Self-propelled delivery carrier for helicobacter pylori diagnosis and gastric mucosa protection and preparation method thereof

Abstract

The invention provides a self-propelled drug delivery carrier for helicobacter pylori diagnosis and gastric mucosa protection and a preparation method thereof. The drug delivery carrier is composed of bismuth oxide particles, a bacterial targeting functional coating B-CS and a gastric acid driven propelling functional coating X. The drug delivery carrier keeps good stability in a gastric acid environment, the carrier is endowed with gastric mucous layer penetrating performance by directionally generating gas in the acid environment, and the carrier can accurately reach a helicobacter pylori infected part through the bacterial targeting functional coating B-CS. Bismuth oxide particles serve as a developing agent, accurate positioning of an infected part is achieved, bismuth ions are released in a gastric acid environment, and the bismuth oxide particles and chitosan jointly play a role in protecting gastric mucosa. The drug delivery carrier has a self-propelling capability and a targeting function, improves the delivery efficiency and local concentration of the drug, and is suitable for diagnosis of helicobacter pylori infection and prevention and treatment of stomach diseases.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedical materials, and specifically relates to a self-propelled delivery carrier for Helicobacter pylori diagnosis and gastric mucosal protection and a preparation method thereof. Background Art

[0002] Helicobacter pylori (H.pylori) is a common gastric pathogen with a very high infection rate and drug resistance. About 50% of the world's population is infected with H. pylori, especially in developing countries, where the infection rate is even higher. H. pylori infection is one of the main causes of chronic gastritis, peptic ulcer, gastric bleeding and gastric cancer. According to reports from the World Health Organization (WHO) and the International Agency for Research on Cancer (IARC), H. pylori has been listed as a Class I carcinogen for gastric cancer. The pathogenic mechanism of H. pylori mainly includes the following aspects: (1) H. pylori enters the gastric mucus layer through flagella and moves freely in it, closely contacts with gastric epithelial cells, and directly invades the gastric mucosa. (2) H. pylori can produce urease, which decomposes urea into carbon dioxide and ammonia through enzymatic reactions, forming an ammonia cloud protective layer, neutralizing gastric acid and protecting the bacteria from being killed by gastric acid. (3) Virulence factors released by Helicobacter pylori, such as CagA and VacA, can stimulate gastric mucosal cells, neutrophils, and macrophages to secrete a large number of inflammatory factors, triggering severe mucosal inflammatory reactions and leading to gastric mucosal damage.

[0003] In the prior art, a variety of methods have been used for the diagnosis and treatment of Helicobacter pylori, but these methods have significant limitations and gastric safety risks. At present, the diagnostic methods of Helicobacter pylori mainly include breath tests, gastroscopy and blood tests. However, breath tests are easily affected by diet and drugs, resulting in inaccurate results; gastroscopy is invasive and costly, and the commonly used dyes methylene blue and iodine solution are sprayed on the surface of the gastric mucosa in the body, which can easily cause chemical damage to the gastric mucosa, leading to inflammation and discomfort, and may cause gastric mucosal damage, bleeding and infection; blood tests cannot accurately reflect the real-time infection status of the stomach. Even the existing improved urea[ 13 C] Breath test reagents (such as Chinese patent 202310448606.0) solve the problem of drugs coming into contact with bacteria in the oral cavity, esophagus and other digestive tracts during administration, but because their drug formulas contain acidifiers, these acidifiers may irritate the gastric mucosa when released in the stomach, leading to inflammation and damage to the gastric mucosa. Therefore, it is of great clinical significance to develop a non-invasive, simple, rapid, accurate and efficient method for diagnosing Helicobacter pylori that does not damage the gastric mucosa.

[0004] In terms of gastric drug delivery, delivery carrier technology shows great potential, but how to enhance the efficiency of delivery carriers penetrating the gastric mucus barrier has always been the focus and difficulty. Among the existing technologies for carrier gastric mucus penetration, common methods include (1) enhancing the interaction between nanoformulations and mucin by introducing functional groups such as thiol or maleimide groups (such as Chinese Patent 2022105858333), but the passive diffusion efficiency is low and the clearance rate is high. (2) Although loading proteases or disulfide bond reducing agents (such as Chinese Patent 2015106394016) improves penetration ability, it may destroy the structure of the gastric mucus layer and affect its natural defense function. (3) Designing water-soluble, negatively charged nanoformulations (such as Chinese Patent 202310903615.4) reduces retention, but lacks power, resulting in low passive diffusion efficiency. In contrast, the self-propelled delivery carrier of the present invention achieves efficient, safe and rapid gastric delivery through a unique design. The outermost gastric acid-driven propulsion functional coating can produce gas in a directional manner under gastric acid conditions through the design of an uneven coating, which can drive the movement of the carrier and significantly improve the efficiency of drug penetration through the gastric mucus layer. The chitosan coating in the middle layer enhances the gastric mucosal viscosity of the carrier, prolongs the residence time of the carrier in the stomach, and increases the local concentration of the drug. The combination of chitosan prolonging the residence time in the stomach and the directional drive of the gastric acid-driven propulsion functional coating achieves a rapid, efficient, and safe penetration of the gastric mucus layer by the carrier, ensuring effective delivery and treatment of drugs in the stomach.

[0005] In addition, the main problems with existing delivery vector technologies for Helicobacter pylori in practical applications are: (1) Many delivery vectors are easily degraded in the gastric acid environment, resulting in premature release of drugs, affecting the therapeutic effect. (2) Existing delivery vectors have limited ability to penetrate the gastric mucus layer and are difficult to effectively reach the site of infection. (3) Many delivery vectors lack an effective targeting mechanism in the stomach, and drugs are easily distributed in non-lesion areas, reducing the efficiency of diagnosis and treatment and increasing side effects. (4) At present, there is no effective multifunctional vector that can both diagnose Helicobacter pylori and provide gastric protection. Therefore, it is of great clinical significance and application value to develop a delivery vector that can stably exist in the gastric acid environment, effectively penetrate the gastric mucus layer, have self-propelling properties, efficiently target Helicobacter pylori, and have both Helicobacter pylori diagnosis and gastric mucosal protection.

[0006] The present invention provides a self-propelled delivery carrier for Helicobacter pylori diagnosis and gastric mucosal protection and a preparation method thereof. The delivery carrier is composed of the following three layers: the core layer is bismuth oxide microparticles with a particle size of about 50 to 500 nm, which can release bismuth ions to protect the gastric mucosa while playing the role of bismuth oxide developer; the middle layer is a bacteria targeting functional coating B-CS, which contains chitosan and bacteria targeting substances to enhance the stability and targeting performance of the carrier; the outermost layer is a gastric acid driven propulsion functional uneven coating X, which produces gas in a directional manner under a gastric acid environment to drive the carrier to move. The delivery carrier has self-propulsion capability and has both Helicobacter pylori diagnosis and gastric mucosal protection functions.

[0007] Compared with the existing Helicobacter pylori diagnosis method, the present invention has the following advantages: (1) Through the design of the gastric acid driven propulsion functional coating, the delivery carrier can produce gas in a directional manner under the gastric acid environment, promote the directional movement of the carrier to the gastric epithelial cell site, improve the drug delivery efficiency, significantly improve the distribution and local concentration of the drug in the stomach, and enhance the therapeutic effect. (2) The bismuth oxide coating can release bismuth ions in the gastric acid environment. Bismuth ions have a protective effect on the gastric mucosa, can reduce gastric inflammation and damage, and improve the patient's comfort. At the same time, bismuth oxide itself can play a diagnostic role in the lesion site. Its distribution in the stomach can be detected by imaging methods such as MRI to achieve accurate positioning of the Helicobacter pylori infection site. (3) Chitosan coating and boric acid group modification can enhance the targeting performance of the delivery carrier, making it easier to reach the infection site. The chitosan coating can also protect the drug from being destroyed by gastric acid, improve the stability of the drug, and ensure that the drug will not be released prematurely before reaching the infection site. At the same time, it can combine with the Helicobacter pylori cell wall to play an antibacterial role and form a protective film on the surface of the gastric mucosa to reduce the stimulation of gastric acid and drugs to the gastric mucosa. (4) Through the diagnostic effect of bismuth oxide as a contrast agent and the gastric mucosal protective effect of bismuth ions and chitosan, the dual functions of Helicobacter pylori infection diagnosis and gastric mucosal protection are achieved.

[0008] In summary, the present invention provides a self-propelled delivery carrier for Helicobacter pylori diagnosis and gastric mucosal protection and a preparation method thereof, which has the characteristics of stable existence in gastric acid environment, effective penetration of gastric mucus layer, self-propelled performance, efficient targeting of Helicobacter pylori, and the ability to diagnose Helicobacter pylori and protect gastric mucosa. The delivery carrier can effectively solve the limitations of the existing technology, improve the diagnosis and treatment effects of Helicobacter pylori, and has important clinical application prospects. Summary of the invention

[0009] In view of the above-mentioned deficiencies in the prior art, the purpose of the present invention is to provide a self-propelled delivery vehicle for Helicobacter pylori diagnosis and gastric mucosal protection, which comprehensively solves the diagnosis problem of Helicobacter pylori infection from four aspects: improving stability in the stomach, enhancing the permeability of the gastric mucus layer, imparting bacterial targeting and realizing the dual functions of diagnosis and protection.

[0010] Another object of the present invention is to provide the application of the self-propelled delivery carrier for Helicobacter pylori diagnosis and gastric mucosal protection.

[0011] In order to achieve the above object, the present invention adopts the following technical solutions:

[0012] In a first aspect, a self-propelled delivery carrier for Helicobacter pylori diagnosis and gastric mucosal protection is provided, wherein the delivery carrier is composed of 50 to 150 parts by weight of bismuth oxide particles, 0.5 to 20 parts by weight of a bacteria-targeting functional coating B-CS, and a gastric acid-driven propulsion functional coating X with a thickness of 0.1 to 5.0 μm; in the bacteria-targeting functional coating B-CS, B is a bacteria-targeting substance and CS is chitosan; in the gastric acid-driven propulsion functional coating X, X is a gastric acid-driven substance that is unevenly coated on the outermost layer of the carrier by ion sputtering technology, and has a thickness of 0.5 to 2 μm, and the specific thickness can be customized by adjusting the sputtering time; the bismuth oxide particles are pure bismuth oxide (Bi2O3) particles, prepared by a sol-gel method, and have a particle size of about 50 to 500 nm.

[0013] Furthermore, the bismuth oxide particle core is prepared by the following method: 0.90-1.8g bismuth nitrate (Bi(NO3)3·5H2O) and 0.1-0.2g surfactant Triton-X-100 are weighed, dissolved in 10-20mL 1.12mol / L nitric acid, and stirred until transparent. The solution is slowly added dropwise to 100-200mL 0.2mol / L sodium hydroxide aqueous solution, stirring while adding dropwise to generate a white precipitate. The mixture is transferred to a clean flask and heated in a 90°C oil bath for 3 hours. The mixture gradually turns yellow, indicating that Bi2O3 is formed. After cooling to room temperature, it is washed three times with double distilled water and ethanol to remove impurities. The precipitate is dried in an oven at 80°C for 3 hours, ground into fine powder and passed through a 500-mesh sieve to obtain pure bismuth oxide (Bi2O3) particles.

[0014] Furthermore, the bacterial targeting substance is any one of 4-carboxyphenylboronic acid, N-butylthiophosphorothioate (NBPT), amoxicillin-polyethylene glycol conjugate, L-ornithine-phenylalanine dipeptide or antisense oligonucleotide.

[0015] Furthermore, the chitosan is derived from any one of low molecular weight chitosan (molecular weight 10,000-50,000 Da), medium molecular weight chitosan (molecular weight 50,000-150,000 Da) or high molecular weight chitosan (molecular weight 150,000-500,000 Da).

[0016] Further, the bacterial targeting functional coating B-CS is prepared by the following method: 0.05-0.1g chitosan is dissolved in 100mL deionized water, 0.1-0.2g sodium dodecyl sulfate (SDS) and 0.2mL acetic acid are added, and the mixture is stirred to form a stable chitosan solution; the chitosan solution is mixed with bismuth oxide particles to ensure uniform coverage of the surface of the bismuth oxide particles; after stirring at room temperature for 4 hours, centrifuge at 10,000rpm for 10 minutes to obtain chitosan-coated bismuth oxide particles. The chitosan-coated bismuth oxide particles are transferred to a round-bottom flask, 10mL deionized water and 40-60mg bacterial targeting substances are added, and the reaction is stirred overnight under ice bath conditions; subsequently, the mixture is washed with tetrahydrofuran (THF) and deionized water several times to remove unreacted reagents and by-products, and the mixture is naturally air-dried or dried in a constant temperature oven at 40-50°C, and the treated bismuth oxide particles (B-CS / Bi2O3 particles) are finally collected.

[0017] Furthermore, the gastric acid driven propulsion functional coating X is prepared by the following method: synthesized chitosan-coated bismuth oxide microparticles are dispersed in 5 mL of ethanol and evenly spread on a glass slide; after the ethanol evaporates, the glass slide is treated with plasma to make it hydrophilic; the glass slide is placed on an ion sputtering instrument to sputter the gastric acid driven substance, and the thickness is customized by adjusting the sputtering time; the glass slide is immersed in ethanol, ultrasonically treated for 1 minute, and the micromotor derived from the chitosan coated bismuth oxide particles is separated; centrifuged at 6000g for 10 minutes, and the supernatant is collected to obtain a self-propelled delivery carrier (X / B-CS / Bi2O3 micromotor) for Helicobacter pylori diagnosis and gastric mucosal protection.

[0018] Furthermore, in the gastric acid-driven propulsion functional coating X, X is any one of metal magnesium, metal zinc, magnesium alloy, zinc alloy, sodium carbonate or sodium bicarbonate.

[0019] In a second aspect, the present invention provides a method for preparing a self-propelled delivery vehicle for Helicobacter pylori diagnosis and gastric mucosal protection, comprising the following steps:

[0020] (1) Bismuth oxide microparticle core: Weigh 0.95g bismuth nitrate and 0.1g surfactant Triton-X-100, dissolve in 10mL 1.12mol / L nitric acid, and stir thoroughly until transparent. Slowly add the solution dropwise into 100mL 0.2mol / L sodium hydroxide aqueous solution, stirring while adding dropwise, to generate a white precipitate. Transfer the mixture to a clean flask, place it in a 90℃ oil bath and heat for 3 hours. The mixture gradually turns yellow, indicating that Bi2O3 is formed. After cooling to room temperature, wash it three times with double distilled water and ethanol to remove impurities. Dry the precipitate in an oven at 80℃ for 3 hours, grind it into fine powder and pass it through a 500-mesh sieve to obtain pure bismuth oxide (Bi2O3) microparticles.

[0021] (2) Preparation of chitosan solution: 0.05 g of chitosan was dissolved in 100 mL of deionized water and stirred thoroughly until completely dissolved. Then, 0.1 g of sodium dodecyl sulfate (SDS) was added and continued to be stirred evenly. Finally, 0.2 mL of acetic acid was added to ensure that all components were completely dissolved and mixed evenly to form a stable chitosan solution.

[0022] (3) Preparation of chitosan-coated bismuth oxide microparticles: Use a micropipette to mix the prepared chitosan solution with the bismuth oxide particles, and add about 1-2 mL of the chitosan solution each time to ensure that the solution can evenly cover the surface of the bismuth oxide microparticles; after the addition is completed, gently shake the round-bottom flask to spread the solution evenly on the surface of the bismuth oxide microparticles to ensure that the solution covers all the bismuth oxide surfaces that need to be coated with chitosan; then, stir at room temperature for 4 hours and centrifuge at 10,000 rpm for 10 minutes, and the precipitate is the chitosan-coated bismuth oxide particles.

[0023] (4) Binding of bacterial targeting substances: Transfer the chitosan-coated bismuth oxide particles into a clean round-bottom flask, add 10 mL of deionized water, gently shake to suspend the microparticles in the solvent, and use a pipette to gently blow to help the microparticles disperse evenly; add 40-60 mg of bacterial targeting substances, start stirring the reaction under ice bath conditions, and use an ice water bath or dry ice ethanol bath to maintain low temperature. Stir the reaction under ice bath conditions overnight (at least 12 hours) to ensure that the reaction is complete. Use an appropriate amount of tetrahydrofuran (THF) to wash the microparticles multiple times to remove unreacted reagents and by-products, and ensure that they are clean, then wash them multiple times with deionized water to remove residual organic solvents; place the washed microparticles in a well-ventilated environment to dry naturally, or place them in a constant temperature oven at a temperature of 40-50°C to accelerate the evaporation of water; after the chitosan layer is completely dry, collect the treated bismuth oxide microparticles (B-CS / Bi2O3 particles).

[0024] (5) Preparation of gastric acid driven propulsion functional coating X: The synthesized chitosan coated bismuth oxide microparticles were dispersed in 5 mL of ethanol, and the mixture was vortexed to be uniformly dispersed; the mixture (100 μL) was transferred to a glass slide and evenly spread on the glass slide with the help of a spatula; as the ethanol evaporated, the chitosan coated bismuth oxide microparticles remained on the glass slide; the glass slide was treated with plasma to make it hydrophilic; the glass slide was placed on an ion sputtering instrument table equipped with a gastric acid driven material disk to sputter the gastric acid driven material, and the thickness of the gastric acid driven material layer could be customized by adjusting the sputtering time; the glass slide was immersed in ethanol and subjected to ultrasonic treatment for 1 min to separate the micromotors derived from the chitosan coated bismuth oxide particles; centrifuged at 6000 g for 10 min, the supernatant was discarded, and the collected precipitate was a self-propelled delivery carrier (X / B-CS / Bi2O3 micromotor) for Helicobacter pylori diagnosis and gastric mucosal protection.

[0025] In a third aspect, the present invention also provides the use of the above-mentioned delivery vector in the preparation of a Helicobacter pylori diagnostic agent, wherein the diagnostic agent is developed in the stomach through a bismuth oxide coating to locate the site of Helicobacter pylori infection.

[0026] The delivery carrier is developed in the stomach through the bismuth oxide coating to achieve the positioning of the Helicobacter pylori infection site; the gastric acid-driven propulsion functional coating X produces gas in a directional manner in the gastric acid environment to drive the carrier movement, the chitosan coating enhances the stability and gastric viscosity of the carrier, and the bacteria-targeting substance on the chitosan achieves targeted driving of Helicobacter pylori; the chitosan coating and the bismuth oxide core release bismuth ions in the gastric acid environment, and jointly play a protective role in the gastric mucosa, and are suitable for preventing and treating gastric diseases such as gastritis and gastric ulcers.

[0027] Beneficial effects: The existing delivery carrier technology has problems such as low gastric mucus layer penetration efficiency, poor stability, lack of effective gastric mucosal protection mechanism, lack of targeting, etc. in the treatment of Helicobacter pylori infection. In view of these problems, the present invention innovatively proposes a self-propelled delivery carrier for Helicobacter pylori diagnosis and gastric mucosal protection, which successfully overcomes the above problems through the gas production characteristics of the gastric acid-driven propulsion function coating X, the targeting ability of the bacteria-targeting substance, the development and protection function of the bismuth oxide coating, and the stability and antibacterial properties of the chitosan coating.

[0028] Specifically, the delivery carrier generates gas in gastric acid through the gastric acid-driven propulsion functional coating X, which pushes the carrier to penetrate the gastric mucus layer, significantly improving the drug delivery efficiency; the targeting substance in the bacteria-targeted functional coating B-CS specifically binds to Helicobacter pylori, accurately delivers the drug to the lesion area, improves the local concentration and therapeutic effect of the drug, and the chitosan coating enhances the stability and gastric viscosity of the carrier, prolongs the residence time of the drug in the stomach, and the antibacterial properties of chitosan further inhibit the growth of Helicobacter pylori, improving the safety and effectiveness of the treatment; the bismuth oxide coating can not only release bismuth ions in gastric acid to protect the gastric mucosa, but also accurately locate the site of Helicobacter pylori infection through imaging, thereby improving the accuracy of diagnosis.

[0029] In summary, the present invention achieves efficient drug delivery, precise targeting, gastric mucosal protection and integrated diagnosis through innovative design strategies, significantly improves the therapeutic effect and patient comfort, and provides a new perspective and possibility for the diagnosis and treatment of Helicobacter pylori, which has important practical significance and good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creativity and labor. Among them:

[0031] Figure 1 The electron microscopic appearance of the delivery vector prepared in the example is shown.

[0032] Figure 2 The solution appearance of the delivery vehicle prepared in the example is shown.

[0033] Figure 3 The figure shows the changes in the position, morphology and microenvironment pH of the delivery vehicle prepared in the example in the simulated gastric mucus layer over time.

[0034] Figure 4 Phenol red staining changes of gastric homogenate after bacterial infection are shown. DETAILED DESCRIPTION

[0035] The following examples are only for illustrative purposes and explanation of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies realized based on the above content of the present invention are included in the scope of protection of the present invention. It should be noted that the raw materials and reagents of the present invention are all commercially available products.

[0036] Example 1: Preparation of Bismuth Oxide Microparticle Cores

[0037] Weigh 0.95 g of bismuth nitrate (Bi(NO3)3·5H2O) and 0.1 g of surfactant Triton-X-100, dissolve in 10 mL of 1.12 mol / L nitric acid, and stir thoroughly until completely dissolved. 3 + ions completely dissolved to form a clear solution.

[0038] The bismuth nitrate solution was slowly added dropwise into 100 mL of 0.2 mol / L sodium hydroxide aqueous solution while stirring. A white precipitate was gradually generated during the addition.

[0039] The mixture, which produced a white precipitate, was transferred to a clean flask.

[0040] The flask was heated in an oil bath at 90°C for 3 hours.

[0041] During heating, the mixture gradually turned yellow due to the formation of Bi2O3.

[0042] After heating was complete, the mixture was cooled to room temperature.

[0043] Wash thoroughly three times with double distilled water and ethanol to remove any potential impurities and unwanted yellow precipitate.

[0044] Transfer the washed pellet to a clean dish.

[0045] Dry in an oven at 80 °C for 3 h to completely remove moisture.

[0046] The dried bismuth oxide particles were ground into fine powder using a grinder.

[0047] The large particles are removed through a 500 mesh sieve to ensure the uniformity and fineness of the particles.

[0048] Example 2: Preparation of bacteria-targeting functional coating B-CS

[0049] Weigh 0.05 g of chitosan, dissolve it in 100 mL of deionized water, and stir thoroughly until it is completely dissolved.

[0050] Then, 0.1 g of sodium dodecyl sulfate (SDS) was added and the mixture was stirred evenly.

[0051] Finally, 0.2 mL of acetic acid was added to ensure that all components were completely dissolved and mixed evenly to form a stable chitosan solution.

[0052] Use a micropipette to mix the prepared chitosan solution with the bismuth oxide particles, adding about 500 μL of chitosan solution each time to ensure that the solution can evenly cover the surface of the bismuth oxide particles.

[0053] After the addition is completed, the round-bottom flask is gently shaken to spread the solution evenly on the surface of the bismuth oxide particles, ensuring that the solution covers all bismuth oxide surfaces that need to be coated with chitosan.

[0054] Subsequently, the mixture was stirred at room temperature for 4 hours.

[0055] After centrifugation at 10,000 rpm for 10 minutes, the precipitate is the chitosan-coated bismuth oxide particles.

[0056] Transfer the chitosan-coated bismuth oxide particles into a clean round-bottom flask.

[0057] Add 10 mL of deionized water, shake gently to suspend the microparticles in the solvent, and use a pipette to gently blow to help the microparticles disperse evenly.

[0058] Weigh 35-55 mg of 4-carboxyphenylboronic acid and 35-55 mg of N,N'-dicyclohexylcarbodiimide (DCC), and dissolve the two reagents in 20 mL of tetrahydrofuran (THF) to form a reaction solution. DCC, as a coupling agent, can promote the chemical reaction between 4-carboxyphenylboronic acid and chitosan.

[0059] Add the prepared modification solution (20 mL THF) into the centrifuge tube containing the suspended microparticles, ensuring that the microparticles are completely immersed in the modification solution.

[0060] Start stirring the reaction under ice bath conditions. Ice bath conditions can be maintained at low temperatures using an ice water bath or a dry ice ethanol bath. Stir the reaction under ice bath conditions overnight (at least 12 hours) to ensure that the reaction is complete.

[0061] The microparticles are washed several times with an appropriate amount of tetrahydrofuran (THF) to remove unreacted reagents and by-products, and after being cleaned, they are washed several times with deionized water to remove residual organic solvents.

[0062] Place the cleaned microparticles in a well-ventilated environment to dry naturally, or place them in a constant temperature oven at 40-50°C to accelerate the evaporation of moisture.

[0063] After the chitosan layer is completely dried, the treated bismuth oxide microparticles (B-CS / Bi2O3 particles) are collected.

[0064] Example 3: Preparation of gastric acid driven propulsion functional coating X

[0065] Disperse the synthesized chitosan-coated bismuth oxide microparticles in 5 mL of ethanol, and vortex the mixture into a uniform dispersion.

[0066] The mixture (100 μL) was transferred to a glass slide and evenly spread on the slide with the help of a spatula.

[0067] As the ethanol evaporates, the chitosan-coated bismuth oxide microparticles remain on the glass slide.

[0068] The slides were then treated with plasma to make them hydrophilic.

[0069] The glass slide was placed on an ion sputtering stage equipped with a magnesium (Mg) disk to sputter magnesium. The thickness of the Mg layer can be customized by adjusting the sputtering time.

[0070] The slides were immersed in ethanol and subjected to ultrasonic treatment for 1 min to separate the micromotors derived from chitosan-coated bismuth oxide particles.

[0071] After centrifugation at 6000 g for 10 min, the supernatant was discarded and the collected precipitate was the self-propelled delivery carrier (X / B-CS / Bi2O3 micromotor) for Helicobacter pylori diagnosis and gastric mucosal protection.

[0072] Through the above embodiments, the present invention provides an efficient self-propelled delivery carrier for Helicobacter pylori diagnosis and gastric mucosal protection, which has good stability and biocompatibility, can achieve self-propulsion and targeted driving in a gastric acid environment, and improve the delivery efficiency and stability of drugs.

[0073] The serial numbers of the embodiments of the present invention are only for description and do not represent the advantages and disadvantages of the embodiments. The embodiments of the present invention are described above, but the present invention is not limited to the above-mentioned specific implementation methods. The above-mentioned specific implementation methods are only illustrative and not restrictive. Under the enlightenment of the present invention, those skilled in the art can also make many forms without departing from the scope of protection of the purpose of the present invention and the claims, all of which are within the protection of the present invention.

Claims

1. A self-propelled delivery vehicle for Helicobacter pylori diagnosis and gastric mucosal protection, characterized in that: The delivery carrier is composed of 50 to 150 parts by weight of bismuth oxide particles, 0.5 to 20 parts by weight of bacteria-targeting functional coating B-CS, and 0.1 to 5.0 μm thick gastric acid-driven propulsion functional coating X; in the bacteria-targeting functional coating B-CS, B is a bacteria-targeting substance, and CS is chitosan; in the gastric acid-driven propulsion functional coating X, X is a gastric acid-driven substance located on the outermost layer of the carrier.

2. A self-propelled delivery vehicle for Helicobacter pylori diagnosis and gastric mucosal protection according to claim 1, characterized in that: The carrier can drive the gas production of the propulsion functional coating X in the gastric acid environment to promote the directional movement of the carrier; the bacteria-targeting functional coating B-CS enhances the stability and gastric viscosity of the carrier, and the bacteria-targeting substance on the chitosan can achieve targeted driving of Helicobacter pylori; the carrier can play a protective role in the gastric mucosa through the bismuth ions released by the chitosan coating and bismuth oxide in the gastric acid environment, and is suitable for preventing and treating gastric diseases such as gastritis and gastric ulcer.

3. The delivery vector according to claim 1, characterized in that The bismuth oxide particle core is 50 to 150 parts by weight, and the bismuth oxide particle core is prepared by the following method: bismuth nitrate (Bi(NO3)3·5H2O) and surfactant Triton-X-100 are dissolved in an acidic solution; slowly added dropwise into an alkaline solution and stirred to generate a white precipitate; the generated precipitate is heated to gradually turn yellow to form bismuth oxide (Bi2O3); the washed precipitate is dried and ground into fine powder to obtain pure bismuth oxide (Bi2O3) particles.

4. The delivery vector according to claim 1, characterized in that The bacterial targeting functional coating B-CS is prepared by the following method: dissolving chitosan in deionized water, adding sodium dodecyl sulfate (SDS) and acetic acid, and stirring to form a stable chitosan solution; mixing the chitosan solution with bismuth oxide particles and uniformly covering the surface of the bismuth oxide particles; stirring at room temperature and then centrifuging to obtain chitosan-coated bismuth oxide particles; adding deionized water to suspend the chitosan-coated bismuth oxide particles, adding a bacterial targeting substance B, and stirring to react; washing the microparticles multiple times to remove unreacted reagents and by-products, and drying to obtain bismuth oxide microparticles (B-CS / Bi2O3 particles).

5. The carrier according to claim 4, characterized in that The chitosan is derived from at least one of low molecular weight chitosan (molecular weight 10,000-50,000 Da), medium molecular weight chitosan (molecular weight 50,000-150,000 Da) or high molecular weight chitosan (molecular weight 150,000-500,000 Da).

6. The carrier according to claim 4, characterized in that The bacteria targeting substance is any at least one of 4-carboxyphenylboronic acid, N-butylthiophosphorothioic triamide (NBPT), amoxicillin-polyethylene glycol conjugate, L-ornithine-phenylalanine dipeptide or antisense oligonucleotide.

7. The delivery vector according to claim 1, characterized in that The non-uniform gastric acid driven propulsion functional coating X is prepared by the following method: dispersing bismuth oxide microparticles wrapped in chitosan in ethanol and evenly spreading them on a glass slide; after the ethanol evaporates, treating the glass slide with plasma to make it hydrophilic; placing the glass slide on an ion sputtering instrument to sputter the gastric acid driven substance X; then, immersing the glass slide in ethanol and ultrasonically treating it to separate the micromotor; and collecting the precipitate by centrifugation to obtain a self-propelled delivery carrier (X / B-CS / Bi2O3 micromotor) for Helicobacter pylori diagnosis and gastric mucosal protection.

8. The delivery vector according to claim 7, characterized in that In the gastric acid driven propulsion functional coating X, X is any at least one of metal magnesium, metal zinc, magnesium alloy, zinc alloy, sodium carbonate or sodium bicarbonate; the thickness of the gastric acid driven propulsion functional coating X is 0.1 to 5.0 μm, and the specific thickness can be customized by adjusting the ion sputtering time.

9. The delivery vector according to any one of claims 1 to 8, characterized in that The delivery carrier has self-propulsion ability and targeting function in the gastric acid environment, can effectively release drugs and protect the gastric mucosa, and is suitable for the diagnosis and treatment of Helicobacter pylori infection and the prevention and treatment of gastric diseases.

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