A drug-loaded microbubble ultrasound contrast agent modified by MOF film and preparation method thereof

Abstract

The present invention belongs to the field of nanomaterial technology, specifically a drug-loaded microbubble ultrasound contrast agent modified by a MOF film and a preparation method thereof. The drug-loaded microbubble ultrasound contrast agent of the present invention is composed of a hydrogel microbubble, a microsphere composed of a MOF film and a Pt layer deposited on the surface of the microbubble, and a drug loaded on the surface of the microsphere; the outer layer of the hydrogel microbubble is a shell structure, the shell is composed of a surfactant and an oily mixed solution after solidification, and the interior is an air core structure, the MOF film is completely coated on the outer surface of the hydrogel microbubble, and the Pt layer is coated on one side of the microsphere to form an asymmetric structure, thereby realizing the driving function. The present invention combines traditional medical ultrasound contrast agents with MOF films and micro-nano motor technology to form a multifunctional medical diagnosis and treatment microsystem that is visualized, drug-loaded, and targeted. The present invention makes full use of the porous structure of micro-nano motors and MOFs on the basis of the contrast function of the hydrogel hollow material to enhance the function, and has important application prospects in the field of biomedicine, such as medical ultrasound detection, targeted drug-loaded therapy, etc.

Description

Technical Field

[0001] The invention belongs to the technical field of nanomaterials, and in particular relates to a drug-loaded microbubble ultrasound contrast agent and a preparation method thereof. Background Art

[0002] Ultrasound Contrast Agent (UCA) is a type of diagnostic agent that can significantly enhance medical ultrasound detection signals. It uses the principle that the reflection of sound waves on gas is nearly 1,000 times greater than that on liquid. The ultrasound echo signal is enhanced by using gas-containing microbubbles to obtain higher contrast resolution, which is beneficial for the diagnosis of diseases.

[0003] Ultrasound imaging is a widely used, inexpensive diagnostic tool second only to radiography in clinical imaging. Its popularity stems from its tolerability, low cost, portability, and ability to monitor dynamic processes in real time. However, ultrasound suffers from a low signal-to-noise ratio and low contrast when imaging small vessels due to weak scattering of the signal by blood cells. To address this issue, contrast agents can be used to enhance the acoustic signal. Currently commercially available contrast agents consist of gas-filled bubbles less than 10 mm in size, stabilized with proteins or other surfactants. Due to their high compressibility and low density, their acoustic response differs significantly from that of tissues and fluids, resulting in high contrast.

[0004] MOF materials have been widely used in the field of biological drug delivery due to their structural characteristics such as abundant unsaturated coordination nodes, large specific surface area, and transition metal ion coordination. MOF can overcome the limitations of drug delivery for many drugs, such as poor water solubility, instability, and drug distribution problems in the body. Many stimuli-responsive MOFs can release drugs loaded in them under various biological environmental stimuli, such as the acidic environment of tumor tissue, temperature changes, and near-infrared irradiation. In particular, the sensitivity of coordination bonds in MOF to external acidity has led to its wide application in drug release. Among them, there are many studies on ZIFs materials, such as ZIF-8 and MAF-4. ZIF-8 can be used to load anticancer drugs such as doxorubicin, paclitaxel, and 5-fluorouracil, as well as biomolecules such as genes and proteins. Under the acidic conditions of the tumor site, the loaded drug molecules will be slowly released to achieve the purpose of precise disease treatment.

[0005] In the existing technology, traditional microbubble contrast agents are expensive, have a single function, and are difficult to prepare. In contrast, this project prepares porous MOF materials on hydrogel microbubbles. The composite material preparation method is simple, has a multi-level pore surface with abundant active sites and diverse functions. In addition, the composite structure microbubbles combine the function of micro-nano motors on the basis of ultrasound contrast function, which can achieve directional transport of drugs and has important application prospects in the field of biomedicine. Summary of the invention

[0006] The object of the present invention is to provide a MOF film-modified drug-loaded microbubble ultrasound contrast agent with excellent ultrasound contrast performance, convenient preparation and low cost, and a preparation method thereof.

[0007] The present invention prepares hydrogel microbubbles by microfluidic technology, and then deposits zinc oxide thin film by ALD to assist the growth of MOF thin film, and finally obtains micromotors by electron beam evaporation deposition. Thus, a multi-layer composite structure multifunctional drug-loaded microbubble ultrasound contrast agent with excellent performance and diverse functions is obtained, and the preparation process is environmentally friendly, the process is simple, and the preparation cost is low.

[0008] The drug-loaded microbubble ultrasound contrast agent modified by MOF film provided by the present invention has a structure as shown in Figure 1 As shown in the figure, it consists of hydrogel microbubbles, microspheres composed of MOF thin films and Pt layers deposited on the surface of the microbubbles, and drugs loaded on the surface of the microspheres. The inside of the hydrogel microbubbles is gas phase, the MOF thin film is completely coated on the outer surface of the hydrogel microbubbles, and the Pt layer is coated on one side of the microspheres (no more than half of the part), forming an asymmetric structure, thereby realizing the driving function.

[0009] The hydrogel microbubbles are prepared by a multiphase microfluidic device.

[0010] The hydrogel microbubble shell is formed by curing a mixed solution of a surfactant, a monomer, a crosslinking agent, and a photoinitiator, wherein the surfactant is selected from polyvinyl alcohol, polyethylene glycol, polypropylene glycol, and the like.

[0011] The gas core is N 2 , O 2 , air and other gases.

[0012] The size of the microspheres ranges from 10 to 300 μm and is adjustable.

[0013] The thickness of the MOF film is 50-500 nm.

[0014] The thickness of the Pt layer is 5-10 nm.

[0015] The MOF film is a PCN-333 (Fe) film or a PCN-333 (Al) film.

[0016] The preparation method of the drug-loaded microbubble ultrasound contrast agent modified by MOF film provided by the present invention comprises the following specific steps:

[0017] (1) preparing a suitable microfluidic chip device, using microfluidic technology to pass a surfactant solution into the external phase channel of the microfluidic chip; passing a mixed solution of a monomer, a crosslinker, and a photoinitiator into the intermediate phase channel of the microfluidic chip, and passing a gas into the internal phase channel of the microfluidic chip; preparing single emulsion highly dispersed hydrogel microbubbles by adjusting a suitable flow rate;

[0018] (2) drying the hydrogel microbubbles prepared in step (1), and then depositing an oxide induction layer on the surface of the microbubbles using atomic layer deposition (ALD) technology;

[0019] (3) growing a MOF film on the microbubbles treated in step (2) by a solvothermal method;

[0020] (4) using vacuum electron beam evaporation to deposit a Pt metal film on one side of the MOF film layer of the microbubbles to form an asymmetric structure and obtain a Pt functional layer (driving layer);

[0021] (5) Soaking the sample prepared in step (4) in a drug solution to load the drug, thereby obtaining a multifunctional drug-loaded microbubble ultrasound contrast agent.

[0022] In step (1), the raw materials for preparing the shell of the hydrogel microbubble are surfactant, methacrylic anhydride, ethylene glycol dimethacrylate, and 2-hydroxy-2-methylpropenone.

[0023] In step (1), the surfactant introduced into the external phase channel can be polyvinyl alcohol, polyethylene glycol, polypropylene glycol, etc.

[0024] In step (1), the gas introduced into the inner phase channel may be N 2 , O 2 , air, etc.

[0025] In step (1), the mass fraction of the polyvinyl alcohol solution used is 4%-5%.

[0026] In step (2), the drying temperature is 50-60°C.

[0027] In step (2), the oxide may be ZnO, Al 2 O 3 .

[0028] In step (3), the MOF film is a PCN-333 (Fe) film, a PCN-333 (Al) film, etc.

[0029] In step (3), the thickness of the MOF film is 50-500 nm.

[0030] In step (4), the thickness of the Pt film is 5-10 nm.

[0031] In step (5), the soaking time is 24-48 hours.

[0032] In step (5), the drug is doxorubicin, paclitaxel, etc.

[0033] The present invention integrates different types of materials into a microbubble structure to obtain a multifunctional drug-loaded microbubble ultrasound contrast agent.

[0034] In the present invention, the hydrogel microbubble is a hollow core-shell structure, which has the structural basis for realizing ultrasound contrast imaging. MOF is wrapped on the surface of the hydrogel microbubble to form a multilayer structure. The MOF material has a multi-level pore structure and can selectively load drugs. The asymmetric Pt functional layer on the outermost surface enables the microbubble to be exposed to trace amounts of H 2 O 2 The multilayer composite structure of the present invention can realize the kinetic energy of ultrasound imaging, micro-nano motors, drug loading, etc., and has broad application prospects in the biomedical field, such as being used to prepare medical ultrasound detection reagents or targeted drug delivery, and to perform medical ultrasound detection and targeted drug delivery therapy.

[0035] Compared with the prior art, the present invention has the following characteristics and positive effects

[0036] (1) The preparation process of the method of the present invention is simple, environmentally friendly, and easy to operate, and is a green chemical preparation method;

[0037] (2) The experimental design of the present invention is ingenious. Through the ALD induction technology, the MOF film layer is simply and effectively wrapped on the surface of the microbubble to prepare a hydrogel microbubble-MOF film composite material;

[0038] (3) The hydrogel microbubbles prepared by the present invention have a multiphase structure of water-in-oil-in-gas and are an ideal material for medical ultrasound angiography;

[0039] (4) The hydrogel microbubble-MOF thin film composite material prepared by the present invention has the advantages of large specific surface area, transition metal ion coordination, stable chemical properties, and a variety of pore sizes, and can selectively load drugs;

[0040] (5) The asymmetric Pt membrane obtained in the present invention enables the entire system to have a movable function, providing a structural basis for targeted drug delivery. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 This is a schematic diagram of the structure of the drug-loaded microbubble ultrasound contrast agent modified by the MOF film of the present invention.

[0042] Figure 2 Optical microscope photograph of hydrogel microbubbles.

[0043] Figure 3Electron micrograph of hydrogel microbubbles.

[0044] Figure 4 This is an electron microscope photograph of the hydrogel microbubble-MOF (PCN-333 (Fe)) film composite structure.

[0045] Figure 5 This is an electron microscope magnified photograph of the MOF layer in the hydrogel microbubble-MOF (PCN-333 (Fe)) thin film composite structure.

[0046] Figure 6 This is the rate-time diagram of the movement of microbubbles in the composite structure.

[0047] Figure 7 is the trajectory of the composite structure microbubble movement.

[0048] Figure 8 This is an ultrasound contrast image of the movement of microbubbles in a composite structure.

[0049] Numbers in the figure: 1 is the gas phase inside the hydrogel microbubble; 2 is the hydrogel shell; 3 is the porous MOF layer; 4 is the asymmetric Pt layer; 5 is the microbubble used as an ultrasound contrast agent. DETAILED DESCRIPTION

[0050] The present invention is described in detail below in conjunction with the accompanying drawings and specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0051] Example 1

[0052] (1) Using a microfluidic chip device, polyvinyl alcohol solution, methacrylic anhydride, ethylene glycol dimethacrylate, 2-hydroxy-2-methylpropenone, and nitrogen were introduced in sequence to prepare monodisperse emulsified hydrogel microbubbles;

[0053] (2) depositing a zinc oxide (ZnO) induction layer on the hydrogel microbubbles using atomic layer deposition (ALD) technology;

[0054] (3) Dissolve 1.62 g of ferric chloride in 100 ml of N,N-dimethylformamide to obtain solution A;

[0055] (4) Dissolve 1.66 g of triazine in 100 ml of N,N-dimethylformamide to obtain solution B;

[0056] (5) Place the hydrogel microbubbles in solutions A and B, heat them to 150 °C in a high temperature oven, and let them stand for 24 h;

[0057] (6) Wash the sample with deionized water for 60 min;

[0058] (7) Drying the washed sample at 60°C to obtain a hydrogel microbubble-MOF (PCN-333 (Fe)) thin film composite material;

[0059] (8) Depositing a 5 nm Pt layer on the prepared hydrogel-MOF (PCN-333 (Fe)) thin film composite using electron beam evaporation;

[0060] (9) releasing the sample obtained in (8) in a hydrogen peroxide solution of a certain concentration;

[0061] (10) placing the prepared multifunctional drug-loaded microbubbles in an artificial agar tube;

[0062] (11) Use optical microscopy, scanning electron microscopy, and ultrasonic probe to characterize the movement of the prepared hydrogel microbubbles, the ultrasonic imaging effect, and the morphology of the MOF (PCN-333 (Fe)) film;

[0063] (12) The electron microscopy test results show that the MOF (PCN-333) membrane composite material prepared in this example has a three-dimensional structure, and the PCN-333 (Fe) film is wrapped on the surface of the microbubbles; see Figure 4 , Figure 5 ; The results of optical microscopy showed that the microbubbles could move autonomously in a certain concentration of hydrogen peroxide solution, and the average movement speed was about 600 μm / s, see Figure 6 , its motion trajectory is as follows Figure 7 As shown; the ultrasound probe shows that the microbubble has a good contrast effect, see Figure 8 .

[0064] Example 2

[0065] (1) Using a microfluidic chip, polyethylene glycol solution, methacrylic anhydride, ethylene glycol dimethacrylate, 2-hydroxy-2-methylpropenone, and nitrogen were introduced in sequence to prepare monodisperse emulsified hydrogel microbubbles;

[0066] (2) A layer of aluminum oxide (Al2O3) is deposited on the hydrogel microbubbles using atomic layer deposition (ALD) technology. 2 O 3 ) induction layer;

[0067] (3) Dissolve 3.24 g of aluminum chloride in 100 ml of N,N-dimethylformamide to obtain solution A;

[0068] (4) Dissolve 3.32 g of triazine in 100 ml of N,N-dimethylformamide to obtain solution B;

[0069] (5) Place the hydrogel microbubbles in solutions A and B, heat them to 150 °C in a high temperature oven, and let them stand for 24 h;

[0070] (6) Wash the sample with deionized water for 60 min;

[0071] (7) Drying the washed sample at 60°C to obtain a hydrogel microbubble-MOF (PCN-333 (Al)) thin film composite material;

[0072] (8) Depositing a 10 nm Pt layer onto the prepared hydrogel-MOF (PCN-333 (Al)) thin film composite using electron beam evaporation;

[0073] (9) Use optical microscopy, scanning electron microscopy, and ultrasonic detection to characterize the morphology and imaging properties of the prepared hydrogel-MOF (PCN-333 (Al)) thin film composites;

[0074] (10) Microscope test results show that the hydrogel-MOF (PCN-333 (Al)) film composite material prepared in this example has a three-dimensional structure, and the PCN-333 (Al) film is wrapped on the surface of the hydrogel microbubbles.

[0075] Example 3

[0076] (1) Using a microfluidic chip, polypropylene glycol solution, methacrylic anhydride, ethylene glycol dimethacrylate, 2-hydroxy-2-methylpropenone, and nitrogen were introduced in sequence to prepare monodisperse emulsified hydrogel microbubbles;

[0077] (2) depositing a zinc oxide (ZnO) induction layer on the hydrogel microbubbles using atomic layer deposition (ALD) technology;

[0078] (3) Dissolve 3.24 g of ferric chloride in 100 ml of N,N-dimethylformamide to obtain solution A;

[0079] (4) Dissolve 3.32 g of triazine in 100 ml of N,N-dimethylformamide to obtain solution B;

[0080] (5) Place the hydrogel microbubbles in solutions A and B, heat them to 150 °C in a high temperature oven, and let them stand for 24 h;

[0081] (6) Wash the sample with deionized water for 60 min;

[0082] (7) Drying the washed sample at 60°C to obtain a hydrogel microbubble-MOF (PCN-333 (Fe)) thin film composite material;

[0083] (8) Depositing a 10 nm Pt layer onto the prepared hydrogel-MOF (PCN-333 (Fe)) thin film composite material using electron beam evaporation;

[0084] (9) Use optical microscopy, scanning electron microscopy, and ultrasonic detection to characterize the morphology and imaging properties of the prepared hydrogel-MOF (PCN-333) film composites;

[0085] (10) Microscope test results show that the hydrogel-MOF (PCN-333 (Fe)) film composite material prepared in this example has a three-dimensional structure, and the PCN-333 film is wrapped on the surface of the hydrogel microbubbles.

[0086] Example 4

[0087] (1) Using a microfluidic chip, polyvinyl alcohol solution, methacrylic anhydride, ethylene glycol dimethacrylate, 2-hydroxy-2-methylpropenone, and nitrogen were introduced in sequence to prepare monodisperse emulsified hydrogel microbubbles;

[0088] (2) A layer of aluminum oxide (Al2O3) was deposited on the hydrogel microbubbles using atomic layer deposition (ALD) technology. 2 O 3 ) induction layer;

[0089] (3) Dissolve 1.62 g of aluminum chloride in 100 ml of N,N-dimethylformamide to obtain solution A;

[0090] (4) Dissolve 1.66 g of triazine in 100 ml of N,N-dimethylformamide to obtain solution B;

[0091] (5) Place the hydrogel microbubbles in solutions A and B, heat them to 150 °C in a high temperature oven, and let them stand for 24 h;

[0092] (6) Wash the sample with deionized water for 60 min;

[0093] (7) Drying the washed sample at 60°C to obtain a hydrogel microbubble-MOF (PCN-333 (Al)) thin film composite material;

[0094] (8) Depositing a 5 nm Pt layer onto the prepared hydrogel-MOF (PCN-333 (Al)) thin film composite material using electron beam evaporation;

[0095] (9) Immerse the prepared microbubbles in a doxorubicin (2 mg / ml) solution for 24 hours, then take out the microbubbles for targeted drug delivery to cancer cells;

[0096] (10) Use optical microscopy, scanning electron microscopy, and ultrasonic detection to characterize the morphology and imaging properties of the prepared hydrogel-MOF (PCN-333 (Al)) thin film composites;

[0097] (11) The electron microscopy test results show that the MOF (PCN-333 (Al)) thin film composite material prepared in this example has a three-dimensional structure. The PCN-333 (Al) thin film is wrapped on the surface of the microbubbles and has a good drug loading structure. 2 O 2 In vivo, Pt catalyzes H 2 O 2 The decomposition produces bubbles, which push the drug-loaded microbubbles in the opposite direction and achieve directional drug delivery.

[0098] Example 5

[0099] (1) Using a microfluidic chip, polyethylene glycol solution, methacrylic anhydride, ethylene glycol dimethacrylate, 2-hydroxy-2-methylpropenone, and nitrogen were introduced in sequence to prepare monodisperse emulsified hydrogel microbubbles;

[0100] (2) Depositing a zinc oxide (ZnO) induction layer on the hydrogel microbubbles using atomic layer deposition (ALD) technology;

[0101] (3) Dissolve 1.62 g of ferric chloride in 100 ml of N,N-dimethylformamide to obtain solution A;

[0102] (4) Dissolve 1.66 g of triazine in 100 ml of N,N-dimethylformamide to obtain solution B;

[0103] (5) Place the hydrogel microbubbles in solutions A and B, heat them to 150 °C in a high temperature oven, and let them stand for 24 h;

[0104] (6) Wash the sample with deionized water for 60 min;

[0105] (7) Drying the washed sample at 60°C to obtain a hydrogel microbubble-MOF (PCN-333 (Fe)) thin film composite material;

[0106] (8) Depositing a 10 nm Pt layer onto the prepared hydrogel-MOF (PCN-333(Fe)) thin film composite material using electron beam evaporation;

[0107] (9) Immerse the prepared microbubbles in a doxorubicin (2 mg / ml) solution for 24 hours, then take out the microbubbles for targeted drug delivery to cancer cells;

[0108] (10) Use optical microscopy, scanning electron microscopy, and ultrasonic detection to characterize the morphology and imaging properties of the prepared hydrogel-MOF (PCN-333 (Fe)) thin film composites;

[0109] (11) The electron microscopy test results show that the hydrogel-MOF (PCN-333 (Fe)) film composite material prepared in this example has a three-dimensional structure. The PCN-333 (Fe) film is wrapped on the surface of the hydrogel microbubbles and can be used for drug delivery. 2 O 2 In vivo, Pt catalyzes H 2 O 2 Decomposition produces bubbles, which push back the movement of drug-loaded microbubbles and achieve directional drug delivery.

[0110] In the above embodiments, the thickness of the prepared MOF can be adjusted according to the actual situation by the concentration of the solvent. In addition, the diameter of the prepared ultrasonic microbubbles can also be regulated according to the microfluidic flow rate. The above description of the embodiments is to facilitate the understanding and use of the invention by ordinary technicians in this technical field. It is obvious that personnel familiar with the technology in this field can easily make various modifications to these embodiments and apply the general principles described here to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A drug-loaded microbubble ultrasound contrast agent modified with MOF film, It is characterized in that The microspheres are composed of hydrogel microbubbles, MOF thin films and Pt layers deposited on the surface of the microbubbles, and drug molecules loaded in the MOF pores; wherein the hydrogel microbubbles have an air core inside, the MOF thin film completely covers the outer surface of the hydrogel microbubbles, and the Pt layer covers one side of the microspheres to form an asymmetric structure, thereby realizing the driving function; The hydrogel microbubbles are prepared by a multiphase microfluidic device; the hydrogel microbubble shell is formed by curing a mixed solution of a surfactant, a monomer, a crosslinking agent, and a photoinitiator, wherein the surfactant is selected from polyvinyl alcohol, polyethylene glycol, and polypropylene glycol; the monomer, the crosslinking agent, and the photoinitiator are methacrylic anhydride, ethylene glycol dimethacrylate, and 2-hydroxy-2-methylpropenone, respectively; The gas core is N 2 ; The size of the microspheres is 10-300 μm; The thickness of the MOF film is 50-500 nm; The thickness of the Pt layer is 5-10 nm; The MOF film is a PCN-333 (Fe) film or a PCN-333 (Al) film; The specific steps of forming the contrast agent are: (1) Using a microfluidic chip device and microfluidic technology, a surfactant solution is introduced into the external phase channel of the microfluidic chip, a mixed solution of a monomer, a crosslinker, and a photoinitiator is introduced into the intermediate phase channel of the microfluidic chip, and a gas is introduced into the internal phase channel of the microfluidic chip. By adjusting the appropriate flow rate, single emulsion highly dispersed hydrogel microbubbles are prepared; (2) drying the hydrogel microbubbles prepared in step (1), and then depositing an oxide induction layer on the surface of the microbubbles using atomic layer deposition technology; (3) growing a MOF film on the microbubbles treated in step (2) by a solvothermal method; (4) using vacuum electron beam evaporation to deposit a Pt metal film on one side of the MOF film layer of the microbubbles to form an asymmetric structure and obtain a Pt functional layer; (5) Soaking the sample prepared in step (4) in a drug solution to load the drug, thereby obtaining a multifunctional drug-loaded microbubble ultrasound contrast agent.

2. A method for preparing the MOF film-modified drug-loaded microbubble ultrasound contrast agent as claimed in claim 1, It is characterized in that The specific steps are: (1) Using a microfluidic chip device and microfluidic technology, a surfactant solution is introduced into the external phase channel of the microfluidic chip, a mixed solution of a monomer, a crosslinker, and a photoinitiator is introduced into the intermediate phase channel of the microfluidic chip, and a gas is introduced into the internal phase channel of the microfluidic chip. By adjusting the appropriate flow rate, single emulsion highly dispersed hydrogel microbubbles are prepared; (2) drying the hydrogel microbubbles prepared in step (1), and then depositing an oxide induction layer on the surface of the microbubbles using atomic layer deposition technology; (3) growing a MOF film on the microbubbles treated in step (2) by a solvothermal method; (4) using vacuum electron beam evaporation to deposit a Pt metal film on one side of the MOF film layer of the microbubbles to form an asymmetric structure and obtain a Pt functional layer; (5) Soaking the sample prepared in step (4) in a drug solution to load the drug, thereby obtaining a multifunctional drug-loaded microbubble ultrasound contrast agent.

3. The method for preparing the drug-loaded microbubble ultrasound contrast agent modified by MOF film according to claim 2, It is characterized in that In step (1), the mass fraction of the surfactant solution used is 4%-5%; the gas introduced into the inner phase is N 2 .

4. The method for preparing the drug-loaded microbubble ultrasound contrast agent modified by MOF film according to claim 2, It is characterized in that In step (2), the drying temperature is 50-60°C; the oxide is ZnO or Al 2 O 3 .

5. The method for preparing the drug-loaded microbubble ultrasound contrast agent modified by MOF film according to claim 2, It is characterized in that In step (5), the soaking time is 24-48 h, and the drug is doxorubicin or paclitaxel.

6. Use of the MOF film modified drug-loaded microbubble ultrasound contrast agent as claimed in claim 1 in the preparation of medical ultrasound detection reagents or targeted drug-loaded microbubble ultrasound contrast agents.

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