly comprises inorganic materials such as metal oxide microspheres and ionic liquid, the microwave thermal sensitization performance of the microwave sensitizer is insufficient, and the problems of biological safety and the like also face challenges. Therefore, the development of the nano-grade sensitizing material with good biocompatibility and high microwave heat conversion rate has great significance for the further development of the microwave thermotherapy of the tumor.
Microwave power, as a novel therapy in tumor treatment, is to generate active oxygen species in a tumor microenvironment to generate an oxidation reaction with tumor cells so as to induce the necrosis and apoptosis of the tumor cells. The combination of the microwave power and the microwave thermotherapy effectively solves the problem of incomplete tumor ablation in the microwave thermotherapy and further enhances the microwave therapy efficiency of the tumor. Therefore, the nano-scale microwave sensitizer which can enhance the microwave thermal sensitivity of the tumor part and generate active oxygen species under the stimulation of microwave is developed, and has important significance for the research of microwave power and microwave thermal therapy.
In order to effectively alleviate the pain of cancer patients, the diagnosis and treatment integrated technology has become the mainstream of the current research. The development of various contrast agents and imaging probes and their application in imaging techniques such as fluorescence imaging, CT, MR etc. have developed endlessly. The optical imaging technology has become a widely used imaging mode due to its advantages of small invasiveness, strong real-time performance, wide range, high sensitivity, etc. However, the ordinary optical imaging has the existence of autofluorescence which causes poor imaging signal-to-noise ratio, and the insufficient penetration depth in the tissue also severely limits the application development. The X-ray fluorescence imaging refers to optical imaging excited by X-rays, and as a novel imaging technology, the X-ray fluorescence imaging has the advantages of deep penetration depth of biological tissues, high spatial resolution, good three-dimensional imaging effect and the like, so that people pay extensive attention to the X-ray fluorescence imaging, and the development of nanotechnology further promotes the application development of X-ray fluorescence probes. At present, the widely researched X-ray fluorescent nano probe mainly comprises gold nanoclusters, nano phosphide, rare earth doped inorganic nano materials (Tb/Eu-NaGdF 4, er/Yb-NaYF4 and the like) and other metal-based nano frame materials with high atomic number and large X-ray attenuation coefficient.
Disclosure of Invention
In order to improve the technical problems, the invention provides a microwave diagnosis and treatment reagent integrating biodegradability, high microwave heat conversion efficiency, microwave active oxygen generation and imaging performance, a preparation method thereof and application thereof in tumor microwave diagnosis and treatment.
In order to achieve the purpose, the invention is realized by the following technical scheme:
a core-shell structure is characterized in that a bismuth-based nano complex is adopted as an inner core of the core-shell structure, and a degradable Covalent Organic Framework (COF) is adopted as a shell.
According to an embodiment of the present invention, the degradable Covalent Organic Framework (COF) is an acid degradable Covalent Organic Framework (COF), preferably, the Covalent Organic Framework (COF) contains amide bonds, which can be degraded under acidic conditions.
According to an embodiment of the invention, the inner core and the outer shell are connected by a bond, for example an amide bond.
According to an embodiment of the present invention, the bismuth-based nanocomplexes have a carboxyl group, which forms an amide bond with an amino group in a Covalent Organic Framework (COF).
According to the embodiment of the invention, the bismuth-based nano complex of the core contains carboxyl, the carboxyl is bonded with a COF monomer containing amino functional groups through an amide bond, then the amide bond is formed again through other amino groups in the COF monomer and the COF monomer containing aldehyde groups, and the core-shell structure is formed through sequential bonding.
According to an embodiment of the invention, the nucleocapsid structure is selectively degradable in a tumor weakly acidic microenvironment.
According to the embodiment of the invention, the bismuth-based nano complex has imaging performances such as X-ray fluorescence imaging, CT, MR and the like.
According to an embodiment of the present invention, the bismuth-based nanocomplexes are nanoparticles containing bismuth ion complexes, and optionally may also contain other metal ion complexes, such as cobalt ions, gadolinium ions, manganese ions, iron ions, and the like.
The ligand of the complex may be an organic ligand containing a carboxyl group, such as one, two or more of porphyrin (e.g., meso-tetra (4-carboxyphenyl) porphine), trimesic acid, terephthalic acid, fumaric acid, L-tyrosine, and L-arginine, which have a carboxyl group.
According to an embodiment of the present invention, the COF shell layer is coated with an amino functional group-containing COF monomer (e.g., 1,3,5-tris (4-aminophenyl) benzene, 4,4',4"- (1,3,5-triazine-2,4,6-triyl) triphenylamine, p-phenylenediamine, etc.) and an aldehyde group-containing COF monomer (e.g., 2,5-dimethoxybenzene-1,4-dicarboxaldehyde, 2,4,6-trihydroxy-1,3,5-benzenetricarboxylic aldehyde, terephthaldehyde, 1,3,5-trimesic aldehyde, etc.) by forming an amide bond on a nanocomplex as an inner core.
According to the embodiment of the invention, the length and width of the core-shell core bismuth-based nano complex range from 50nm to 300nm, and the thickness of the external COF shell layer ranges from 5nm to 100nm.
According to an embodiment of the present invention, the core-shell structure is a porous core-shell structure, the core is a degradable bismuth-based nano-complex, pores exist between each complex molecule, and the average pore diameter of the core is preferably about 5-10 nm, exemplary 6nm, 6.7nm, 7nm, 8nm; the shell is a degradable porous COF shell layer, and the average pore diameter of the core-shell structure obtained after COF coating is about 14-22 nm, such as 14nm, 15nm, 15.5nm, 16.1nm and 18nm.
According to the embodiment of the invention, the core-shell structure is a microwave diagnosis and treatment reagent.
The invention also provides a preparation method of the core-shell structure, which comprises the following steps:
1) Mixing bismuth salt, optional other metal salt and organic ligand containing carboxyl, and reacting for a period of time to obtain a nano complex;
2) Mixing the nano complex prepared in the step 1) with a COF monomer containing an amino functional group for reaction, wherein carboxyl carried by the nano complex reacts with amino carried by the monomer to form an amido bond;
3) Mixing the product obtained in the step 2) with a COF monomer containing aldehyde groups for reaction, wherein amino in the product obtained in the step 2) reacts with aldehyde groups in the monomer containing aldehyde groups to form a COF-coated core-shell structure;
4) Mixing the product obtained in the step 3) with a COF monomer containing an amino functional group and an aldehyde group-containing monomer, and reacting to obtain a COF-coated core-shell structure with a thicker shell layer.
According to an embodiment of the present invention, in step 1), the bismuth salt may be selected from at least one of bismuth nitrate, bismuth acetate, and bismuth chloride.
The other metal salt may be selected from, for example, one, two or more of cobalt nitrate, cobalt chloride, gadolinium nitrate, gadolinium chloride, manganese chloride, and ferric chloride.
The organic ligand having a carboxyl group includes, for example: porphyrin bearing carboxyl groups (e.g., meso-tetra (4-carboxyphenyl) porphine), trimesic acid, terephthalic acid, fumaric acid, L-tyrosine, and L-arginine.
According to an embodiment of the present invention, in the above-mentioned steps 2) to 4), the COF monomer having an amino functional group and the COF monomer having an aldehyde group have the meanings as described above.
According to an embodiment of the present invention, in step 2), the mass ratio of the core nanocomplex to the COF monomer containing an amino functional group is preferably 1.5.
According to the embodiment of the invention, in the step 4), the mass ratio of the inner core nano complex to the aldehyde group-containing monomer is preferably 2:1-3:1.
According to an embodiment of the present invention, in the above steps 1) to 4), the reaction is performed in the presence of a solvent, for example, the solvent in step 1) is DMF, and the solvent in steps 2) to 4) is acetonitrile.
According to an embodiment of the present invention, in the above steps 1) to 4), a surfactant is preferably added to increase dispersibility and reduce self-aggregation, for example, the surfactant may be selected from polyvinylpyrrolidone (PVP).
In one embodiment of the invention, in the above steps 2) -4), an appropriate amount of alcohol (such as methanol, or ethanol) can be added to reduce the surface tension of the solution, thereby inhibiting the occurrence of COF self-nucleation.
In one embodiment of the present invention, in the step 4), a proper amount of glacial acetic acid may be added to facilitate the coating of the COF on the surface of the core, and at the same time, the core nanocomplex is not damaged.
In one embodiment of the present invention, the preparation method comprises the steps of:
1) Dissolving bismuth salt and optional other metal salts in N, N-Dimethylformamide (DMF), adding organic ligand containing carboxyl and surface active agent PVP for increasing dispersibility, performing ultrasonic treatment to uniformly disperse the mixture, and stirring at room temperature for 2-12h to obtain a core nano complex product;
2) Dissolving the core nano complex product prepared in the step 1) in acetonitrile, adding PVP (polyvinyl pyrrolidone), and then stirring;
3) Respectively and sequentially adding acetonitrile solutions of two monomers (a COF monomer containing an amino functional group and a monomer containing an aldehyde group) required for forming a COF into the core nano complex solution prepared in the step 2), adding alcohol, reacting, sequentially centrifuging and washing, and dissolving the obtained precipitate into the acetonitrile solution containing PVP again;
4) And (4) sequentially adding two monomers (a COF monomer containing an amino functional group and a COF monomer containing an aldehyde group) required for forming COF into the solution prepared in the step (3), uniformly mixing the three, adding alcohol and glacial acetic acid again, stirring for 2-12h, centrifuging, and washing with ethanol to obtain the microwave diagnosis and treatment reagent with the core-shell structure.
According to the embodiment of the invention, in the step 1), the molar ratio of the metal ions to the organic ligands in the metal salt (bismuth salt and optional other metal salts) is 2:1-4:1, and the mass ratio of the sum of the mass of the metal salt (bismuth salt and optional other metal salts) and the mass of the organic ligands to the mass of the PVP is 1:7-1.
According to an embodiment of the invention, in step 2), the mass ratio of the inner core nanocomplex to PVP is 1:5-1.
According to an embodiment of the present invention, in step 3), the ratio of the volume of the alcohol to the volume of the acetonitrile is 1.
According to an embodiment of the present invention, in step 4), the ratio of the volume of glacial acetic acid to the volume of acetonitrile is 1.
The invention also provides application of the core-shell structure in high-efficiency microwave thermal conversion, microwave generation of active oxygen and CT/MR/X-ray fluorescence imaging.
The invention also provides the core-shell structure used as a microwave diagnosis and treatment reagent.
According to an embodiment of the invention, the nucleocapsid structure is used for the diagnosis and/or treatment of a tumor.
The invention has the beneficial effects that:
(1) The core-shell structure has high-efficiency microwave heat conversion performance, can obviously enhance the specific temperature rise of microwaves at the tumor and enhances the local killing effect on the tumor. Meanwhile, the product has the performance of generating active oxygen under the stimulation of microwave, and can be used for dynamic therapy to further enhance the curative effect on heat-tolerant tumor cells. In addition, the microwave diagnosis and treatment reagent also has the imaging performance at the tumor. The good biological safety of the core-shell structure also lays a foundation for clinical transformation of the core-shell structure.
(2) The main chemical bond required by the formation of the nano complex-based porous core-shell structure is an amido bond, and the bond can be selectively degraded in a tumor weak acid environment; meanwhile, in the porous core-shell structure, the core nano complex and the shell COF shell layer both have large pi electron groups, so that a pi-pi conjugated effect exists between the core nano complex and the shell COF shell layer, so that the obtained COF shell layer is more compact, and the core-shell structure is more stable; the thickness of the shell layer in the core-shell structure can be controllably adjusted by regulating the mass ratio of the core to the COF monomer and the stirring time, and the longer the stirring time is, the more the amino group and the aldehyde group in the external COF shell layer are bonded, so that the more the number of the layers of the COF shell layer is, the thicker the shell layer is.
(3) According to the invention, an amido bond is formed by a carboxyl functional group of the core nano complex and an amino group in a COF monomer, an amido bond is formed by other amino groups in the COF monomer and a COF monomer containing an aldehyde group, and the core-shell structure is formed by sequentially forming bonds.
(4) The core-shell structure has good biocompatibility, the core-shell structure formed by the core bismuth-based nano complex and the shell nano COF shell layer has high microwave heat conversion efficiency, microwave active oxygen generation property and CT/MR/X-ray fluorescence imaging performance, and can realize imaging at tumor sites, microwave heat and microwave dynamic therapy. Can be used as a microwave diagnosis and treatment reagent to realize tumor diagnosis and treatment integration.
(5) The inner core and the outer shell of the core-shell structure can be degraded in a human body and discharged out of the human body, and cannot be enriched in the human body. Thus, can be safely used.
Drawings
FIG. 1 is a diagram illustrating the morphology of the degradable bismuth-based microwave diagnostic reagent prepared in example 1.
FIG. 2 is a schematic diagram of the microwave heating effect of the degradable bismuth-based microwave diagnostic reagent prepared in example 1.
FIG. 3 is a schematic diagram showing the relationship between the intensity of CT contrast signals and the concentration of the degradable bismuth-based microwave diagnostic reagent prepared in example 1.
FIG. 4 is a graph of the degradable bismuth manganese-based microwave diagnostic reagent prepared in example 2.
Fig. 5 is a schematic representation of microwave dynamic performance of the degradable bismuth manganese-based microwave diagnosis and treatment reagent prepared in example 2.
Fig. 6 is a shape representation of the degradable bismuth-iron-based microwave diagnostic reagent prepared in example 3.
Fig. 7 is a morphological characterization of the degradable bismuth-porphyrin-arginine-based microwave diagnostic reagent prepared in example 6.
Fig. 8 is a graph of the degradable bismuth-porphyrin-tyrosine-based microwave diagnostic reagent prepared in example 7.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the techniques realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Example 1
A preparation method of a degradable bismuth-based microwave diagnosis and treatment reagent comprises the following steps:
1) Weighing 60mg Bi (NO) 3 ·5H 2 Dissolving O in 77mL of DMF solution, weighing 48mg of meso-tetra (4-carboxyphenyl) porphin (TCPP) to be dissolved in 77mL of DMF, adding the solution into a metal salt solution, carrying out ultrasonic mixing to uniformly mix the solution, then adding 1200mg of PVP, carrying out magnetic stirring reaction at room temperature for 8 hours, centrifuging, and washing with DMF and ethanol to obtain a core nano complex;
2) Weighing 60mg of the core nano complex product obtained in the step 1), dissolving the core nano complex product in 30mL of acetonitrile, adding 300mg of PVP, and stirring and ultrasonically treating the mixture to ensure that the mixture is uniform;
3) Weighing 30mg of 1,3, 5-tris (4-aminophenyl) benzene, dissolving in 30mL of acetonitrile, adding 6mL of methanol, adding the mixture to the step 2), magnetically stirring for 1h, centrifuging, washing with ethanol, dissolving in 30mL of acetonitrile again, and adding 300mg of PVP;
4) Weighing 2,5-dimethoxybenzene-1,4-diformaldehyde 24mg, dissolving in 30mL of acetonitrile, adding 6mL of methanol, adding the mixture into the step 3), magnetically stirring for 1h, centrifuging, washing with ethanol, dissolving in 30mL of acetonitrile again, and adding 300mg of PVP;
5) Weighing 1,3,5-tri (4-aminophenyl) benzene and 2,5-dimethoxybenzene-1,4-dicarboxaldehyde which are in the same amount in the steps 2) and 3) again, adding the weighed materials into the solution obtained in the step 4), adding 6mL of methanol and 450 mu L of acetic acid, magnetically stirring for 8 hours, centrifuging, and washing with ethanol to obtain the required bismuth-based microwave diagnosis and treatment reagent.
The observation under a Transmission Electron Microscope (TEM) shows that the bismuth-based microwave diagnosis and treatment reagent prepared in the embodiment has a cuboid inner core with the length of about 210nm and the width of about 110nm, and a COF shell with the thickness of about 30nm (figure 1).
The bismuth-based microwave diagnosis and treatment reagent prepared by the embodiment has good microwave thermal sensitization, and the infrared thermal imaging real-time monitoring result is shown in fig. 2. The results in the figure show that the temperature of the material group (the bismuth-based microwave diagnostic and therapeutic agent prepared in example 1) gradually increases with the increase of the microwave time and shows concentration dependence when the microwave irradiation starts. Compared with the control group (without the bismuth-based microwave diagnostic reagent prepared in example 1), the material group shows good microwave temperature rising effect.
The bismuth-based microwave diagnosis and treatment reagent prepared by the embodiment can realize CT, X-ray fluorescence imaging and tumor microwave thermotherapy. The bismuth-based microwave diagnosis and treatment reagent prepared in the embodiment is dispersed in water, and then the CT imaging effect of the bismuth-based microwave diagnosis and treatment reagent aqueous solution with different concentrations is tested, and the result is shown in FIG. 3. The results in the figure show that: the bismuth-based microwave diagnosis and treatment reagent prepared by the embodiment has good CT imaging performance and shows obvious concentration dependence.
In a nude mouse transplantation tumor model, the material prepared in example 1 was injected intravenously at a dose of 50mg/kg according to the weight of a mouse, and the mouse was placed in a computed tomography scanner for observing the CT imaging performance of the tumor of the mouse at 0h, 2h, 4h, 8h, 12h, and 24h after injection, again characterizing that the material can be specifically accumulated at the tumor and show excellent CT imaging performance.
Example 2
A preparation method of a degradable bismuth manganese-based microwave diagnosis and treatment reagent comprises the following steps:
1) 68mg of Bi (CH) are weighed 3 CH 2 OH) 3 And 9mg of MnCl 2 ·4h 2 Dissolving O in 77mL of DMF solution, weighing 62mg of TCPP, dissolving in 77mL of DMF, adding the TCPP into metal salt solution, performing ultrasonic treatment to uniformly mix the TCPP and the metal salt solution, adding 1200mg of PVP, performing magnetic stirring reaction at room temperature for 4 hours, centrifuging, and washing with DMF and ethanol to obtain a core nano complex;
2) Weighing 60mg of the core nano complex in the step 1), dissolving in 30mL of acetonitrile, adding 300mg of PVP, stirring, and carrying out ultrasonic treatment to obtain a uniform solution;
3) Weighing 30mg of 1,3, 5-tris (4-aminophenyl) benzene, dissolving in 30mL of acetonitrile, adding 2mL of ethanol, adding the mixture to the step 2), magnetically stirring for 1h, centrifuging, washing with ethanol, dissolving in 30mL of acetonitrile again, and adding 300mg of PVP;
4) Weighing 2,5-dimethoxybenzene-1,4-diformaldehyde 24mg, dissolving in 30mL acetonitrile, adding 2mL ethanol, adding into step 3), magnetically stirring for 1h, centrifuging, washing with ethanol, dissolving in 30mL acetonitrile again, and adding 300mg PVP;
(5) And weighing 1,3,5-tri (4-aminophenyl) benzene and 2,5-dimethoxybenzene-1,4-dicarboxaldehyde which are in the same amount in the steps 2) and 3), adding the weighed materials into the step 4), adding 2mL of ethanol and 350 mu L of acetic acid, magnetically stirring for 4 hours, centrifuging, and washing with ethanol to obtain the bismuth manganese-based microwave diagnosis and treatment reagent (named BMC).
The observation under a Transmission Electron Microscope (TEM) shows that the inner core of the bismuth manganese-based microwave diagnosis and treatment reagent prepared in the embodiment is a cube, the length and the width of the inner core are about 100-120nm, and the thickness of a COF shell layer is about 20nm (figure 4).
The bismuth-manganese-based microwave diagnosis and treatment reagent prepared by the embodiment has good microwave power sensitivity, bismuth-manganese-based microwave diagnosis and treatment reagent aqueous solutions with different concentrations are subjected to Microwave (MW), equivalent DCFH-DA (2 ',7' -dichlorofluorescein diacetate) indicators are respectively added, after incubation for 30min, the bismuth-manganese-based microwave diagnosis and treatment reagent aqueous solutions are centrifuged, and the fluorescence intensity of a supernatant is measured. The higher the amount of active oxygen produced, the stronger the fluorescence of DCF (2 ',7' -dichlorofluorescein), and the results are shown in FIG. 5, which shows: the fluorescence intensity is sequentially increased along with the increase of the concentration of the aqueous solution of the bismuth manganese-based microwave diagnosis and treatment reagent, and good concentration dependence is shown. Therefore, the bismuth manganese-based microwave diagnosis and treatment reagent prepared by the embodiment can generate obvious active oxygen under the microwave stimulation, and can be used for performing microwave dynamic therapy on tumors.
The bismuth manganese-based microwave diagnosis and treatment reagent prepared by the embodiment can realize CT, MR and X-ray fluorescence imaging and microwave thermal and microwave dynamic treatment of tumors.
Example 3
A preparation method of a degradable bismuth-iron-based microwave diagnosis and treatment reagent comprises the following steps:
1) Weighing 68mg Bi (NO) 3 ·5H 2 O and 46mg FeCl 3 ·6H 2 Dissolving O in 77mL of DMF solution, weighing 230mg of trimesic acid, dissolving in 77mL of DMF, adding the solution into a metal salt solution, performing ultrasonic treatment to uniformly mix the solution, adding 2400mg of PVP, performing magnetic stirring reaction at room temperature for 12 hours, centrifuging, and washing with DMF and ethanol to obtain a core nano complex;
2) Weighing 60mg of the core nano complex in the step 1), dissolving in 30mL of acetonitrile, adding 300mg of PVP, stirring, and carrying out ultrasonic treatment to obtain a uniform solution;
3) 24mg of 1,3, 5-tris (4-aminophenyl) benzene was weighed, dissolved in 30mL of acetonitrile, and 1mL of 1-propanol was added, and this was added to step 2), magnetically stirred for 1h, then centrifuged, washed with ethanol, dissolved again in 30mL of acetonitrile, and 300mg of PVP was added;
4) Weighing 2,5-dimethoxybenzene-1,4-diformaldehyde 20mg, dissolving in 30mL acetonitrile, 1mL 1-propanol, adding into step 3), magnetically stirring for 1h, then centrifuging, washing with ethanol, dissolving again in 30mL acetonitrile, and adding 300mg PVP;
(5) Weighing 1,3,5-tri (4-aminophenyl) benzene and 2,5-dimethoxybenzene-1,4-dicarboxaldehyde which are in the same amount in the steps 2) and 3), adding the weighed materials into the step 4), adding 1mL of 1-propanol and 350 mu L of acetic acid, magnetically stirring for 2 hours, centrifuging, and washing with ethanol to obtain the bismuth-iron-based microwave diagnosis and treatment reagent.
The observation under a Transmission Electron Microscope (TEM) shows that the bismuth iron-based microwave diagnosis and treatment reagent prepared in the embodiment has a cuboid core with a length of about 300nm and a width of about 250nm, and an external COF shell layer with a thickness of 5nm (FIG. 6).
The bismuth-iron-based microwave diagnosis and treatment reagent prepared by the embodiment can realize CT, MR and X-ray fluorescence imaging and tumor microwave thermal and microwave dynamic therapy.
Example 4
A preparation method of a degradable bismuth gadolinium-based microwave diagnosis and treatment reagent comprises the following steps:
1) Weighing 68mg Bi (NO) 3 ·5H 2 O and 43mg Gd (NO) 3 ) 3 ·6H 2 Dissolving O in 77mL DMF solution, weighing 62mg TCPP in 77mL DMF, adding into metal salt solution, and adding intoAdding 1200mg of PVP after the PVP is mixed uniformly, magnetically stirring at room temperature for reaction for 2 hours, centrifuging, and washing with DMF and ethanol to obtain a core nano complex;
2) Weighing 60mg of the core nano complex in the step 1), dissolving in 30mL of acetonitrile, adding 300mg of PVP, stirring, and carrying out ultrasonic treatment to obtain a uniform solution;
3) Weighing 40mg of 1,3, 5-tris (4-aminophenyl) benzene, dissolving in 30mL of acetonitrile, adding 6mL of 2-propanol, adding the mixture to the step 2), magnetically stirring for 1h, centrifuging, washing with ethanol, dissolving in 30mL of acetonitrile again, and adding 300mg of PVP;
4) Weighing 2,5-dimethoxybenzene-1,4-diformaldehyde 30mg, dissolving in 30mL of acetonitrile, adding 6mL of 2-propanol, adding into the step 3), magnetically stirring for 1h, centrifuging, washing with ethanol, dissolving in 30mL of acetonitrile again, and adding 300mg of PVP;
(5) Weighing 1,3,5-tri (4-aminophenyl) benzene and 2,5-dimethoxybenzene-1,4-dicarboxaldehyde which are in the same amount in the steps 2) and 3), adding the weighed materials into the step 4), adding 6mL of 2-propanol and 375 mu L of acetic acid, magnetically stirring for 12 hours, centrifuging, and washing with ethanol to obtain the bismuth gadolinium-based microwave diagnosis and treatment reagent.
Observation under a Transmission Electron Microscope (TEM) shows that the bismuth gadolinium-based microwave diagnosis and treatment reagent prepared by the embodiment has a spherical inner core, the diameter of the spherical inner core is about 50nm, the thickness of an external COF shell layer is about 100nm, and CT, MR and X-ray fluorescence imaging and tumor microwave thermal and microwave dynamic therapy can be realized.
Example 5
A preparation method of a degradable bismuth-cobalt-based microwave diagnosis and treatment reagent comprises the following steps:
1) Weighing 68mg Bi (NO) 3 ·5H 2 O and 5mg Co (NO) 3 ) 2 ·6H 2 Dissolving O in 77mL of DMF solution, weighing 62mg of TCPP, dissolving in 77mL of DMF, adding the TCPP into metal salt solution, performing ultrasonic treatment to uniformly mix the TCPP and the metal salt solution, adding 1200mg of PVP, performing magnetic stirring reaction at room temperature for 4 hours, centrifuging, and washing with DMF and ethanol to obtain a core nano complex;
2) Weighing 60mg of the core nano complex in the step 1), dissolving in 30mL of acetonitrile, adding 600mg of PVP, stirring, and carrying out ultrasonic treatment to obtain a uniform solution;
3) Weighing 40mg of 1,3, 5-tris (4-aminophenyl) benzene, dissolving in 30mL of acetonitrile, adding 2mL of 2-pentanol, adding it to step 2), magnetically stirring for 1h, centrifuging, washing with ethanol, dissolving again in 30mL of acetonitrile, and adding 300mg of PVP;
4) Weighing 2,5-dimethoxybenzene-1,4-diformaldehyde 20mg, dissolving in 30mL acetonitrile, 2mL 2-pentanol, adding into step 3), magnetically stirring for 1h, then centrifuging, washing with ethanol, dissolving again in 30mL acetonitrile, and adding 600mg PVP;
(5) And weighing 1,3,5-tris (4-aminophenyl) benzene and 2,5-dimethoxybenzene-1,4-dicarboxaldehyde which are in the same amount in the steps 2) and 3), adding the solution into the step 4), adding 2mL 2-pentanol and 350 mu L acetic acid, magnetically stirring for 10 hours, centrifuging, and washing with ethanol to obtain the bismuth-cobalt-based microwave diagnosis and treatment reagent.
The observation under a Transmission Electron Microscope (TEM) shows that the bismuth-cobalt-based microwave diagnosis and treatment reagent prepared by the embodiment has a cuboid inner core, the length of the inner core is about 200nm, the width of the inner core is about 150nm, and the thickness of an external COF shell layer is about 50nm, so that CT, photoacoustic and X-ray fluorescence imaging and tumor microwave thermal and dynamic treatment can be realized.
Example 6
A preparation method of a degradable bismuth-porphyrin-arginine-based microwave diagnosis and treatment reagent comprises the following steps:
1) 60mg of BiCl was weighed 3 Dissolving in 77mL of DMF solution, weighing 24mg of TCPP, and 5mg of L-arginine, dissolving in 77mL of DMF, adding into metal salt solution, performing ultrasonic treatment to uniformly mix the solution, adding 1200mg of PVP, performing magnetic stirring reaction at room temperature for 4 hours, centrifuging, and washing with DMF and ethanol to obtain a core nano complex;
2) Weighing 60mg of the core nano complex in the step 1), dissolving in 30mL of acetonitrile, adding 300mg of PVP, stirring, and carrying out ultrasonic treatment to obtain a uniform solution;
3) Weighing 30mg of 1,3, 5-tris (4-aminophenyl) benzene, dissolving in 30mL of acetonitrile, adding 4mL of ethanol, adding the mixture to the step 2), magnetically stirring for 1h, centrifuging, washing with ethanol, dissolving in 30mL of acetonitrile again, and adding 300mg of PVP;
4) Weighing 2,5-dimethoxybenzene-1,4-dialdehyde 26mg, dissolving in 30mL of acetonitrile, adding 4mL of ethanol, adding into the step 3), magnetically stirring for 1h, centrifuging, washing with ethanol, dissolving in 30mL of acetonitrile again, and adding 300mg of PVP;
(5) And weighing 1,3,5-tri (4-aminophenyl) benzene and 2,5-dimethoxybenzene-1,4-dicarboxaldehyde which are the same in the amount in the step 2) and the step 3), adding the weighed materials into the step 4), adding 4mL of ethanol and 750 mu L of acetic acid, magnetically stirring for 12 hours, centrifuging, and washing with ethanol to obtain the bismuth-porphyrin-arginine-based microwave diagnosis and treatment reagent.
The observation of the bismuth-porphyrin-arginine-based microwave diagnostic reagent under a Transmission Electron Microscope (TEM) shows that the core of the bismuth-porphyrin-arginine-based microwave diagnostic reagent prepared in the embodiment is a cuboid, the length of the core is about 180nm, the width of the core is about 120nm, and the thickness of the external COF shell is about 80nm (fig. 7).
The bismuth-porphyrin-arginine-based microwave diagnosis and treatment reagent prepared by the embodiment can realize CT and X-ray fluorescence imaging and microwave thermal and microwave dynamic treatment of tumors.
Example 7
A preparation method of a degradable bismuth-porphyrin-tyrosine-based microwave diagnosis and treatment reagent comprises the following steps:
1) Weighing 60mg Bi (NO) 3 ·5H 2 Dissolving O in 77mL of DMF solution, weighing 24mg of TCPP and 6mg of L-tyrosine, dissolving in 77mL of DMF, adding the obtained mixture into metal salt solution, performing ultrasonic treatment to uniformly mix the obtained mixture, adding 1200mg of PVP, performing magnetic stirring reaction for 4 hours, centrifuging, and washing with DMF and ethanol to obtain a core nano complex;
2) Weighing 60mg of the core nano complex in the step 1), dissolving in 30mL of acetonitrile, adding 300mg of PVP, stirring, and carrying out ultrasonic treatment to obtain a uniform solution;
3) 24mg of 1,3, 5-tris (4-aminophenyl) benzene is weighed, dissolved in 30mL of acetonitrile, 2mL of methanol is added, the mixture is added to the step 2), the mixture is magnetically stirred for 1h, then the mixture is centrifuged, washed with ethanol and dissolved in 30mL of acetonitrile again, and 300mg of PVP is added;
4) Weighing 2,5-dimethoxybenzene-1,4-dialdehyde 20mg, dissolving in 30mL of acetonitrile, adding 2mL of methanol, adding into the step 3), magnetically stirring for 1h, centrifuging, washing with ethanol, dissolving in 30mL of acetonitrile again, and adding 300mg of PVP;
(5) Weighing 1,3,5-tri (4-aminophenyl) benzene and 2,5-dimethoxybenzene-1,4-dicarboxaldehyde which are in the same amount in the steps 2) and 3), adding the weighed materials into the step 4), adding 2mL of methanol and 350 mu L of acetic acid, magnetically stirring for 12 hours, centrifuging, and washing with ethanol to obtain the bismuth-porphyrin-tyrosine-based microwave diagnosis and treatment reagent.
Observed under a Transmission Electron Microscope (TEM), the core of the bismuth-porphyrin-tyrosine-based microwave diagnostic reagent prepared in this example is a cube, the length of the core is about 130nm, and the thickness of the external COF shell layer is about 40nm (fig. 8).
The bismuth-porphyrin-tyrosine-based microwave diagnosis and treatment reagent prepared by the embodiment can realize CT and X-ray fluorescence imaging and microwave thermal and microwave dynamic treatment of tumors.
Example 8
A preparation method of a degradable bismuth-porphyrin-fumarate-based microwave diagnosis and treatment reagent comprises the following steps:
1) Weighing 60mg Bi (NO) 3 ·5H 2 Dissolving O in 77mL of DMF solution, then weighing 24mg of TCPP, and 3mg of fumaric acid, dissolving in 77mL of acetonitrile, then adding the TCPP and the fumaric acid into the metal salt solution, performing ultrasonic treatment to uniformly mix the TCPP and the fumaric acid, then adding 1200mg of PVP, performing magnetic stirring reaction at room temperature for 4 hours, centrifuging, and washing with DMF and ethanol to obtain a core nano complex;
2) Weighing 60mg of the core nano complex in the step 1), dissolving in 30mL of acetonitrile, adding 600mg of PVP, stirring, and carrying out ultrasonic treatment to obtain a uniform solution;
3) Weighing 40mg of 1,3, 5-tris (4-aminophenyl) benzene, dissolving in 30mL of acetonitrile, adding 4mL of 1-propanol, adding the mixture to the step 2), magnetically stirring for 1h, centrifuging, washing with ethanol, dissolving in 30mL of acetonitrile again, and adding 300mg of PVP;
4) Weighing 2,5-dimethoxybenzene-1,4-diformaldehyde 30mg, dissolving in 30mL of acetonitrile, adding 4mL of 1-propanol, adding into the step 3), magnetically stirring for 1h, centrifuging, washing with ethanol, dissolving in 30mL of acetonitrile again, and adding 600mg of PVP;
(5) And weighing 1,3,5-tri (4-aminophenyl) benzene and 2,5-dimethoxybenzene-1,4-dicarboxaldehyde which are the same in the amount in the step 2) and the step 3), adding the weighed materials into the step 4), adding 4mL of 1-propanol and 750 mu L of acetic acid, magnetically stirring for 6 hours, centrifuging, and washing with ethanol to obtain the bismuth-porphyrin-fumaric acid-based microwave diagnosis and treatment reagent.
The observation under a Transmission Electron Microscope (TEM) shows that the bismuth-porphyrin-fumarate-based microwave diagnosis and treatment reagent prepared in the embodiment has a cubic inner core, the length of the inner core is about 150nm, the thickness of an external COF shell layer is about 80nm, and CT and X-ray fluorescence imaging and tumor microwave thermal and microwave dynamic treatment can be realized.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (16)

1. A core-shell structure is characterized in that the core of the core-shell structure is a bismuth-based nano complex, and the shell of the core-shell structure is a degradable Covalent Organic Framework (COF); the bismuth-based nano complex has carboxyl which forms amido bond with amino in a Covalent Organic Framework (COF);
the bismuth-based nano complex is a nano particle, which contains a bismuth ion complex and optionally also contains other metal ion complexes; the ligand of the complex is an organic ligand containing carboxyl;
the metal ions are cobalt ions, gadolinium ions, manganese ions or iron ions;
the ligand of the complex is porphyrin with carboxyl and one, two or more of trimesic acid, terephthalic acid, fumaric acid, L-tyrosine and L-arginine are optionally contained;
the COF shell layer is coated on a nano complex used as a core by a COF monomer containing an amino functional group and a COF monomer containing an aldehyde group through forming an amido bond;
the COF monomer containing amino functional group is 1,3,5-tri (4-aminophenyl) benzene, 4,4',4' ' - (1,3,5-triazine-2,4,6-triyl) triphenylamine or p-phenylenediamine;
the COF monomer containing aldehyde group is 2,5-dimethoxybenzene-1,4-dicarboxaldehyde, 2,4,6-trihydroxy-1,3,5-benzenetricarboxylic aldehyde, terephthalaldehyde or 1,3,5-trimesic aldehyde.
2. The core-shell structure of claim 1, wherein the porphyrin with carboxyl groups is meso-tetra (4-carboxyphenyl) porphine.
3. The core-shell structure of claim 1, wherein the core bismuth-based nanocomplex of the core-shell structure has length and width dimensions in the range of 50-300nm, and the outer COF shell layer has a thickness in the range of 5-100nm.
4. A method for preparing a core-shell structure according to any of claims 1 to 3, characterized in that the method comprises the steps of:
1) Mixing bismuth salt, optional other metal salt and organic ligand containing carboxyl, and reacting for a period of time to obtain a nano complex;
2) Mixing the nano complex prepared in the step 1) with a COF monomer containing an amino functional group for reaction, wherein carboxyl carried by the nano complex reacts with amino carried by the monomer to form an amido bond;
3) Mixing the product obtained in the step 2) with a COF monomer containing aldehyde groups for reaction, wherein amino in the product obtained in the step 2) reacts with aldehyde groups in the monomer containing aldehyde groups to form a COF-coated core-shell structure;
4) And 3) mixing the product obtained in the step 3) with a COF monomer containing an amino functional group and a COF monomer containing an aldehyde group, and reacting to obtain a COF-coated core-shell structure with a thicker shell layer.
5. The method according to claim 4, wherein in the step 1), the bismuth salt is at least one selected from the group consisting of bismuth nitrate, bismuth acetate and bismuth chloride.
6. The method according to claim 4, wherein the other metal salt is one or two or more selected from the group consisting of cobalt nitrate, cobalt chloride, gadolinium nitrate, gadolinium chloride, manganese chloride, and ferric chloride.
7. The method according to claim 4, wherein the organic ligand having a carboxyl group is porphyrin having a carboxyl group and optionally contains one, two or more of trimesic acid, terephthalic acid, fumaric acid, L-tyrosine and L-arginine.
8. The method according to claim 4, wherein the porphyrin having a carboxyl group is meso-tetra (4-carboxyphenyl) porphine.
9. The method according to claim 4, wherein in step 2), the mass ratio of the core nanocomplex to the COF monomer containing an amino functional group is 1.5-2.5.
10. The preparation method according to claim 4, wherein in the step 4), the mass ratio of the core nanocomplex to the COF monomer containing an aldehyde group is 2:1-3:1.
11. The method of any one of claims 4 to 10, comprising the steps of:
1) Dissolving bismuth salt and optional other metal salts in N, N-Dimethylformamide (DMF), adding organic ligand containing carboxyl and surface active agent PVP for increasing dispersibility, performing ultrasonic treatment to uniformly disperse the mixture, and stirring at room temperature for 2-12h to obtain a core nano complex product;
2) Dissolving the core nano complex product prepared in the step 1) in acetonitrile, adding PVP (polyvinyl pyrrolidone), and then stirring;
3) Adding an acetonitrile solution of a COF monomer containing an amino functional group and a COF monomer containing an aldehyde group required for forming COF into the core nano complex solution prepared in the step 2), adding alcohol, reacting, centrifuging and washing sequentially, and dissolving the obtained precipitate into the acetonitrile solution containing PVP again;
4) Adding COF monomers containing amino functional groups and COF monomers containing aldehyde groups required for forming COF into the solution prepared in the step 3), uniformly mixing the COF monomers, the COF monomers and the COF monomers, adding alcohol and glacial acetic acid again, stirring for 2-12h, centrifuging, and washing with ethanol to obtain the microwave diagnosis and treatment reagent with the core-shell structure.
12. The preparation method according to claim 11, wherein in step 1), the molar ratio of the metal ions to the organic ligands in the bismuth salt and the optional other metal salts is 2:1-4:1, and the mass ratio of the sum of the mass of the bismuth salt and the optional other metal salts and the mass of the organic ligands to the mass of the PVP is 1:7-1.
13. The method of claim 11, wherein in step 2), the mass ratio of the inner core nanocomplex to PVP is 1:5-1.
14. The method of claim 11, wherein in step 3), the ratio of the volume of the alcohol to the volume of the acetonitrile is 1.
15. The method of claim 11, wherein in step 4), the ratio of the volume of glacial acetic acid to the volume of acetonitrile is 1.
16. Use of the core-shell structure according to any of claims 1 to 3 for the preparation of microwave medical agents for microwave thermal conversion, microwave generation of active oxygen, CT/MR/X-ray fluorescence imaging.
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