Hydrogen-producing acid-resistant liquid metal particle and preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to hydrogen-producing acid-resistant liquid metal particles and a preparation method and application thereof. The hydrogen-producing acid-resistant liquid metal particle comprises a liquid gallium-indium alloy nanoparticle, a hyaluronic acid layer wrapping the liquid gallium-indium alloy nanoparticle and a sodium alginate layer wrapping the hyaluronic acid layer, and the hydrogen-producing acid-resistant liquid metal particle can completely pass through gastric juice and trigger hydrogen to be continuously released in a colon alkalescence environment, so that intestinal mucosa injury is repaired, and the intestinal mucosa healing effect is improved. The disordered intestinal flora can be improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a hydrogen-producing acid-resistant liquid metal particle, its preparation method, and its application. Background Technology

[0002] Inflammatory bowel disease (IBD) is a chronic, recurrent inflammatory disease affecting various parts of the gastrointestinal tract, including ulcerative colitis and Crohn's disease. Clinical drug interventions for IBD primarily include aminosalicylic acid, antibiotics, corticosteroids, and immunosuppressants. However, most of these drugs do not address the underlying causes of IBD, such as intestinal mucosal damage, impaired intestinal barrier function, and gut microbiota imbalance. Furthermore, long-term use of these drugs can easily cause serious adverse events, including nausea, headache, acne, edema, and nasopharyngitis. Summary of the Invention

[0003] To address the problem that existing drugs cannot solve intestinal mucosal damage, this invention provides hydrogen-producing acid-resistant liquid metal particles, their preparation method, and applications. These hydrogen-producing acid-resistant liquid metal particles can pass completely through gastric juice and trigger the continuous release of hydrogen gas in the weakly alkaline environment of the colon, thereby repairing intestinal mucosal damage.

[0004] The technical solution provided by this invention is as follows: In a first aspect, the present invention provides hydrogen-producing acid-resistant liquid metal particles, comprising: Liquid gallium-indium alloy nanoparticles; A hyaluronic acid layer encapsulating the liquid gallium indium alloy nanoparticles; And a sodium alginate layer that encapsulates the hyaluronic acid layer.

[0005] In conjunction with the first aspect of the present invention, in some embodiments, the mass ratio of gallium to indium in the liquid gallium-indium alloy nanoparticles is (3~6):1.

[0006] In conjunction with the first aspect of the present invention, in some embodiments, the particle size of the liquid gallium indium alloy nanoparticles is 40-150 nanometers.

[0007] In conjunction with the first aspect of the present invention, in some embodiments, the thickness of the hyaluronic acid layer is 3-20 nanometers, and the thickness of the sodium alginate layer is 3-20 nanometers.

[0008] In conjunction with the first aspect of the present invention, in some embodiments, the particle size of the hydrogen-producing acid-resistant liquid metal particles is 56-190 nanometers.

[0009] Secondly, the present invention provides a method for preparing hydrogen-producing acid-resistant liquid metal particles, comprising the following steps: Liquid gallium-indium alloy was mixed with hyaluronic acid solution and subjected to ultrasonic treatment to form hydrogen-producing nanomedicine cores; The hydrogen-producing nanomedicine core is mixed with sodium alginate solution to form a sodium alginate layer; The hydrogen-producing acid-resistant liquid metal particles were obtained by centrifugation and washing.

[0010] In conjunction with a second aspect of the invention, in some embodiments, the concentration of hyaluronic acid in the hyaluronic acid solution is 2-5 mg / mL; and / or, The concentration of sodium alginate in the sodium alginate solution is 2~5 mg / mL.

[0011] In conjunction with the second aspect of the present invention, in some embodiments, the ultrasonic treatment is performed in an ice bath environment; and / or, the power of the ultrasonic treatment is 600~1000W; and / or, the duration of the ultrasonic treatment is 10~50 minutes.

[0012] Thirdly, the present invention provides the use of the above-mentioned hydrogen-producing acid-resistant liquid metal particles in the preparation of a medicament for treating inflammatory bowel disease.

[0013] In conjunction with a third aspect of the invention, in some embodiments, the inflammatory bowel disease is ulcerative colitis and / or Crohn's disease.

[0014] In conjunction with a third aspect of the invention, in some embodiments, the treatment of inflammatory bowel disease includes: (1) Restore intestinal barrier function; and / or, (2) Improve disordered gut microbiota.

[0015] In conjunction with a third aspect of the invention, in some embodiments, the treatment of inflammatory bowel disease is manifested as a change in one or more of the following indicators: (1) Decreased FITC-glucan permeability; and / or, (2) Increase the relative abundance of beneficial bacteria and decrease the relative abundance of opportunistic pathogens.

[0016] In conjunction with a third aspect of the invention, in some embodiments, the drug is an oral formulation, an enema, or a colon-targeted formulation.

[0017] Compared with the prior art, the present invention has the following beneficial effects: The method for preparing hydrogen-producing acid-resistant liquid metal particles provided by this invention is simple, the composition is safe and reliable, and the prepared hydrogen-producing acid-resistant liquid metal particles can achieve efficient targeted delivery of hydrogen to the intestinal inflammatory site, thereby relieving inflammation, regulating immunity and promoting regeneration. Attached Figure Description

[0018] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0019] Figure 1 Characterization diagram of hydrogen-producing acid-resistant liquid metal particles; where: a: TEM images of LM, LMH, and LMHS; b: Zeta potentials of LM, LMH, and LMHS; c: Photos of LMHS before and after standing in H2O, SGF, SIF and SCF for 2 hours; d: Photographs of LM and LMHS after incubation with SGF for 2 hours and redispersion in SCF; e: Normalized Ga K-edge XANES spectra of reference samples (Ga2O3 and Ga foil), synthesized LMHS, and colon contents samples taken from IBD mice at 6 and 12 hours after oral administration of LMHS. f: by k 3 The FT magnitude derived from the weighted Ga K-edge EXAFS spectrum; g: k-space representation of the Ga K-edge EXAFS spectrum; h: WT analysis of Ga foil, LMHS, and colon contents samples taken from IBD mice at 6 and 12 hours after LMHS administration; i: Evaluation of H2 generation in SCF after LM, LMH and LMHS (Ga concentration of 150 μg / mL) were incubated with SGF for 0.5, 1.0, 2.0, 4.0 and 6.0 hours, respectively; the samples in the inset from left to right are H2O, HRW, LM, LMH and LMHS, respectively. j: The ability of LM, LMH and LMHS to remove oxTMB after etching in SGF for 1.0, 2.0, 4.0 and 6.0 hours, respectively; k: The ability of LM, LMH and LMHS to remove ABTS• after being etched in SGF for 1.0, 2.0, 4.0 and 6.0 hours, respectively.

[0020] Figure 2 A diagram illustrating the cell compatibility and immunomodulatory capabilities of hydrogen-producing acid-resistant liquid metal particles; where: a: Cell viability of HUVECs after co-incubation with different concentrations of LMHS for 24 hours; b: Cell viability of NCM460 cells after co-incubation with different concentrations of LMHS for 24 hours; c: Cell viability of RAW 264.7 cells after co-incubation with different concentrations of LMHS for 24 hours; d: Relative cell viability of NCM460 cells after co-incubation with 100 μg / mL LMHS and 2 mM H2O2 for 24 hours; e: Schematic diagram of LMHS inhibiting macrophage activation; f: Relative mRNA expression levels of TNF-α in RAW 264.7 cells after different treatments: g: Relative IL-6 mRNA expression levels in RAW 264.7 cells after different treatments: h: Relative mRNA expression level of IL-1β in RAW 264.7 cells after different treatments: i: Relative CCL2 mRNA expression levels in RAW 264.7 cells after different treatments: j: Relative mRNA expression level of iNOS in RAW 264.7 cells after different treatments; k: Relative mRNA expression level of Arg-1 in RAW 264.7 cells after different treatments; l: Flow cytometry was used to detect the relative proportion of M1 macrophages after specified treatment; m: Flow cytometry analysis of CD86 expression in RAW 264.7 cells after 24 hours of different treatments; Data are expressed as mean ± standard deviation (n≥3); : P<0.05， : P<0.01， P < 0.001 P < 0.0001 (one-way ANOVA).

[0021] Figure 3 This image illustrates how hydrogen-producing, acid-resistant liquid metal particles can target intestinal inflammation sites in vivo and alleviate intestinal inflammation; among which: a: C57BL / 6 mice were given plain water or water containing 2.5% DSS for 7 days, and then orally administered HA+SA, 5-ASA, LM or LMHS on days 5, 7 and 9. b: Immunofluorescence staining of EPCAM and F4 / 80 in colon tissue of healthy mice or IBD mice after oral administration of Cy5.5-labeled LMHS; c: In vivo fluorescence imaging of intestinal tissue from healthy mice after oral administration of Cy5.5-labeled LMH or LMHS; d: In vivo fluorescence imaging of intestinal tissue in IBD mice after oral administration of Cy5.5-labeled LMH or LMHS; e: The mean fluorescence intensity of mouse colon tissue treated with Cy5.5-LMH or Cy5.5-LMHS; f: Biodistribution of gallium in major organs and colon tissue after oral administration of LM; g: Biodistribution of gallium in major organs and colon tissue after oral administration of LMH; h: Biodistribution of gallium in major organs and colon tissue after oral administration of LMHS; i: Representative photographs of colon tissue from mice in each treatment group on day 10; j: Quantitative measurement results of colon length in animals under all treatment conditions; k: The intensity of fluorescence signal in the blood of experimental mice 4 hours after oral administration of FITC-glucan (4 kDa) on day 10; l: H&E staining image of colon tissue of experimental mice at the end of treatment; Data are expressed as mean ± standard deviation (n≥3); : P<0.05， ：P<0.01， ： P<0.001, P < 0.0001 (one-way ANOVA).

[0022] Figure 4 This is a diagram illustrating the use of hydrogen-producing, acid-resistant liquid metal particles and gallium ions to treat enteritis; where: a: Oral Ga 3+ Results of quantitative measurement of colon length in mice after LMHS; b: Oral Ga 3+ Quantitative measurement results of mouse weight change after LMHS.

[0023] Figure 5 A diagram illustrating the regulation of gut microbiota by hydrogen-producing, acid-resistant liquid metal particles; where: a: Observed OTU richness in the microbial community; b: Alpha diversity as expressed by the Shannon index; c: Classification of gut microbiota at the phylum level; d: β diversity based on PCoA analysis (one mouse per data point, n = 5); e: Relative abundance of Bifidobacterium; f: Relative abundance of Lactobacillus spp.; g: Relative abundance of Akkermansia; h: LDA values ​​of LEfSe analysis for samples after different treatments (only species with LDA scores > 3.5 are shown); i: Branching diagram of gut microbiota community composition in experimental mice based on LEfSe analysis (LDA threshold set to 3.5); j: Short-chain fatty acid content in fecal samples from each treatment group; Data are expressed as mean ± standard deviation (n = 5); statistical significance was determined by one-way ANOVA. P < 0.05 P < 0.01 P < 0.001, ns: no significant difference.

[0024] Figure 6 An illustration of the in vitro biosafety of hydrogen-producing acid-resistant liquid metal particles; where: a: Cell viability of NCM460 cells after co-incubation with different concentrations of HA+SA for 24 hours; b: Cell viability of NCM460 cells after co-incubation with different concentrations of LM or LMHS for 24 hours; c: Fluorescence micrographs of NCM460 cells (normal colonic epithelial cells) stained with calcein AM (green fluorescence, live cells) and propidium iodide (red fluorescence, dead cells) after different treatments; Scale bar: 50 μm; d: Passed through PBS and Ga... 3+ Centrifuge tubes of blood samples treated with HA+SA, LM, LMH and LMHS (gallium concentrations of 100, 200 and 400 μg / mL, respectively).

[0025] Figure 7 This diagram illustrates the in vivo biocompatibility of hydrogen-producing, acid-resistant liquid metal particles; where each sub-figure represents the condition of the experimental mice at the end of treatment. a: Alanine aminotransferase (ALT) level; b: Alkaline phosphatase (ALP) level; c: Creatinine level; d: H&E staining images of heart, liver, spleen, lung and kidney tissues. Detailed Implementation

[0026] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below in conjunction with the embodiments of this invention. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0027] For simplicity, this invention only explicitly discloses some numerical ranges. However, any lower limit can be combined with any upper limit to form a range not explicitly stated; and any lower limit can be combined with other lower limits to form a range not explicitly stated. Similarly, any upper limit can be combined with any other upper limit to form a range not explicitly stated. Furthermore, although not explicitly stated, every point or individual value between the endpoints of the range is included within that range. Therefore, each point or individual value can be used as its own lower or upper limit and combined with any other point or individual value or with other lower or upper limits to form a range not explicitly stated.

[0028] It should be noted that, in the description of this invention, unless otherwise stated, "above" and "below" include the stated number, and "multiple" in "one or more" means two or more. Relational terms such as "first" and "second" are used merely to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0029] In the description of this invention, the terms "any embodiment / mode," "one embodiment / mode," "some embodiments / modes," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment / mode or example, which are included in at least one embodiment / mode or example of the invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment / mode or example. Moreover, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments / modes or examples. Furthermore, without contradiction, those skilled in the art can combine and integrate the different embodiments / modes or examples described in this specification, as well as the features of different embodiments / modes or examples.

[0030] The hydrogen-producing acid-resistant liquid metal particles provided by this invention include: liquid gallium indium alloy nanoparticles, a hyaluronic acid layer encapsulating the liquid gallium indium alloy nanoparticles, and a sodium alginate layer encapsulating the hyaluronic acid layer. They can pass completely through gastric juice and trigger the continuous release of hydrogen gas in the weakly alkaline environment of the colon, thereby repairing intestinal mucosal damage.

[0031] Existing technologies report that hydrogen can selectively scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS) without interfering with physiologically functional ROS in the body, thereby effectively alleviating oxidative stress. However, hydrogen has low solubility, making it difficult to accurately deliver it to inflamed sites in the intestines and achieve controlled release. Currently, clinical administration mainly relies on high-dose, long-term inhalation, which is not only inconvenient but also fails to achieve ideal therapeutic effects in the complex structure and variable microenvironment of the intestines. This invention delivers hydrogen-producing, acid-resistant liquid metal particles into the intestines, utilizing the alkaline environment of the colon to generate hydrogen from a gallium-indium alloy, thereby alleviating oxidative stress in the colon.

[0032] Gallium is an amphoteric metal, and during oral delivery of liquid gallium-indium alloy nanoparticles, it is easily decomposed by gastric acid, making it difficult to reach the inflamed area of ​​the colon intact, which is a major obstacle to its clinical application. This invention encapsulates liquid gallium-indium alloy nanoparticles with a protective layer: an outer layer of sodium alginate and an inner layer of hyaluronic acid. In the highly acidic environment of the stomach, the carboxyl groups on the sodium alginate (SA) molecular chain undergo protonation, causing the molecular chain to contract and form a denser sodium alginate protective layer. Simultaneously, the intermolecular hydrogen bonding of sodium alginate molecules is enhanced, making the gel network structure of the entire sodium alginate layer more compact, effectively preventing gastric acid penetration and protecting the internal liquid gallium-indium alloy nanoparticles from premature decomposition. The alkaline environment of the colon causes the sodium alginate layer to deprotonate, and the negatively charged molecular chains repel each other, causing the gel network structure to loosen and releasing the liquid gallium-indium alloy nanoparticles encapsulated in the hyaluronic acid layer. The lesions in inflammatory bowel disease typically overexpress a receptor called CD44. Hyaluronic acid (HA) is a natural ligand for the CD44 receptor. Therefore, liquid gallium indium alloy nanoparticles encapsulated in a hyaluronic acid layer can actively recognize and accumulate in inflamed tissues through ligand-receptor binding. Furthermore, the hyaluronic acid layer is a hydrophilic layer with a three-dimensional porous network structure. This porous structure allows intestinal fluid to permeate and contact the internal liquid gallium indium alloy nanoparticles, triggering a chemical reaction that releases hydrogen gas.

[0033] In some embodiments of the present invention, the mass ratio of gallium to indium in the liquid gallium-indium alloy nanoparticles is (3~6):1. The gallium-indium alloy with a mass ratio of (3~6):1 has a melting point below body temperature (37°C), ensuring that the liquid gallium-indium alloy nanoparticles remain liquid in vivo. Its fluidity allows fresh metal surfaces to be continuously exposed to the reaction environment, thereby ensuring a continuous and stable release of hydrogen. Furthermore, compared to solid metal nanoparticles, liquid metal nanoparticles have a smoother surface and greater fluidity, which may reduce physical stimulation and damage to cells, thus exhibiting superior biocompatibility.

[0034] In some embodiments of the present invention, the liquid gallium indium alloy nanoparticles have a particle size of 40-150 nanometers. Particles with a size in the range of 40-150 nanometers can more easily pass through the highly permeable blood vessels caused by inflammation and remain in the intestinal inflammatory tissue by utilizing a principle similar to the high permeability and retention effect of solid tumors.

[0035] In some embodiments of the present invention, the thickness of the hyaluronic acid layer is 3-20 nanometers, preferably 3-10 nanometers, and more preferably 5-10 nanometers. In some embodiments of the present invention, the thickness of the sodium alginate layer is 3-20 nanometers, preferably 3-10 nanometers, and more preferably 5-10 nanometers. This range forms a continuous and complete coating layer, achieving complete protection of the internal substances. Simultaneously, it does not excessively hinder the permeation of colonic fluid into the core liquid metal or the rate of hydrogen diffusion outwards.

[0036] In some embodiments of the present invention, the particle size of the hydrogen-producing acid-resistant liquid metal particles is 56-190 nanometers.

[0037] The present invention also provides a method for preparing hydrogen-producing acid-resistant liquid metal particles, comprising the following steps: mixing liquid gallium-indium alloy with hyaluronic acid solution and ultrasonically treating it to form a hydrogen-producing nanomedicine core; mixing the hydrogen-producing nanomedicine core with sodium alginate solution to form a sodium alginate layer; and obtaining the hydrogen-producing acid-resistant liquid metal particles by centrifugation and washing.

[0038] In some embodiments of the present invention, the concentration of hyaluronic acid in the hyaluronic acid solution is 2-5 mg / mL, and the concentration of sodium alginate in the sodium alginate solution is 2-5 mg / mL. This concentration ensures that there are sufficient HA or SA polymer chains in the solution to completely cover the surface of the liquid gallium indium alloy nanoparticles, forming a continuous, defect-free coating layer. At the same time, excessively high concentrations will not make the solution too viscous, which would not only affect the mixing efficiency during the preparation process but also easily lead to cross-linking and aggregation of nanoparticles, affecting the uniformity and stability of the product.

[0039] In some embodiments of the present invention, the ultrasonic treatment is performed in an ice bath environment; during the ultrasonic process, the probe converts a large amount of energy into heat, causing the system temperature to rise rapidly. Liquid gallium-indium alloys are more easily oxidized at high temperatures, forming an oxide layer on their surface, which alters their surface properties and affects the effective coating of hyaluronic acid. The ice bath environment can continuously remove heat, maintain a low temperature, and ensure the purity and reactivity of the liquid gallium-indium alloy nanoparticles.

[0040] In some embodiments of the present invention, the power of the ultrasonic treatment is 600~1000W; and / or the ultrasonic treatment time is 10~50 minutes. Within this power and time range, hydrogen-producing nanoparticle cores with uniform particle size and stable particles can be obtained, while ensuring efficiency.

[0041] This invention also provides the use of the above-described hydrogen-producing, acid-resistant liquid metal particles in the preparation of medicaments for treating inflammatory bowel disease. In some embodiments of this invention, the inflammatory bowel disease is ulcerative colitis and / or Crohn's disease. Example 10 demonstrates that the above-described hydrogen-producing, acid-resistant liquid metal particles have a therapeutic effect on a DSS-induced ulcerative colitis (UC) model, and Example 11 demonstrates that the above-described hydrogen-producing, acid-resistant liquid metal particles can improve the inflammatory microenvironment by modulating the intestinal flora.

[0042] The technical solution of the present invention will be described in detail below through specific embodiments: Example 1: Preparation of Hydrogen-Generating Acid-Resistant Liquid Metal Particles (1) Preparation of hydrogen-producing nanomedicine cores: 200 mg of liquid gallium-indium alloy with a mass ratio of 3:1 was added to 15 mL of deoxygenated ultrapure water containing 50 mg of hyaluronic acid. The mixture was ultrasonicated for 40 minutes with a 6 mm ultrasonic probe and 800 W power under ice-water bath conditions to obtain a mixed solution. The mixture was centrifuged at 1000 rpm for 5 minutes, the supernatant was collected, and then centrifuged at 8000 rpm for 5 minutes to obtain the hydrogen-producing nanomedicine core (LMH). The LMH was then washed three times with deoxygenated ultrapure water.

[0043] (2) Preparation of hydrogen-producing acid-resistant liquid metal particles: The hydrogen-producing nanomedicine core obtained in step (1) was added to 15 mL of sodium alginate solution with a concentration of 4 mg / mL. After stirring magnetically for 12 hours, the resulting mixture was centrifuged at 8000 rpm for 10 min, and the precipitate was washed three times with deoxygenated ultrapure water to obtain hydrogen-producing acid-resistant liquid metal particles (LMHS).

[0044] (3) Preparation of gallium-based liquid metal nanoparticles: 200 mg of liquid gallium-indium alloy with a mass ratio of 3:1 was added to 15 mL of deoxygenated ultrapure water containing 70 mg of methoxy polyethylene glycol mercaptan. The mixture was ultrasonicated for 40 minutes with a 6 mm ultrasonic probe and 800 W power under ice-water bath conditions to obtain a mixed solution. The mixture was centrifuged at 1000 rpm for 5 minutes, the supernatant was collected, and then centrifuged at 8000 rpm for 5 minutes to obtain gallium-based liquid metal nanoparticles (LM). The gallium-based liquid metal nanoparticles were then washed three times with deoxygenated ultrapure water.

[0045] Example 2: Characterization and Detection of Hydrogen-Generating Acid-Resistant Liquid Metal Particles Figure 1 Figures a and b in the figure show transmission electron microscopy and zeta potentials of gallium-based liquid metal nanoparticles (LM), hydrogen-producing nanomedicine cores (LMH), and hydrogen-producing acid-resistant liquid metal particles (LMHS), respectively.

[0046] like Figure 1 As shown in figure a, the morphological dimensions of LM and LMH are 50-150 nanometers, while the thicknesses of the hyaluronic acid layer and the sodium alginate layer are approximately 6.5 nanometers and 7.9 nanometers, respectively; Figure 1 As shown in b, with the adhesion of hyaluronic acid and sodium alginate, the Zeta potential on the LM surface decreased from +31.7 mV to approximately +12.3 mV (LMH), and eventually transformed into -11.9 mV (LMHS), confirming the successful construction of LMHS.

[0047] Example 3: In vitro acid resistance test of hydrogen-generating acid-resistant liquid metal particles I. Experimental Procedure 1. Suspensions of LM, LMH and LMHS with a concentration of 1 mg / mL were prepared in deoxygenated ultrapure water, simulated gastric juice (SGF) (Yuanye Biotechnology, R22155), simulated intestinal juice (SIF) (Yuanye Biotechnology, R24021) and simulated colonic juice (SCF) (Yuanye Biotechnology, R28268); 2. After ultrasonic treatment of the suspension at 100W and 40 kHz for 5 minutes, the sample was allowed to settle, and photos were taken at 0 and 2 hours. 3. Centrifuge the SGF-treated sample at 10,000 rpm for 1 minute. Redisperse the resulting precipitate in SCF and photograph its redispersibility.

[0048] II. Results Analysis like Figure 1 As shown in cd, LMHS precipitates significantly in SGF, while almost no change is observed in deoxygenated ultrapure water, SIF, or SCF. This is due to the protonation effect of SA and HA. After redispersing in SCF by ultrasound, the color of the LMHS solution is restored, indicating that HA and SA can protect LMHS from degradation in an acidic environment.

[0049] Example 4: In vivo acid resistance test of hydrogen-producing acid-resistant liquid metal particles I. Experimental Procedure 1. Fifteen 6-8 week old mice were randomly divided into three groups of five each. The mice in each group were orally administered 0.1 mL of LM, LMH and LMHS deoxygenated ultrapure aqueous dispersion at a concentration of 2 mg / mL, respectively. The colon contents of the mice were collected 6 hours and 12 hours after administration.

[0050] 2. After washing the colon contents obtained in step 1 three times with deoxygenated ultrapure water and centrifuging, the resulting precipitate was subjected to synchrotron X-ray absorption fine structure (XAFS) spectroscopy analysis.

[0051] II. Results Analysis like Figure 1 As shown in Figure e, the XANES spectrum of Ga K-edges shows that the absorption edge of the colonic contents after 6 hours is similar to that of the synthesized LMHS, and is closest to Ga foil; while the absorption edge of the colonic contents after 12 hours is closest to Ga2O3. Figure 1 As shown in fh, k 3 Fourier transform and EXAFS wavelet transform (WT) analyses of the weighted Ga K-edge EXAFS spectra revealed a fairly strong Ga-Ga bond signal in the 6-hour colonic contents, while a strong coordination signal between Ga and O atoms was observed in the 12-hour colonic contents. The Fourier transform to R-space results showed that the main peaks in the 6-hour colonic contents appeared at ~1.3 Å (Ga-O) and ~2.0 Å (Ga-Ga), similar to LMHS; however, the main peak in the 12-hour colonic contents appeared only at ~1.3 Å (Ga-O), with almost no Ga-Ga signal detected. These results indicate that LMHS can penetrate the acidic environment of the stomach.

[0052] Example 5: Hydrogen production performance testing of acid-resistant liquid metal particles for hydrogen production I. Experimental Procedure 1. LM, LMH and LMHS (concentrations of 150 μg / mL or 300 μg / mL, respectively) were treated with SGF for 0, 0.5, 1, 2, 4 and 6 hours, respectively.

[0053] 2. After washing three times with deoxygenated ultrapure water, the nanoparticles were resuspended in 1 mL of SCF containing the detection reagent.

[0054] After 3.5 minutes, centrifuge at 10,000 rpm for 1 min, and measure the UV-Vis spectrum of the supernatant using methylene blue (MB) and platinum black detection solution.

[0055] II. Results Analysis like Figure 1 As shown in Figure i, LMHS significantly reduced the absorbance of MB and lightened its color in SCF solution, indicating that LMHS can continuously generate H2 in SCF (MB can be reduced by H2 under the catalysis of platinum black, and its ultraviolet (UV) absorbance is proportional to concentration). With prolonged treatment time in SGF, the residues of LM and LMH in SGF, except for LMHS, could not fade MB in SCF. This proves that LMHS can withstand acidic environments and generate H2 in weakly alkaline solutions.

[0056] Example 6: Testing the oxidation resistance of hydrogen-producing acid-resistant liquid metal particles I. Experimental Procedure 1. Incubate 200 μg of LM, LMH, and LMHS in 1 mL of SGF for 0, 1, 2, 4, and 6 hours, respectively. Note: Control group for 0 hours: Centrifuge in step 2 immediately after adding SGF, and incubate for 0 hours.

[0057] 2. After incubation, centrifuge all samples at 10,000 rpm for 1 minute, and wash the resulting precipitate three times with deoxygenated ultrapure water.

[0058] 3. Resuspend the washed precipitate in 250 μL of SCF, then add the nanoparticle suspension to freshly prepared 3,3',5,5'-tetramethylbenzidine (TMB) (OD200). 652 =0.65) and 2,2'-adiazon-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) (OD 734 =1.1) The working solutions are mixed at a volume ratio of 1:1.

[0059] 4. After reacting the mixture at 37°C in the dark for 10 minutes, centrifuge at 10,000 rpm for 1 minute and analyze the supernatant by UV-Vis spectroscopy.

[0060] II. Results Analysis like Figure 1 As shown in Figure j, after pretreatment in SGF for 1, 2, 4, or 6 hours, LM failed to alter the absorbance intensity of the SCF solution containing oxidized TMB compared to the blank group without any nanoparticle treatment. After acidification in SGF for 2 hours, over 50% of the TMB in the LMH-treated SCF solution was oxidized by hydroxyl radicals (•OH), indicating that HA has limited protective effect on LM in SGF. Under the dual protection of HA and SA, the UV absorption of oxidized TMB in the LMHS-treated SCF solution was almost undetectable, demonstrating that LMHS can remove almost all •OH from the SCF solution. Figure 1 As shown in k, the ABTS• removal experiment results are similar to those of the TMB experiment; LMHS removes almost all ABTS• from the SCF solution. These results indicate that LMHS can withstand the acidification process in SGF and generate H2 to remove RONS.

[0061] Example 7: Cellular compatibility of hydrogen-producing acid-resistant liquid metal particles I. Experimental Procedure 1. Human umbilical vein endothelial cells (HUVECs), human colonic mucosal epithelial cells (NCM460), and mouse mononuclear macrophage leukemia cells (RAW 264.7) were cultured at 5 × 10⁶ cells per well. 3 Cells were seeded at a density of 1,000 cells per well in 96-well plates and cultured for 12 hours.

[0062] 2. Cells were treated with different concentrations (26.3, 39.5, 59.3, 88.9, 133.3 and 200 mg / L) of LMHS for 24 hours.

[0063] 3. After treatment, cell viability was assessed using the MTT assay.

[0064] II. Results Analysis like Figure 2 As shown in ac, approximately 90% of HUVECs, NCM460, and RAW 264.7 cells remained viable after treatment with different concentrations of LMHS.

[0065] Example 8: Protective effect of hydrogen-producing acid-resistant liquid metal particles against •OH-induced cytotoxicity I. Experimental Procedure 1. Spread NCM460 cells at a density of 5 × 10⁶ cells per well. 3 Cells were seeded at a density of 1,000 cells per well in 96-well plates and cultured for 12 hours.

[0066] 2. NCM460 cells were pretreated with 100 mg / L LMHS for 4 hours and then exposed to 0.5 mM hydrogen peroxide for 24 hours.

[0067] 3. After treatment, cell viability was assessed using the MTT assay.

[0068] II. Results Analysis like Figure 2 As shown in d, after exposure to 0.5 mM hydrogen peroxide, approximately 80% of the control group NCM460 cells died. LMHS treatment increased the cell survival rate to more than three times that of the control group, indicating that LMHS has a significant cell protective effect.

[0069] Example 9: Regulatory effect of hydrogen-producing acid-resistant liquid metal particles on immune cells I. Experimental Procedure 1. Group processing Control group: RAW 264.7 cells were introduced at a rate of 1 × 10⁶ cells per well. 5 Cells were seeded at a density of 1,000 cells per well in 6-well plates and cultured for 24 hours without LPS stimulation; then treated with PBS for 24 hours.

[0070] LPS model group (LPS): RAW 264.7 cells were grown at a density of 1 × 10⁶ cells per well. 5 Cells were seeded at a density of 1,000 cells per well in 6-well plates and stimulated with 200 ng / mL LPS in the culture medium for 24 hours; then treated with PBS for 24 hours.

[0071] LPS+HA+SA group: RAW 264.7 cells were added at a rate of 1×10⁶ cells per well. 5 Cells were seeded at a density of 1000 g / mL in 6-well plates and stimulated with 200 ng / mL LPS for 24 hours. Then, the cells were treated with medium containing 10 µg / mL HA and 10 µg / mL SA for 24 hours.

[0072] LPS+LM group: RAW 264.7 cells were added at a rate of 1×10⁶ cells per well. 5 Cells were seeded at a density of 100 μg / mL in 6-well plates, and stimulated with 200 ng / mL LPS for 24 hours; then the medium was replaced with a solution containing 100 µg / mL (as Ga... 3+ Treat LM culture medium for 24 hours.

[0073] LPS+LMHS group: RAW 264.7 cells were added at a rate of 1×10⁶ cells per well. 5 Cells were seeded at a density of 100 μg / mL in 6-well plates, and stimulated with 200 ng / mL LPS for 24 hours; then the medium was replaced with a solution containing 100 µg / mL (as Ga... 3+ LMHS culture medium was treated for 24 hours.

[0074] LPS+Ga 3+ Group: RAW 264.7 cells were added at a rate of 1 × 10⁶ cells per well. 5 Cells were seeded at a density of 100 μg / mL in 6-well plates, and stimulated with 200 ng / mL LPS for 24 hours; then the medium was replaced with a solution containing 100 µg / mL Ga 3+ The culture medium was treated for 24 hours.

[0075] 2. After treatment, cells were collected, and the mRNA expression levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), CC motif chemokine ligand 2 (CCL2), inducible nitric oxide synthase (iNOS), and arginase-1 (Arg-1), were analyzed by quantitative real-time PCR (qPCR). The M1 polarization ratio of RAW 264.7 cells in each group was analyzed by flow cytometry.

[0076] II. Results Analysis Figure 2 e is a schematic diagram illustrating the regulation of LPS-activated RAW 264.7 cells by LMHS; as shown in 2f-i, LMHS can reduce the mRNA expression of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, CCL2) in LPS-activated RAW 264.7 cells. The HA+SA treatment group showed almost no reduction, while the LM treatment group showed only a slight reduction. 3+The treatment group showed a reduction rate that was similar to or even better than that of the LMHS treatment group; for example Figure 2 As shown in Figure j, LMHS significantly reduced iNOS mRNA expression in LPS-activated RAW 264.7 cells. The HA+SA treatment group showed no reduction, while the LM treatment group only showed a slight reduction. 3+ The treatment group showed a slightly better reduction compared to the LMHS treatment group; for example Figure 2 As shown in k, LMHS treatment upregulated Arg-1 mRNA expression, HA+SA treatment showed almost no upregulation, and LM treatment showed only a slight upregulation. 3+ The treatment group's increase was similar to that of the LMHS treatment group; for example Figure 2 As shown in lm, the fluorescence signal detected by anti-mouse CD86 antibody labeled with allophycocyanin (APC) decreased after LMHS treatment, indicating that LMHS treatment significantly reduced the proportion of CD86-positive macrophages. The HA+SA treatment group did not show a reduction, and the LM treatment group only showed a slight reduction. Ga 3+ The reduction in the treatment group was similar to that in the LMHS treatment group. All of this evidence suggests that LMHS can suppress an overactive immune response, downregulate inflammatory macrophages, and effectively alleviate the inflammatory response.

[0077] Example 10: Hydrogen-producing acid-resistant liquid metal particles target intestinal inflammatory sites in mice with enteritis I. Experimental Procedure (I) Construction of Cy5.5-labeled LMH (LMH-Cy5.5) and Cy5.5-labeled LMHS (LMHS-Cy5.5) 1. Dissolve 50 mg HA in 10 mL PBS, and then add Cy5.5-NHS ester DMSO stock solution (5 mg / mL) at a ratio of 1:100 (w / w). 2. Adjust the pH of the solution to 6.0 and stir magnetically for 12 hours; 3. The reaction mixture was dialyzed with deoxygenated ultrapure water for 24 hours under light-protected conditions to obtain Cy5.5-labeled HA (hereinafter referred to as HA-Cy5.5). 4. Add 200 mg of liquid gallium-indium alloy with a mass ratio of 3:1 (gallium:indium) to 15 mL of deoxygenated ultrapure water containing 50 mg of HA-Cy5.5. Under ice-water bath conditions, sonicate with a 6 mm probe at 800 W power for 40 minutes to obtain a mixture. 5. Centrifuge the mixture at 1000 rpm for 5 minutes, collect the supernatant, and then centrifuge at 8000 rpm for 5 minutes to obtain LMH-Cy5.5; 6. After washing LMH-Cy5.5 three times with deoxygenated ultrapure water, add 15 mL of sodium alginate solution with a concentration of 4 mg / mL, stir magnetically for 12 hours, centrifuge the resulting mixture at 8000 rpm for 10 minutes, and wash the precipitate three times with deoxygenated ultrapure water to obtain LMHS-Cy5.5.

[0078] (II) Detection of LMHS-targeted intestinal inflammatory sites using fluorescence imaging and fluorescence staining 1. A mouse model of inflammatory bowel disease (IBD) was established by administering a 2.5% DSS aqueous solution to the drinking water for one week. During this period, the mice were fed a non-fluorescent diet. 2. Mice were administered 100 µL of LMH-Cy5.5 or LMHS-Cy5.5 at a concentration of 2 mg / mL via oral gavage. 3. After 12 hours, the mice were euthanized and their intestines were removed for fluorescence imaging and immunofluorescence staining; their major organs, including the heart, liver, spleen, lungs, kidneys, stomach, small intestine, and colon, were collected. Inductively coupled plasma mass spectrometry (ICP-MS) was used to analyze gallium ions (Ga) in these organs. 3+ Quantitative analysis of the content was performed.

[0079] II. Results Analysis Figure 3 a is a schematic diagram of constructing a mouse model of inflammatory bowel disease; as shown in Figure 1. Figure 3 As shown in b, compared to healthy mice, the colonic tissue of IBD mice showed weaker fluorescence signals of epithelial cell adhesion molecule (EPCAM, pink) and stronger strong green fluorescence of anti-F4 / 80 antibody, indicating that the colonic epithelium of IBD mice was destroyed, inflammatory macrophages accumulated in large numbers, and the inflammatory bowel disease model was successfully established. After oral administration of LMHS-Cy5.5 to IBD mice, the strongest Cy5.5 red fluorescence signal was detected in their colonic tissue, indicating that LMHS-Cy5.5 can accumulate in colonic tissue; Figure 3 As shown in the fluorescence imaging image of c, almost no fluorescence was detected in the colon tissue of healthy mice treated with LMH-Cy5.5 and LMHS-Cy5.5, presumably because the healthy intestine lacks HA receptors, making it difficult for nanoparticles to accumulate. Figure 3 As shown in de, compared with LMH-treated mice, LMHS-treated mice exhibited the strongest fluorescence signal from Cy5.5-labeled HA, indicating that the hyaluronic acid layer enhances the ability of LMHS to reach the colon. Figure 3 As shown in fh, in mice treated with LM, LMH, and LMHS, a large amount of Ga 3+The presence of Ga in gastrointestinal tissues, rather than the heart, liver, spleen, lungs, and kidneys, indicates that the drug does not diffuse systemically. Compared to IBD mice treated with LM and LMH, IBD mice treated with oral LMHS showed significantly higher levels of Ga in their colon tissues. 3+ This indicates that SA and HA can enhance the accumulation of LMHS in the colon. All these results demonstrate that LMHS achieves targeted accumulation in inflamed colonic tissue.

[0080] Example 11: Therapeutic effect of hydrogen-producing acid-resistant liquid metal particles on IBD mice I. Experimental Procedure 1. After acclimatizing to an SPF (specific pathogen-free) environment for 7 days, 6-8 week old C57BL / 6 mice were randomly divided into 6 groups. Five experimental groups were given water containing 2.5% DSS for 7 days to induce colitis, while the control group drank plain water throughout the experiment.

[0081] 2. On days 5, 7, and 9, the experimental groups were administered 100 µL of the following treatments via oral gavage: water, HA (0.2 mg / mL) + SA (0.2 mg / mL), 5-aminosalicylic acid (5-ASA, 8 mg / mL), LM, and Ga... 3+ (2 mg / mL) or LMHS (Ga concentration, 2 mg / mL); 3. On day 10, before sacrifice, all mice were fasted for 4 hours and then administered FITC-glucan (0.6 mg / g body weight) by gavage. Three hours later, blood and colon tissue were collected for analysis.

[0082] II. Results Analysis like Figure 3 As shown in Figure 1, mice treated with LMHS had colon lengths close to those of healthy mice and were significantly longer than mice treated with HA+SA, 5-ASA, and LM; Figure 3 As shown in k, a large amount of fluorescence from fluorescein isothiocyanate (FITC)-glucan was detected in the blood of DSS colitis mice, indicating that their intestinal barrier function was severely impaired. Compared with other treatments, the fluorescence intensity in the blood of mice treated with LMHS was close to that of healthy mice, demonstrating that LMHS can restore the intestinal barrier function of colitis mice and prevent systemic exposure to FITC-glucan in DSS colitis mice after oral gavage; Figure 3 As shown in Figure 1, in hematoxylin-eosin staining analysis, the intestinal glands of colitis mice were severely damaged, and the colonic epithelium also showed severe injury. Compared with IBD mice, 5-ASA or LM could only partially repair the damaged intestinal glands and severe colonic epithelial damage, while the histological microstructure of mice treated with LMHS had recovered to a state similar to that of healthy mice. Figure 4 As shown in ab, Ga 3+ The drug did not produce a therapeutic effect in IBD mice, indicating that the therapeutic effect was mainly achieved by the hydrogen gas produced by the drug. These results suggest that LMHS treatment can alleviate DSS-induced colitis and restore colonic barrier function.

[0083] Example 12: Regulation of gut microbiota in IBD mice by hydrogen-producing acid-resistant liquid metal particles I. Experimental Procedure 1. After acclimatizing to an SPF (specific pathogen-free) environment for 7 days, 6-8 week old C57BL / 6 mice were randomly divided into 6 groups. Five experimental groups were given water containing 2.5% DSS for 7 days to induce colitis, while the control group drank plain water throughout the experiment.

[0084] 2. On days 5, 7 and 9, the experimental groups were administered 100 µL of the following treatments by oral gavage: water, HA (0.2 mg / mL) + SA (0.2 mg / mL), 5-aminosalicylic acid (5-ASA, 8 mg / mL), LM or LMHS (Ga concentration, 2 mg / mL). 3. On day 10, mouse feces were collected for 16S ribosomal RNA gene sequencing and metabolomics analysis.

[0085] II. Results Analysis like Figure 5 As shown in ab, the abundance of bacterial operational taxonomic units and Shannon diversity index in mice treated with LMHS were not significantly different from those in healthy mice; Figure 5 As shown in c, in mice treated with LMHS, the relative abundance of Bacteroidetes and Lactobacilliaceae increased, while the proportion of Enterobacteriaceae decreased; Figure 5 Principal coordinate analysis showed that the gut microbiota composition of colitis mice treated with LMHS was significantly different from that of IBD mice and more closely resembled that of healthy mice; Figure 5 As shown in the example, LMHS treatment increased the abundance of Bifidobacteria, Lactobacillus, and Akkermansia muciniphila; Figure 5 As shown in the figure, after LMHS treatment, beneficial Bacteroidetes bacteria were significantly enriched in DSS colitis mice. Figure 5 As shown in Figure j, LMHS treatment increased the levels of total short-chain fatty acids, including acetic acid, propionic acid, valeric acid, butyric acid, isobutyric acid, isovaleric acid, and hexanoic acid. These results indicate that LMHS treatment can effectively improve disordered gut microbiota and promote the production of short-chain fatty acids, thereby creating a favorable microecological environment for alleviating colitis in mice.

[0086] Example 13: Biosafety Testing of Hydrogen-Generating Acid-Resistant Liquid Metal Particles I. Experimental Procedure 1. For cell viability analysis, NCM460 cells were cultured at 5 × 10⁶ cells per well. 3 Cells were seeded at a density of 1000 mg / L in 96-well plates and cultured for 12 hours. They were then treated for 24 hours with different concentrations of HA+SA (1.2, 1.8, 2.6, 4, 5.9, 8.9, 13.3 mg / L), LM (12, 18, 26, 40, 59, 89, 133 mg / L), or LMH (12, 18, 26, 40, 59, 89, 133 mg / L). Cell viability was then assessed by MTT assay.

[0087] 2. For live / dead cell analysis, cells were cultured in 6-well plates for 12 hours and treated with HA+SA (20 mg / L), LM (200 mg / L), or LMHS (200 mg / L) for 24 hours, followed by staining with Calcein-AM / PI and imaging by fluorescence microscopy.

[0088] 3. For the hemolysis test, whole blood anticoagulated with sodium citrate (1:9) was centrifuged at 1000 rpm for 10 min. The lower layer of blood cells was collected, washed with 1 mL of PBS buffer, and centrifuged again. This process was repeated once. The lower layer of blood cells was then diluted with PBS buffer to prepare a 5% blood cell suspension. 500 μL of the blood cell suspension was then diluted with PBS and Ga... 3+ HA+SA, LM, LMH, and LMHS (gallium concentrations of 100, 200, and 400 μg / mL, respectively) were incubated at 37°C for 1 hour and photographed.

[0089] 4. For in vivo biocompatibility assessment of the DSS-induced UC (ulcerative colitis) mouse model, major organs (heart, liver, spleen, lung, and kidney) were collected for hematoxylin-eosin (H&E) staining to assess tissue morphology. Blood samples were collected from mice to detect alanine aminotransferase (ALT), alkaline phosphatase (ALP), and creatinine levels.

[0090] II. Results Analysis like Figure 6 As shown in c, bright green fluorescence was detected in NCM460 cells treated with HA+SA, LM, and LMHS, while red fluorescence was not obvious; Figure 6 As shown in ab, over 90% of the NCM460 cells remained viable; Figure 6 As shown in d, compared with the control group or PBS group, compared with Ga 3+ No obvious hemolysis was observed in blood samples incubated with HA+SA, LM, LMH, or LMHS; Figure 7As shown in the diagram, after LMHS treatment, the levels of important liver function markers in the blood, such as alanine aminotransferase (ALT) and alkaline phosphatase (ALP), as well as the important renal function biomarker creatinine, were closer to the values ​​in healthy mice, indicating that LMHS had no effect on liver and kidney function in DSS colitis mice; Figure 7 As shown in Figure d, no obvious pathological abnormalities were detected in the major organs (heart, liver, spleen, lungs, and kidneys) of the mice, indicating that LMHS had no tissue toxicity to the experimental mice during treatment. These results demonstrate that the LMHS designed in this invention has good biocompatibility and is suitable for biomedical applications.

[0091] Those skilled in the art will appreciate that various modifications to the above embodiments can be made without departing from the overall spirit and concept of the present invention. All such modifications fall within the protection scope of the present invention. The protection scheme of the present invention is defined by the appended claims.

Claims

1. A hydrogen-producing acid-resistant liquid metal particle, characterized in that, include: Liquid gallium-indium alloy nanoparticles; A hyaluronic acid layer encapsulating the liquid gallium indium alloy nanoparticles; And a sodium alginate layer that encapsulates the hyaluronic acid layer.

2. The hydrogen-producing acid-resistant liquid metal particles according to claim 1, characterized in that: The mass ratio of gallium to indium in the liquid gallium-indium alloy nanoparticles is (3~6):

1.

3. The hydrogen-producing acid-resistant liquid metal particles according to claim 1, characterized in that: The liquid gallium-indium alloy nanoparticles have a particle size of 40-150 nanometers; and / or, The thickness of the hyaluronic acid layer is 3-20 nanometers; and / or, The thickness of the sodium alginate layer is 3-20 nanometers; and / or, The particle size of the hydrogen-producing acid-resistant liquid metal particles is 56~190 nanometers.

4. A method for preparing hydrogen-producing acid-resistant liquid metal particles, characterized in that, Includes the following steps: Liquid gallium-indium alloy was mixed with hyaluronic acid solution and subjected to ultrasonic treatment to form hydrogen-producing nanomedicine cores; The hydrogen-producing nanomedicine core is mixed with sodium alginate solution to form a sodium alginate layer; The hydrogen-producing acid-resistant liquid metal particles were obtained by centrifugation and washing.

5. The preparation method according to claim 4, characterized in that: The concentration of hyaluronic acid in the hyaluronic acid solution is 2-5 mg / mL; and / or, The concentration of sodium alginate in the sodium alginate solution is 2~5 mg / mL.

6. The preparation method according to claim 4, characterized in that: The ultrasonic treatment is performed in an ice bath environment; and / or, The power of the ultrasonic treatment is 600~1000W; and / or, The ultrasonic treatment time is 10-50 minutes.

7. Use of the hydrogen-producing acid-resistant liquid metal particles according to any one of claims 1 to 3 in the preparation of a medicament for treating inflammatory bowel disease.

8. The use according to claim 7, characterized in that: The inflammatory bowel disease is ulcerative colitis and / or Crohn's disease.

9. The use according to claim 7, characterized in that: The treatment of inflammatory bowel disease includes: (1) Restore intestinal barrier function; and / or, (2) Improve disordered gut microbiota.

10. The use according to claim 7, characterized in that: The drug is an oral preparation, an enema, or a colon-targeted preparation.

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