Phenylboronic acid derivative modified silicon dioxide particles as well as preparation and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to phenylboronic acid derivative modified silicon dioxide particles as well as preparation and application thereof. The phenylboronic acid derivative modified silicon dioxide particles obtained by the preparation method disclosed by the invention can be used for reducing digestion and absorption of food in a body by interacting with saccharides (monosaccharide, disaccharide and polysaccharide) and inhibiting the activity of digestive enzymes, so that the application of reducing blood sugar and blood lipid is realized. The invention provides new thoughts and references for enriching and developing different types of organic and inorganic materials modified by boric acid groups, and also provides new strategies and choices for enriching and developing different types of hypoglycemic and lipid-lowering products.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a silica particle modified with a phenylboronic acid derivative and its preparation and application. Background Art

[0002] Diabetes, as a chronic metabolic disease widely existing globally, is increasingly becoming an important problem affecting human health. It is mainly characterized by chronic hyperglycemia caused by insufficient insulin secretion or insulin action disorder, combined with syndromes of protein and fat metabolism disorders. There are already various drugs for treating diabetes on the market, but they all have certain defects. For example, metformin can improve insulin sensitivity, improve muscle glycogen synthesis, and reduce intestinal glucose absorption, but it has gastrointestinal reactions and is not suitable for long-term use; acarbose, as an α-glucosidase inhibitor, delays carbohydrate absorption by inhibiting glycosidic bond hydrolysis, but has gastrointestinal adverse reactions such as abdominal distension and increased flatulence; sulfonylurea drugs, such as glibenclamide and gliclazide, promote insulin secretion, but are prone to hypoglycemia risk and cause weight gain; meglitinide drugs, such as repaglinide and nateglinide, have a short action time and are not good at controlling fasting blood glucose; thiazolidinedione drugs, such as pioglitazone and rosiglitazone, reduce insulin resistance and improve insulin sensitivity, but have a slow onset and patients with heart failure are prone to increase the risk of heart failure; dipeptidyl peptidase-4 (DPP-4) inhibitors, such as sitagliptin and linagliptin, promote insulin secretion and at the same time inhibit glucagon secretion to lower blood glucose, but the drug price is relatively high and there are adverse reactions such as headache, dizziness, nasopharyngitis, and cough; glucagon-like peptide-1 (GLP-1) receptor agonists, such as liraglutide and exenatide, activate the GLP-1 receptor and enhance insulin secretion in a glucose concentration-dependent manner, but have gastrointestinal discomfort, nausea, vomiting, and diarrhea adverse reactions; insulin drugs are currently widely used in clinical practice. One of the most common side effects of insulin treatment is hypoglycemia. When insulin is overused or combined with other hypoglycemic drugs, it will cause hypoglycemia, which may lead to unconsciousness or coma. In addition, long-term insulin injection may cause lipoatrophy, sclerosis, or infection at the injection site. Based on the above problems, how to find and develop diabetes treatment means with wide applicability, mild preparation conditions, high patient compliance, no side effects or lower side effects to achieve the purpose of stable blood glucose is a difficult problem that urgently needs to be solved in the development of diabetes-related drugs.

[0003] In recent years, in order to solve the limitations in the use of the above hypoglycemic drugs, efforts have mainly focused on preparing new materials for coating insulin to achieve controlled release of insulin. For example, researchers such as Gu Zhen and Wang Jinqiang from Zhejiang University prepared an amphiphilic diblock copolymer, which can combine with negatively charged and hydrophobic insulin / Zn 2+Form worm-like micelles to achieve internal loading of insulin, protect it from gastrointestinal degradation, accumulate in the liver and release insulin in a glucose-responsive manner to achieve long-term blood glucose regulation performance. Some studies have also reported a nanoformulation that combines insulin with silver sulfide quantum dots and is coated with a chitosan / glucose polymer. This formulation is sensitive to glucosidase and can trigger insulin release. Zhu Yingnan and Dong Yuze's team from the School of Pharmacy of Zhengzhou University used an acid-resistant metal-organic framework (PCN-222) to load insulin, modified the outer surface of PCN-224 with sodium dodecyl sulfate (SDS), and encapsulated it in sodium alginate (SA) microspheres to construct an oral insulin delivery platform. This oral delivery system achieved effective penetration and controlled release of insulin through endocytosis. However, the use of insulin may still have inherent defects, such as weight gain, peripheral hyperinsulinemia, and treatment complexity, which limit the safety of long-term use and patient compliance. The present invention is dedicated to developing an effective hypoglycemic and lipid-lowering preparation with good safety, convenient use, and almost no adverse reactions during use. Summary of the Invention

[0004] To overcome the side effects and limitations in the use of existing diabetes treatment drugs, the present invention provides a silica particle modified with a phenylboronic acid derivative and its preparation and application.

[0005] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0006] A silica particle modified with a phenylboronic acid derivative, and the particle is shown in Formula I,

[0007]

[0008] In the formula,

[0009] Linker is the residue structure of the silane coupling agent reacting with the phenylboronic acid derivative and the silica modification reaction respectively;

[0010] The phenylboronic acid derivative is a compound shown in Formula II,

[0011]

[0012] Wherein, R1, R2, R3, R4 and R5 can be the same or different and are selected from H or substituents capable of reacting with the silane coupling agent, and at least one of R1, R2, R3, R4 and R5 is not H.

[0013] The silane coupling agent can be (3-aminopropyl)triethoxysilane (APTES), (3-aminopropyl)trimethoxysilane, N-(2-aminoethyl)-3-aminopropyltrimethoxysilane (AEAPTMS), N-(2-aminoethyl)-3-aminopropylmethyldimethoxysilane, bis(3-trimethoxysilylpropyl)amine, 3-glycidoxypropyltriethoxysilane (GPTES), 3-glycidoxypropyltrimethoxysilane (GPTMS), 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane (ECTMS), 3-mercaptopropyltrimethoxysilane (MPTMS), 3-mercaptopropyltriethoxysilane (MPTES), (3-isocyanatopropyl)triethoxysilane (IPTES), (3-chloropropyl)trimethoxysilane (CPTMS), (3-chloropropyl)triethoxysilane, (3-methacryloxypropyl)trimethoxysilane (MAPTMS), (3-carboxypropyl)trimethoxysilane, (3-bromopropyl)trimethoxysilane, (3-isocyanatopropyl)trimethoxysilane (IPTMS), (3-vinyl)trimethoxysilane (VTMS), vinyltriethoxysilane (VTES), methyltrimethoxysilane (MTMS), vinyltris(2-methoxyethoxy)silane (VTMOEO), octyltriethoxysilane (OTES), (3-anilinopropyl)trimethoxysilane, 3-(2,3-epoxypropoxy)propyltrimethoxysilane, 11-aminoundecyltriethoxysilane, docosyltriethoxysilane, methyltrimethoxysilane, methyltriethoxysilane, n-octyltriethoxysilane, dodecyltrimethoxysilane, hexadecyltrimethoxysilane, octadecyltrimethoxysilane, aminoethylaminopropyltrimethoxysilane, 3-(trimethoxysilyl)propyldimethyloctadecylammonium chloride, phenylaminomethyltrimethoxysilane, 3-ureidopropyltrimethoxysilane, preferably (3-aminopropyl)triethoxysilane (APTES).

[0014] The substituents capable of reacting with the silane coupling agent are amino group, carboxyl group, mercapto group, epoxy group with C3-C8, alkynyl group with C2-C8, azide group, hydroxyl group or aldehyde group.

[0015] The phenylboronic acid derivative is one of the following compounds,

[0016]

[0017] The particles are selected from any one of the following,

[0018]

[0019] The preparation methods of the silica particles include, but are not limited to, sol-gel method (template method), spray drying method, gas phase method, mechanical crushing method, and the commonly used preparation method is sol-gel method.

[0020] The above-mentioned silica particles with a particle size in the range of 5 nm - 100 μm are used.

[0021] And the surface of the above-mentioned silica particles has substituents capable of reacting with silane coupling agents. For example, ① silanization reaction: using a silane coupling agent to react with the hydroxyl groups (-OH) on the surface of the silica particles to form a covalent bond (Si-O-Si bond); ② ligand exchange (surface modification): replacing the original ligands (such as hydroxyl groups, -OH) on the surface of the silica particles with other ligands on the silane coupling agent, such as amino groups (-NH2), carboxyl groups (-COOH), and mercapto groups (-SH).

[0022] An application of the silica particles modified with the phenylboronic acid derivative as described above, which is used in the preparation of drugs, medical devices for preventing or treating hyperglycemia, hyperlipidemia, and glycolipid metabolism disorders, or for the preparation of general foods, health foods, and foods for special medical purposes.

[0023] The present invention has the following advantages and beneficial effects:

[0024] (1) The preparation process is simple and easy to scale up;

[0025] (2) After the silica particles modified with the phenylboronic acid derivative exert their effects in the gastrointestinal tract, most of them are excreted out of the body through feces and are hardly absorbed by the system, with good safety and no obvious adverse reactions;

[0026] (3) In the present invention, the silica particles are modified with the phenylboronic acid derivative. By using the binding of boric acid to diols to adsorb sugars and the interaction with digestive enzymes to inhibit the activity of digestive enzymes, the digestion and absorption of almost all forms of sugars (monosaccharides, disaccharides, polysaccharides, and the digestion and absorption of different foods and beverages), as well as the digestion and absorption of foods, are reduced. Furthermore, a broad-spectrum hypoglycemic effect and a good blood glucose stabilizing effect are achieved;

[0027] (4) Compared with the commercially available preparation acarbose, the silica particles modified with the phenylboronic acid derivative can effectively control the absorption of glucose, solve the limitations and adverse reactions of existing diabetes treatment drugs in clinical applications, and may provide an innovative treatment platform for the treatment of diabetes. Description of the Drawings

[0028] Figure 1 For Example 1, the particle size distribution diagram of the mesoporous silica nanoparticles (sMSN) obtained.

[0029] Figure 2Fourier transform infrared spectroscopy of mesoporous silica particles modified with different phenylboronic acid derivatives (MSN-PBA) in Example 1 1-10 )

[0030] Figure 3 Powder X-ray diffraction patterns of different phenylboronic acid derivatives (PBA 1-10 ) and mesoporous silica particles modified with different phenylboronic acid derivatives (MSN-PBA 1-10 ) in Example 1

[0031] Figure 4 Differential scanning calorimetry patterns of powders of different phenylboronic acid derivatives (PBA 1-10 ) and powders of mesoporous silica particles modified with different phenylboronic acid derivatives (MSN-PBA 1-10 ) in Example 1

[0032] Figure 5 In vitro adsorption sugar ratio diagrams of mesoporous silica particles modified with different phenylboronic acid derivatives MSN-PBA 1-10 in Example 2 and in vitro enzyme activity inhibition ratio diagrams of mesoporous silica particles modified with different phenylboronic acid derivatives MSN-PBA 1-10 in Example 3; wherein, A is the adsorption effect on glucose, B is the adsorption effect on sucrose, C is the adsorption effect on dextrin, D is the inhibition effect on α-glycosidase, E is the inhibition effect on α-amylase, and F is the inhibition effect on lipase

[0033] Figure 6 Particle size distribution and nitrogen adsorption-desorption curves of mesoporous silica particles modified with phenylboronic acid derivatives of three particle sizes in Example 4; wherein, A-1 is the particle size distribution diagram of MSN-PBA4 particles with a particle size of 239.5 nm and A-2 is the pore size distribution diagram, B-1 is the particle size distribution diagram of MSN-PBA4 particles with a particle size of 664.8 nm and B-2 is the pore size distribution diagram, and C-1 is the particle size distribution diagram of MSN-PBA4 particles with a particle size of 5.7 μm and C-2 is the pore size distribution diagram

[0034] Figure 7Oral glucose, sucrose, and starch tolerance test graphs of mesoporous silica particles modified with the phenylboronic acid derivative of Example 5, where A-1 is the blood glucose concentration curve of normal mice after intragastric administration of glucose and different drugs, and A-2 is the area under the blood glucose curve of normal mice after intragastric administration of glucose and different drugs; B-1 is the blood glucose concentration curve of normal mice after intragastric administration of sucrose and different drugs, and B-2 is the area under the blood glucose curve of normal mice after intragastric administration of sucrose and different drugs; C-1 is the blood glucose concentration curve of normal mice after intragastric administration of starch and different foods, and C-2 is the area under the blood glucose curve of normal mice after intragastric administration of starch and different foods; D-1 is the blood glucose concentration curve of type 1 diabetic mice induced by streptozotocin (STZ) after intragastric administration of different drugs and glucose, and D-2 is the corresponding area under the blood glucose curve; E-1 is the blood glucose concentration curve of obese diabetic mice after intragastric administration of glucose and different drugs, and E-2 is the corresponding area under the blood glucose curve.

[0035] Figure 8 Graph of blood glucose level control by mesoporous silica particles modified with 3-nitro-4-carboxyphenylboronic acid (mMSN-PBA4), a phenylboronic acid derivative, in normal mice after intragastric administration of different foods in Example 6, where A-1 is the blood glucose concentration curve of normal mice after intragastric administration of cola and different drugs, and A-2 is the area under the blood glucose curve of normal mice after intragastric administration of cola and different drugs; B-1 is the blood glucose concentration curve of normal mice after intragastric administration of jam and different drugs, and B-2 is the corresponding area under the blood glucose curve; C-1 is the blood glucose concentration curve of normal mice after intragastric administration of peanut butter and different drugs, and C-2 is the corresponding area under the blood glucose curve; D-1 is the blood glucose concentration curve of normal mice after intragastric administration of milk and different drugs, and D-2 is the corresponding area under the blood glucose curve.

[0036] Figure 9 Graph of blood glucose level control by mesoporous silica particles modified with 3-nitro-4-carboxyphenylboronic acid (mMSN-PBA4), a phenylboronic acid derivative, in diet-induced obesity (DIO) obese diabetic mice after intragastric administration of different foods in Example 6, where A-1 is the blood glucose concentration curve of DIO obese diabetic mice after intragastric administration of cola and different drugs, and A-2 is the corresponding area under the blood glucose curve; B-1 is the blood glucose concentration curve of obese diabetic mice after intragastric administration of jam and different drugs, and B-2 is the corresponding area under the blood glucose curve; C-1 is the blood glucose concentration curve of obese diabetic mice after intragastric administration of peanut butter and different drugs, and C-2 is the corresponding area under the blood glucose curve; D-1 is the blood glucose concentration curve of obese diabetic mice after intragastric administration of milk and different drugs, and D-2 is the corresponding area under the blood glucose curve.

[0037] Figure 10Graph showing the changes in body weight and blood glucose of mice in the long-term study on the hypoglycemic and lipid-lowering effects of the phenylboronic acid derivative 3-nitro-4-carboxyphenylboronic acid-modified mesoporous silica particles (mMSN-PBA4) in Example 7; among them, A is the graph of body weight change of type 1 diabetic mice induced by streptozotocin (STZ), B is the graph of blood glucose change of type 1 diabetic mice induced by streptozotocin (STZ), C is the graph of body weight change of DIO obese diabetic mice, and D is the graph of blood glucose change of DIO obese diabetic mice.

[0038] Figure 11 Graph of fecal lipid levels of mice in the long-term study on the hypoglycemic and lipid-lowering effects of the phenylboronic acid derivative 3-nitro-4-carboxyphenylboronic acid-modified mesoporous silica particles (mMSN-PBA4) in Example 7; among them, A is the graph of fecal cholesterol content of type 1 diabetic mice induced by streptozotocin (STZ), B is the graph of fecal triglyceride content of type 1 diabetic mice induced by streptozotocin (STZ), C is the graph of fecal cholesterol content of DIO obese diabetic mice, and D is the graph of fecal triglyceride content of DIO obese diabetic mice.

[0039] Figure 12 Graph of serum lipid levels of STZ-induced type 1 diabetic mice in the long-term study on the hypoglycemic and lipid-lowering effects of the phenylboronic acid derivative 3-nitro-4-carboxyphenylboronic acid-modified mesoporous silica particles (mMSN-PBA4) in Example 7; among them, A is the graph of serum cholesterol content of type 1 diabetic mice induced by streptozotocin (STZ), B is the graph of serum triglyceride content of type 1 diabetic mice induced by streptozotocin (STZ), C is the graph of serum alanine aminotransferase (ALT) content of type 1 diabetic mice induced by streptozotocin (STZ), D is the graph of serum aspartate aminotransferase (AST) content of type 1 diabetic mice induced by streptozotocin (STZ), E is the graph of serum free fatty acid content of type 1 diabetic mice induced by streptozotocin (STZ), and F is the graph of serum high-density lipoprotein content of type 1 diabetic mice induced by streptozotocin (STZ).

[0040] Figure 13Serum lipid level diagrams of DIO obese diabetic mice for the long-term hypoglycemic and lipid-lowering effect study of the phenylboronic acid derivative 3-nitro-4-carboxyphenylboronic acid modified mesoporous silica particles (mMSN-PBA4) in Example 7. A is the serum cholesterol content diagram of DIO obese diabetic mice, B is the serum triglyceride content diagram of DIO obese diabetic mice, C is the serum alanine aminotransferase (ALT) content diagram of DIO obese diabetic mice, D is the serum aspartate aminotransferase (AST) content diagram of DIO obese diabetic mice, E is the serum free fatty acid content diagram of DIO obese diabetic mice, and F is the serum high-density lipoprotein content diagram of DIO obese diabetic mice.

[0041] Figure 14 Liver lipid level diagrams of mice for the long-term hypoglycemic and lipid-lowering effect study of the phenylboronic acid derivative 3-nitro-4-carboxyphenylboronic acid modified mesoporous silica particles (mMSN-PBA4) in Example 7. Among them, A is the liver weight of streptozotocin (STZ)-induced type 1 diabetic mice, B is the liver triglyceride content of streptozotocin (STZ)-induced type 1 diabetic mice, C is the liver cholesterol content of streptozotocin (STZ)-induced type 1 diabetic mice, D is the liver free fatty acid content of streptozotocin (STZ)-induced type 1 diabetic mice, E is the liver weight of obese diabetic mice, F is the liver triglyceride content of obese diabetic mice, G is the liver cholesterol content of obese diabetic mice, and H is the liver free fatty acid content of obese diabetic mice.

[0042] Figure 15 Relative activities of digestive enzymes in mice for the long-term hypoglycemic and lipid-lowering effect study of the phenylboronic acid derivative 3-nitro-4-carboxyphenylboronic acid modified mesoporous silica particles (mMSN-PBA4) in Example 7. Among them, A is the relative activity of intestinal α-glucosidase in streptozotocin (STZ)-induced type 1 diabetic mice, B is the relative activity of intestinal α-amylase in streptozotocin (STZ)-induced type 1 diabetic mice, C is the relative activity of intestinal lipase in streptozotocin (STZ)-induced type 1 diabetic mice, D is the relative activity of intestinal protease in streptozotocin (STZ)-induced type 1 diabetic mice, E is the relative activity of intestinal α-glucosidase in DIO obese diabetic mice, F is the relative activity of intestinal α-amylase in DIO obese diabetic mice, G is the relative activity of intestinal lipase in DIO obese diabetic mice, and H is the relative activity of intestinal protease in DIO obese diabetic mice.

[0043] Figure 16Distribution map of the benzeneboronic acid derivative 3-nitro-4-carboxybenzeneboronic acid modified mesoporous silica particles (mMSN-PBA4) of Example 8 in mice. Among them, A is the overall fluorescence distribution map of the benzeneboronic acid derivative 3-nitro-4-carboxybenzeneboronic acid modified mesoporous silica particles labeled with Cy5.5 fluorescent dye in normal mice, B is the fluorescence distribution map of the benzeneboronic acid derivative 3-nitro-4-carboxybenzeneboronic acid modified mesoporous silica particles labeled with Cy5.5 fluorescent dye in the excised mouse intestine, and C is the fluorescence distribution map of the benzeneboronic acid derivative 3-nitro-4-carboxybenzeneboronic acid modified mesoporous silica particles labeled with Cy5.5 fluorescent dye in the excised mouse organs.

[0044] Figure 17 After 3 months of intragastric administration of PBS and intragastric administration of the benzeneboronic acid derivative 3-nitro-4-carboxybenzeneboronic acid modified mesoporous silica particles (mMSN-PBA4) to the mice of Example 9, pathological section examination diagrams of the key organs (heart, liver, spleen, lung, kidney, stomach, intestine) of the mice. Detailed implementation manners

[0045] The following examples are listed to further illustrate the present invention, rather than limiting the present invention in any way.

[0046] The benzeneboronic acid derivative modified silica particles obtained in the present invention can be applied to reducing blood sugar and lipid by interacting with saccharides (monosaccharides, disaccharides, polysaccharides) and inhibiting the activity of digestive enzymes, thereby reducing the digestion and absorption of food in the body. The present invention prepares silica particles with different particle sizes, modifies the surfaces of the silica particles with different particle sizes with benzeneboronic acid derivatives, introduces boronic acid groups on the surfaces of the silica particles, and utilizes the principle that "boronic acid - diol" can dynamically combine to form borate esters, so that the benzeneboronic acid derivative modified silica particles interact with saccharides and various digestive enzymes, inhibiting the increase of blood sugar, bringing benefits to patients with hyperglycemia and hyperlipidemia-related diseases (such as diabetes, non-alcoholic fatty liver) and healthy people who need to control blood sugar and weight in daily life. The present invention provides new ideas and references for enriching and developing different kinds of organic and inorganic materials modified with boronic acid groups, and also provides new strategies and choices for enriching and developing different kinds of hypoglycemic and lipid-lowering preparations.

[0047] The silica particles modified with benzeneboronic acid derivatives obtained in the present invention interact with saccharides and digestive enzymes, reduce the digestion and absorption of food, achieve the purpose of stable blood sugar, and have the advantages of simple particle preparation process, hardly being absorbed in the body, high safety, and no adverse reactions.

[0048] Example 1

[0049] Preparation of benzeneboronic acid derivative modified mesoporous silica particles

[0050] Take the preparation process of small-sized mesoporous silica nanoparticles (sMSN) as an example. Dissolve 1 g of cetyltrimethylammonium bromide in 480 mL of distilled water, stir magnetically in a water bath at 80 °C, and then add 3 mL of sodium hydroxide solution (2 mol / L) to the cetyltrimethylammonium bromide solution under uniform stirring. After stirring for 15 minutes, add 5.0 mL of tetraethyl orthosilicate dropwise. Subsequently, stir the reaction solution for 2.5 hours. The precipitate is collected by centrifugation and washed three times with distilled water and ethanol respectively. Then the precipitate is uniformly dispersed in a mixture of hydrochloric acid (37%) and methanol, and refluxed in a water bath for 24 hours. Further collect the silica particles, centrifuge (8000 rpm, 10 min), wash with absolute ethanol three times, and dry in vacuum for 12 hours to obtain small-sized mesoporous silica nanoparticles (sMSN) with a particle size of about 230.4 nm, and the particle size distribution is as Figure 1 shown.

[0051] Further modify the amino groups on the surface of the mesoporous silica particles. Disperse the silica particles in absolute ethanol, then add (3-aminopropyl)triethoxysilane, and reflux in a water bath at 80 °C for 12 hours under nitrogen protection. Centrifuge (8000 rpm, 10 min) for separation, wash with ethanol three times, and dry at 60 °C for 5 hours. Further dissolve different phenylboronic acid derivatives (0.36 mmol) and EDC (1.44 mmol) in 10 mL of DMSO respectively, stir for 30 min, and dropwise add them to 40 mL of DMSO dispersing the amino-functionalized mesoporous silica particles, and stir at room temperature for 4 hours. Finally, centrifuge the precipitate (14000 rpm, 10 min), wash with distilled water three times, and collect by vacuum freeze-drying for 24 hours to obtain silica particles modified with different phenylboronic acid derivatives (see Table 1 and Figures 2 - 4 ).

[0052] The above-mentioned silica particles modified with different phenylboronic acid derivatives are respectively:

[0053]

[0054] Use Fourier transform infrared spectroscopy to confirm the structure,

[0055] The results are as Figure 2 shown. In the infrared spectrum, characteristic peaks of the silica particles can be observed for all samples, including the stretching vibration of hydroxyl (-O-H) at 3470 cm -1 , the bending vibration at 1632 cm -1 , the stretching vibration of silanol group (-Si-OH) at 1070 cm -1 , and the stretching vibration of siloxane group (-Si-O-Si) at 1230 cm -1Stretching vibration at [the specified position]. For the aminated mesoporous silica particles, the bending vibration of the amide group (-N-H) can be observed at 1537 cm -1 and the stretching vibration of the boron-oxygen bond (-B-O) can be observed at 1404 cm -1 . The stretching vibration of the benzene ring (-C=C) at 1576 cm -1 can prove that the phenylboronic acid derivative is connected to the surface of the silica particles through amidation.

[0056] Powder X-ray diffraction pattern analysis

[0057] The crystalline forms of different phenylboronic acid derivatives, mesoporous silica particles modified with different phenylboronic acid derivatives, and silica were characterized by powder X-ray diffraction. Each sample was scanned in the range of 10 - 90° (2θ) with a step size of 0.05°, and a tube voltage of 40 kV. The results are as Figure 3 shown.

[0058] As shown in the figure, it can be observed that the phenylboronic acid derivative PBA 1-10 shows sharp characteristic diffraction peaks at the corresponding 2θ values, while the mesoporous silica particles modified with the phenylboronic acid derivative MSN-PBA 1-10 do not appear in the PXRD pattern. The results indicate that the phenylboronic acid derivative exists in a crystalline form, while the mesoporous silica particles modified with the phenylboronic acid derivative exist in an amorphous form.

[0059] Differential scanning calorimetry

[0060] Weighed 6 mg of the powder of the phenylboronic acid derivative PBA 1-10 and the powder of the mesoporous silica particles modified with the phenylboronic acid derivative MSN-PBA 1-10 into a crucible respectively, covered and pressed tightly. Using alumina as a reference, under the condition of nitrogen protection, the heating rate was 10 °C / min, and the scanning ranges were 30 - 210 °C and 30 - 230 °C respectively. The results are as Figure 4 shown.

[0061] As can be seen from the figure, the phenylboronic acid derivative PBA 1-10 shows endothermic melting peaks at 190.43, 184.11, 215.03, 176.03, 186.09, 161.11, 218.92, 191.31, 179.45, 154.49 °C respectively, while the mesoporous silica particles modified with the phenylboronic acid derivative MSN-PBA 1-10 do not show endothermic melting peaks in the range of 30 - 240 °C. It can be clearly observed that there are differences in the crystal morphology between the phenylboronic acid derivative PBA 1-10 and the mesoporous silica particles modified with the phenylboronic acid derivative MSN-PBA 1-10 The phenylboronic acid derivative PBA1-10 In the crystalline state, the mesoporous silica particles MSN-PBA modified with phenylboronic acid derivatives 1-10 In the amorphous state, indicating that the phenylboronic acid derivative PBA 1-10 is grafted onto the silica particles rather than physically mixed.

[0062] Example 2

[0063] Study on the ability of the above-obtained mesoporous silica particles MSN-PBA modified with phenylboronic acid derivatives 1-10 to adsorb sugars in vitro and investigate the ability to adsorb sugars in vitro.

[0064] For monosaccharides (glucose): 4 mL of the obtained different mesoporous silica particles MSN-PBA modified with phenylboronic acid derivatives 1-10 were respectively prepared into suspensions with distilled water (equivalent to 59.4 mmol / L phenylboronic acid derivative PBA 1-10 ) and mixed with 4 mL of glucose solution (10 mg / mL), using simulated intestinal fluid (SIF) as the solvent. The blank group did not add mesoporous silica particles MSN-PBA modified with phenylboronic acid derivatives 1-10 . At the same time, adding silica (MSN) and phenylboronic acid derivative PBA4 were used as controls respectively.

[0065] For disaccharides (sucrose): 4 mL of the obtained different mesoporous silica particles MSN-PBA modified with phenylboronic acid derivatives 1-10 were respectively prepared into suspensions with distilled water (equivalent to 59.4 mmol / L PBA 1-10 ), 4 mL of sucrose solution (10 mg / mL) and α-glucosidase solution (1.0 mg / mL) were uniformly mixed, using simulated intestinal fluid (SIF) as the solvent. The blank group did not add mesoporous silica particles MSN-PBA modified with phenylboronic acid derivatives 1-10 . At the same time, adding silica (MSN) and phenylboronic acid derivative PBA4 were used as controls respectively.

[0066] For polysaccharides (dextrin): 4 mL of the obtained different mesoporous silica particles MSN-PBA modified with phenylboronic acid derivatives 1-10 were respectively prepared into suspensions with distilled water (equivalent to 59.4 mmol / L PBA 1-10 ), 4 mL of dextrin solution (10 mg / mL) and α-glucosidase (1.0 mg / mL) and α-amylase solution (1.0 mg / mL) were uniformly mixed. Compared with the above mixture, the control group did not add mesoporous silica particles MSN-PBA modified with phenylboronic acid derivatives 1-10 , and at the same time, silica (MSN) and phenylboronic acid derivative PBA4 were added as controls respectively.

[0067] The above phenylboronic acid derivatives were modified into mesoporous silica particles MSN-PBA 1-10 The mixture was incubated with sugar in a shaker (37°C, 100 rpm) for 2 hours. The adsorption capacity of sugar was calculated as follows: Sugar adsorption rate (%) = [1-A / B] × 100%, where A is MSN-PBA 1-10 The free glucose concentration of the supernatant of the group A is shown in Table 1. Figure 5 -As shown in ABC.

[0068] The results showed that mesoporous silica particles modified with phenylboronic acid derivatives had good sugar adsorption effect, among which 3-nitro-4-carboxyphenylboronic acid modified mesoporous silica particles MSN-PBA4 had the best sugar adsorption ability for monosaccharides, disaccharides and polysaccharides in SIF.

[0069] Example 3

[0070] Phenylboronic acid derivatives modified mesoporous silica particles MSN-PBA 1-10 Study on Inhibition of Digestive Enzyme Activity in Vitro

[0071] Preparation of mesoporous silica particles MSN-PBA modified with different phenylboronic acid derivatives by in vitro assay 1-10 Inhibition experiments on α-glucosidase, lipase and α-amylase. Preparation of mesoporous silica particles MSN-PBA modified with different phenylboronic acid derivatives 1-10 The simulated intestinal fluid was used to prepare 2 mL suspension (equivalent to 14.4 mmol / L PBA 1-10 ), α-glucosidase, lipase or α-amylase 2mL (0.6U / mL) were uniformly mixed, and simulated intestinal fluid was used as solvent. 1-10 The mixture was used as a blank, and silica (MSN) and phenylboronic acid derivative PBA4 were added as controls; each group of solutions was incubated at 37°C for 30 minutes, p-nitrophenol-β-D-galactoside (100 μL, 2.5 mM) was added and incubated for 30 minutes, and then 200 μL of sodium carbonate solution (0.2 M) was quickly added to terminate the reaction, and finally the absorbance at 405 nm was measured. The inhibitory rate of α-glucosidase (%) was calculated by the formula α-glucosidase inhibition rate (%) = [1-(AB) / (CD)] × 100% 1-10 The enzyme inhibition rate of A, B, C, and D represents the enzyme inhibition rate of each MSN-PBA 1-10 The absorbance values of the experimental group, experimental group blank (without enzyme solution), control group (without MSN-PBAs) and control blank (PBS) were shown in the inhibition test results of α-glucosidase, lipase and α-amylase.Figure 5 -as shown in DEF.

[0072] The results of enzyme inhibition experiments also showed that the phenylboronic acid derivative 3-nitro-4-carboxyphenylboronic acid modified mesoporous silica particles MSN-PBA4 had strong enzyme inhibition ability against α-glycosidase, α-amylase and lipase. The mesoporous silica particles without boronic acid functionalization had almost no sugar adsorption and enzyme inhibition ability, indicating that the inhibition of carbohydrate and enzyme activity was due to the interaction between boronic acid and diol, excluding the possible adsorption effect of the mesoporous silica particles themselves.

[0073] Example 4

[0074] In accordance with the process of preparing mesoporous silica by the soft template method in Example 1, three kinds of phenylboronic acid derivative 3-nitro-4-carboxyphenylboronic acid modified mesoporous silica particles (MSN-PBA4) with different particle sizes were prepared; among them, the volume of sodium hydroxide solution (2 mol / L) was controlled to be 3 mL, and the volume of tetraethyl orthosilicate was 5 mL, and then sMSN-PBA4 (~239.5 nm) was prepared. The volume of sodium hydroxide solution (2 mol / L) was controlled to be 3 mL, and the volume of tetraethyl orthosilicate was 13 mL, and then mMSN-PBA4 (~670.5 nm) was obtained; then the volume of sodium hydroxide was controlled to be 6 mL, and the volume of tetraethyl orthosilicate was 5 mL, and then lMSN-PBA4 (~5.7 μm) was obtained.

[0075] The particle size distribution and nitrogen adsorption-desorption of the obtained particles were measured, as Figure 6 shown, and the pore size distribution is shown in Table 1.

[0076] Table 1. Pore size distribution of mesoporous silica particles modified with 3-nitro-4-carboxyphenylboronic acid (small / medium / large MSN-PBA4) with different particle sizes

[0077]

[0078] From Table 1 and Figure 6 it can be seen that the three kinds of phenylboronic acid derivative 3-nitro-4-carboxyphenylboronic acid modified mesoporous silica particles with different particle sizes prepared have particle sizes of about 239.5 nm, about 664.8 nm, and about 5.7 μm respectively. The pore sizes of the three kinds of particles are about 3-5 nm, and the particle sizes of the three kinds of particles are relatively uniform and the particle size distribution is relatively narrow.

[0079] Example 5

[0080] 1) Oral glucose tolerance test

[0081] (1) Oral glucose tolerance test is a good method to evaluate the effect of phenylboronic acid derivative-modified mesoporous silica particles on reducing the absorption of dietary carbohydrates. First, mice were fasted overnight before the experiment (usually for 13 h, n = 6). On the morning of the experiment day, the fasting blood glucose of mice was measured. 15 min after intragastric administration of a suspension of 3-nitro-4-carboxyphenylboronic acid-modified mesoporous silica particles (MSN-PBA4) prepared with distilled water at 0.2 mL (for mice, equivalent to 1.44 mmol PBA4 / kg), acarbose (10 mg / kg) or PBS, 0.2 mL of a carbohydrate solution (glucose, sucrose or starch) was intragastrically administered at a dose of 2.0 g / kg for wild-type mice. The blood glucose levels of mice were monitored with a blood glucose monitor at 30, 60, 90, and 120 min after intragastric administration of the carbohydrate solution. The results are as Figure 7 shown.

[0082] As Figure 7 shown in A-1, B-1, and C-1, the results of wild-type mice showed that the blood glucose of the PBS group mice increased rapidly within 15 min after intragastric administration of carbohydrates, and the blood glucose levels at different time points were higher than those of the 3-nitro-4-carboxyphenylboronic acid-modified mesoporous silica particles (MSN-PBA4) groups with different particle sizes. Acarbose is an α-glucosidase inhibitor that can reversibly bind to α-glucosidase, thereby inhibiting the activity of α-glucosidase and has been approved by the FDA for relieving postprandial hyperglycemia. As Figure 7 shown in B-1, compared with the PBS group, the blood glucose levels of the acarbose group mice decreased by 42.76% and 31.96% at 15 min after intragastric administration of sucrose, while acarbose had no effect on the glucose after polysaccharide hydrolysis. As Figure 7 shown in A-1, there was no significant difference in the blood glucose levels between the acarbose group and the PBS group mice after intragastric administration of glucose. Obviously, as Figure 7A-2, B-2, C-2. For monosaccharides (glucose), disaccharides (sucrose), and polysaccharides (starch), oral administration of MSN-PBA4 can significantly reduce blood glucose levels. Among them, mMSN-PBA4 (particle size ~670 nm) has the best hypoglycemic effect, with the lowest blood glucose level and the smallest area under the blood glucose curve. Compared with the PBS group, the blood glucose levels in the mMSN-PBA4 group decreased by 22.90%, 45.20%, and 32.11% respectively 15 min after intragastric administration of glucose, sucrose, and starch. In addition, compared with the acarbose group, the incremental area under the blood glucose curve (iAUC) in the mMSN-PBA4 group decreased by 18.92%, 3.91%, and 5.54% respectively after intragastric administration of glucose, sucrose, and starch. It is worth noting that the blood glucose level in the group of mesoporous silica particles mMSN-PBA4 (particle size ~670 nm) modified with 3-nitro-4-carboxyphenylboronic acid remained above the normal value, and there was no risk of hypoglycemia. The results showed that the mesoporous silica particles mMSN-PBA4 (particle size ~670 nm) modified with 3-nitro-4-carboxyphenylboronic acid had good postprandial blood glucose inhibitory ability.

[0083] (2) STZ-induced type 1 diabetic mice were fasted overnight before the experiment (usually for 13 h, n = 6). On the morning of the experimental day, the fasting blood glucose of the mice was measured. After intragastric administration of a suspension of mesoporous silica particles modified with 3-nitro-4-carboxyphenylboronic acid (MSN-PBA4) in distilled water at 0.2 mL (for STZ-induced type 1 diabetic mice, equivalent to 1.44 mmol PBA4 / kg), acarbose (10 mg / kg), or PBS for 15 min, then 0.2 mL of a carbohydrate solution (glucose, sucrose, or starch) was intragastrically administered at a dose of 1 g / kg for STZ-induced type 1 diabetic model mice. At 30, 60, 90, and 120 minutes after intragastric administration of the carbohydrate solution, the blood glucose levels of the mice were monitored using a blood glucose monitor. As Figure 7 D-1. The blood glucose level of STZ-induced type 1 diabetic mice increased significantly 30 min after intragastric administration of glucose (about 153.0 mg / dL -1 ), and then the blood glucose concentration showed a mountain-shaped curve distribution within 2 hours. There was no significant difference in the blood glucose levels between the PBS group and the acarbose group within 2 hours after administration. At each time point after administration, there were significant differences in the blood glucose between the mMSN-PBA4 group and the PBS group. Compared with the PBS group, at 0.5 h, 1 h, and 1.5 h, the blood glucose levels of the mice in the mMSN-PBA4 group decreased by 17.64%, 16.45%, and 20.10% respectively. As Figure 7 D-2. The area under the blood glucose curve in the mMSN-PBA4 group also decreased by 15.39% and 13.27% respectively compared with the PBS and acarbose groups.

[0084] (3) DIO obese mice were fasted overnight before the experiment (usually for 13 h, n = 6). On the morning of the experimental day, the fasting blood glucose of the mice was measured. After intragastric administration of mesoporous silica particles modified with 3-nitro-4-carboxylphenylboronic acid (MSN-PBA4) prepared as a suspension in distilled water at 0.2 mL (for DIO mice, equivalent to 1.44 mmol PBA4 / kg), acarbose (10 mg / kg), or PBS for 15 min, 0.2 mL of a carbohydrate solution (glucose, sucrose, or starch) was then intragastrically administered at a dose of 1 g / kg for DIO diabetic model mice. At 30, 60, 90, and 120 minutes after intragastric administration of the carbohydrate solution, the blood glucose levels of the mice were monitored using a blood glucose monitor. As Figure 7 There were no significant differences in the blood glucose levels and the area under the blood glucose curve (iAUC) between the E-1, 7E-2, PBS group and the acarbose group. As Figure 7 E-1, at different time points after administration, the blood glucose concentrations in the mMSN-PBA4 group were lower than those in the PBS and acarbose groups. At 0.5 h and 1 h after administration, the blood glucose in the mMSN-PBA4 group decreased by 12.84% and 17.48% respectively compared with the acarbose group. As Figure 7 E-2, the area under the blood glucose curve in the mMSN-PBA4 group was reduced by nearly 17.58% and 14.44% respectively compared with the PBS group and the acarbose group. These results indicate that the mesoporous silica particles mMSN-PBA4 modified with 3-nitro-4-carboxylphenylboronic acid can also effectively reduce the postprandial blood glucose levels in type 1 and type 2 diabetic mouse models.

[0085] Example 6

[0086] Investigate the blood glucose level control of the phenylboronic acid derivative 3-nitro-4-carboxylphenylboronic acid-modified mesoporous silica particles (mMSN-PBA4) after consuming food.

[0087] (1) To evaluate the hypoglycemic effect of MSN-PBA4 on foods consumed by people in real life rather than refined carbohydrates, normal mice were intragastrically administered mMSN-PBA4 (0.5 g / kg) and then intragastrically administered 0.2 mL of jam, cola, peanut butter, or milk for the experiment. At 30, 60, 90, and 120 min after intragastric administration of different foods, the blood glucose of normal mice was measured using a blood glucose meter, and the results are as Figure 7 shown.

[0088] As Figure 8 shown in A-1, 1 h after intragastric administration of cola, the blood glucose levels of the mice in the mMSN-PBA4 group decreased by 19.16% and 5.19% respectively compared with the PBS and acarbose groups. As Figure 8 B-1, 8C-1, 8D-1, 1 h after intragastric administration of ketchup, peanut butter, and milk, the blood glucose decreased by 23.36%, 23.07%, and 18.83% respectively compared with the PBS group. As Figure 8A-2, 8B-2, 8C-2, 8D-2. Compared with the PBS group, after intragastric administration of cola, jam, peanut butter, and milk, the areas under the blood glucose curves in the mMSN-PBA4 group decreased by 13.24%, 16.25%, 15.94%, and 16.01%, respectively. mMSN-PBA4 can effectively prevent the increase in blood glucose after mice eat. Thus, it can be seen that the mesoporous silica particles modified with 3-nitro-4-carboxylphenylboronic acid, mMSN-PBA4, have a certain control effect on blood glucose levels in daily diets, suggesting that this preparation may have broad application value in the future.

[0089] (2) To evaluate the hypoglycemic effect of MSN-PBA4 on foods consumed by people in real life rather than refined carbohydrates, DIO mice were intragastrically administered mMSN-PBA4 (0.5 g / kg), and then intragastrically administered 0.2 mL of jam, cola, peanut butter, or milk for experiments. At 30, 60, 90, and 120 min after intragastric administration of different foods, the blood glucose levels of normal mice and DIO mice were measured with a blood glucose meter.

[0090] The results are as Figure 9 A-1, 9B-1, 9C-1, 9D-1. The blood glucose concentration and the area under the blood glucose curve at different time points after administration in the mMSN-PBA4 group were lower than those in the PBS and acarbose groups. As Figure 9 A-2, 9B-2, 9C-2, 9D-2. Compared with the PBS group, after intragastric administration of cola, jam, peanut butter, and milk, the areas under the blood glucose curves in the mMSN-PBA4 group decreased by 24.76%, 13.41%, 11.57%, and 10.5%, respectively. These results indicate that mMSN-PBA4 has a superior hypoglycemic effect and is widely applicable to normal mice and diabetic mice.

[0091] Example 7

[0092] Study on the long-term hypoglycemic and lipid-lowering effects of the phenylboronic acid derivative 3-nitro-4-carboxylphenylboronic acid-modified mesoporous silica particles (particle size ~670 nm) (mMSN-PBA4)

[0093] Investigate the hypoglycemic and lipid-lowering effects of mMSN-PBA4 on diet-induced obesity (DIO) and streptozotocin (STZ)-induced diabetic mice fed a long-term high-sugar and high-fat diet (HFD). DIO mice and STZ-induced diabetic mice were fed a high-sugar and high-fat diet providing 60% of energy from fat (3 g / mouse) daily, and normal mice were fed a normal diet for 6 weeks. The mice were divided into 5 groups: normal group, DIO group (HFD), DIO group (HFD + MSN-PBA4) (0.5 wt%), STZ diabetic group (HFD), STZ diabetic group (HFD + MSN-PBA4) (0.5 wt%) (n = 5). The mMSN-PBA4 in the dosing groups was evenly distributed in the drinking bottles. The body weight and blood glucose levels of the mice were monitored weekly to evaluate the effects of mMSN-PBA4 on the blood glucose levels and body fat of the mice. The results are as Figure 10 shown. Mouse feces were collected at week 6, and a physiological saline solution was added at a ratio of feces weight (g): physiological saline volume (mL) = 1:9. Mechanical homogenization was performed under water bath conditions, followed by centrifugation at 2500 rpm for 10 min. The supernatant was taken, and the contents of total cholesterol and triglyceride (TG) in the feces were detected using a biochemical assay kit. The results are as Figure 11 shown.

[0094] Subsequently, the mice were euthanized, blood was collected, serum was separated by centrifugation, and mouse organs were isolated. Serum biochemical indices, including total cholesterol (TCHO), triglyceride (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and high-density lipoprotein (HDL), were detected using a biochemical assay kit from Nanjing Jiancheng Bioengineering Institute. The results are as Figure 12 , 13. The liver was weighed, 9 times the volume of physiological saline was added, mechanical homogenization was performed under water bath conditions, and the supernatant was extracted after centrifugation. The contents of total cholesterol, triglyceride, and free fatty acids were determined using a biochemical assay kit. The results are as Figure 14 shown. The activities of small intestinal α-glucosidase, α-amylase, lipase, and protease were determined using a biochemical assay kit. The results are as Figure 15 shown.

[0095] As Figure 10 , the body weight and blood glucose levels of normal mice fed a normal diet fluctuated less within 6 weeks, with the body weight maintained at 20 - 23 g and the blood glucose between 180 - 200 ng / mL. As Figure 10 A, B, for STZ-induced type 1 diabetic mice and DIO mice, the growth rates of body weight and blood glucose in mice fed a high-fat diet containing mMSN-PBA4 were slower than those in mice fed only a high-fat diet. For STZ mice, the blood glucose level increased by approximately 91.8 ng / mL in the HFD group at week 6, while it increased by only approximately 56.9 ng / mL in the mMSN-PBA4 group. As Figure 10C, D. For DIO mice, the blood glucose level in the HFD group increased by approximately 30.9 ng / mL at week 6 compared to week 1, while the mMSN-PBA4 group only increased by 19.46 ng / mL. The results confirmed that mMSN-PBA4 could also inhibit the weight gain and blood glucose increase caused by high-sugar and high-fat diets in STZ- and DIO-induced diabetic mice to a certain extent.

[0096] As Figure 11 A, B. The fecal lipid content of mice was measured at week 6. In type 1 diabetic mice induced by STZ, the cholesterol and triglyceride contents in the feces of mice in the mMSN-PBA4 group were 2.55 times and 1.79 times those of the HFD group, respectively. As Figure 11 C, D. For DIO mice, the cholesterol and triglyceride contents in the feces of mice in the mMSN-PBA4 group were 3.31 times and 2.13 times those of the HFD group, respectively. The results showed that in both the STZ-induced type 1 diabetic mouse model and the DIO mouse model, the cholesterol and triglyceride contents in the feces of mice in the mMSN-PBA4 group were significantly higher than those in the HFD group. mMSN-PBA4 could further inhibit the activity of digestive enzymes, promote lipid excretion, and reduce lipid absorption.

[0097] The serum lipid levels of STZ-induced type 1 diabetic mice were as Figure 12 shown, as Figure 11 A. The serum triglyceride level of mice fed a high-sugar and high-fat diet was 1.71 times that of the normal group, suggesting that a long-term high-sugar and high-fat diet may lead to abnormal elevation of blood lipids. As Figure 12 A-C. Compared with the HFD group, the serum triglyceride level in the mMSN-PBA4 group decreased by 23.65%, the cholesterol level decreased by 24.92%, and the high-density lipoprotein level decreased by 10.21%; Figure 12 D-F. There were also significant differences in the ALT level, AST level, and free fatty acid level between the mMSN-PBA4 group and the HFD group. Among them, the serum ALT, AST, and free fatty acid levels in the HFD group were 1.58 times, 1.44 times, and 1.48 times those of the mMSN-PBA4 group, respectively. As Figure 13 A, B. For DIO mice, the serum triglyceride and cholesterol levels in the HFD group were also significantly higher than those in the normal group, indicating that a high-sugar and high-fat diet may lead to an increase in blood lipid (i.e., triglyceride) levels. Figure 13Compared with the HFD group, the serum triglyceride level in the A-F, mMSN-PBA4 groups of mice was 15.82% lower. Similarly, the serum cholesterol level decreased by 27.16%. The HDL level in the mMSN-PBA4 group was also slightly lower than that in the HFD group. Compared with the HFD group, the ALT level in the mMSN-PBA4 group decreased by 28.37%, the AST level decreased by 17.8%, and the free fatty acid level decreased by 32.34%, indicating that mMSN-PBA4 has a certain alleviating effect on hyperlipidemia caused by long-term high-sugar and high-fat diet.

[0098] By measuring the liver lipid levels in mice, the effect of mMSN-PBA4 on liver lipids in DIO mice induced by high-sugar and high-fat feeding and STZ-induced type 1 diabetes was evaluated. For STZ mice, as Figure 14 shown in A, the liver weight in the mMSN-PBA4 group was approximately 0.5 g lighter than that in the HFD group. As Figure 14 shown in B-D, the levels of triglyceride, cholesterol, and free fatty acid in the liver of the HFD group were significantly higher than those in the normal group, being 1.3 times, 1.7 times, and 1.4 times those in the mMSN-PBA4 group, respectively. For DIO mice, as Figure 14 shown in E, the liver weight of the HFD group of mice was approximately 0.28 g heavier than that of the normal group and approximately 0.16 g heavier than that of the mMSN-PBA4 group. The liver weight of the mMSN-PBA4 group was significantly lower than that of the HFD group, indicating that mMSN-PBA4 can reduce fat accumulation in the liver. As Figure 14 shown in F-H, the levels of triglyceride, cholesterol, and free fatty acid in the liver of the HFD group were significantly higher than those in the normal group. Compared with the HFD group, the levels of triglyceride, cholesterol, and free fatty acid in the liver of the mMSN-PBA4 group decreased by 25.8%, 18.1%, and 28.6%, respectively. The results show that mMSN-PBA4 can reduce the accumulation of fat in the liver.

[0099] The activities of mouse intestinal α-glucosidase, α-amylase, lipase, and protease in the above groups were detected using kits. As Figure 15 shown in A-D, for STZ mice, the activities of α-glucosidase, α-amylase, lipase, and protease in the mMSN-PBA4 group decreased by approximately 31.1%, 10.87%, 7.1%, and 25.73% compared with the HFD group. As Figure 15 shown in E-H, for DIO mice, the activities of α-glucosidase, α-amylase, lipase, and protease in the mMSN-PBA4 group decreased by 29.79%, 14.4%, 9.4%, and 35.92% compared with the HFD group, respectively. The results show that mMSN-PBA4 can inhibit the activities of digestive enzymes to a certain extent, thereby avoiding excessive absorption of high-sugar and high-fat diets by the body.

[0100] Example 8

[0101] Investigate the distribution and elimination of 3-nitro-4-carboxyphenylboronic acid modified mesoporous silica particles (mMSN-PBA4) in vivo

[0102] To explore the distribution of mMSN-PBA4 in normal mice after intragastric administration, the mice were fasted and intragastrically administered with Cy5.5-labeled mMSN-PBA4 (0.2 mL, 0.5 g / kg, equivalent to 1.44 mmol / kg). Images were acquired using an IVIS Lumina III In Vivo Imaging System at different time points with excitation at 500 nm and emission at 520 nm. Ex vivo imaging was also performed. The mice were euthanized at different times, and the organs were isolated for imaging. The results are as Figure 16 shown.

[0103] As Figure 16 shown in A, obvious fluorescence was visible in the lower abdomen of the mice at 30 min, 2 h, and 6 h after intragastric administration of Cy5.5-labeled mMSN-PBA4. With the extension of the metabolic time, the fluorescence intensity gradually decreased, and no fluorescence was observed 24 h after intragastric administration. The gastrointestinal tract of the mice was further isolated to study the transport of Cy5.5-labeled mMSN-PBA4 in the gastrointestinal tract, and the fluorescence intensity at different time points after intragastric administration was detected. As Figure 16 shown in B, partial fluorescence was observed in the intestine 30 min after administration, indicating that Cy5.5-labeled mMSN-PBA4 rapidly entered the intestine from the stomach. At 8 h after administration, most of the fluorescence was distributed in the ileum segment, and the fluorescence disappeared at 24 h, indicating that Cy5.5-labeled mMSN-PBA4 had been excreted through the gastrointestinal tract. Subsequently, the key organs (heart, liver, spleen, lung, kidney) were isolated at different time points after administration. As Figure 16 shown in C, no fluorescence was observed, indicating that mMSN-PBA4 was hardly systemically absorbed and was mainly excreted through the gastrointestinal tract after exerting its effect.

[0104] Example 9

[0105] Safety investigation of 3-nitro-4-carboxyphenylboronic acid modified mesoporous silica particles (mMSN-PBA4)

[0106] To evaluate the toxicity of mMSN-PBA4, normal mice were intragastrically administered with a suspension of mMSN-PBA4 prepared with distilled water (0.5 g / kg, equivalent to 1.44 mmol PBAs / kg) or PBS at 0.2 mL per day for 3 months. Adverse side effects were closely monitored. After 24 h of the last intragastric administration, the mice were euthanized, and the organs (heart, liver, spleen, lung, kidney, gastrointestinal tract) were isolated for histological analysis. The results are as Figure 17 shown.

[0107] Figure 17It was shown that there were no obvious abnormalities or deaths in the mice in the mMSN-PBA4 and PBS groups. Pathological section examinations were performed on the key organs (heart, liver, spleen, lung, kidney, stomach, intestine) of the mice, and no obvious abnormalities were found, indicating that mMSN-PBA4 has good safety and no obvious adverse reactions after long-term administration.

[0108] The above detailed description is a specific description of the feasible embodiments of the present invention. This embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or change without departing from the present invention shall be included in the patent protection scope of this case.

Claims

1. A silica particle modified with a phenylboronic acid derivative, characterized in that: The particle is shown in Formula I. In the formula, Linker is the residue structure of the silane coupling agent after modification reactions with the phenylboronic acid derivative and silica respectively; The phenylboronic acid derivative is a compound shown in Formula II, wherein, R1, R2, R3, R4 and R5 may be the same or different and are selected from H or substituents capable of reacting with the silane coupling agent, and at least one of R1, R2, R3, R4 and R5 is not H.

2. The silica particles modified with a phenylboronic acid derivative according to claim 1, wherein: The silane coupling agent may be (3-aminopropyl)triethoxysilane (APTES), (3-aminopropyl)trimethoxysilane, N-(2-aminoethyl)-3-aminopropyltrimethoxysilane (AEAPTMS), N-(2-aminoethyl)-3-aminopropylmethyldimethoxysilane, bis(3-trimethoxysilylpropyl)amine, 3-glycidoxypropyl)triethoxysilane (GPTES), 3-glycidoxypropyl)trimethoxysilane (GPTMS), 2-(3,4-epoxycyclohexyl)ethyltrimethoxysilane (ECTMS), 3-mercaptopropyltrimethoxysilane (MPTMS), 3-mercaptopropyltriethoxysilane (MPTES), (3-isocyanatopropyl)triethoxysilane (IPTES), (3-chloropropyl)trimethoxysilane (CPTMS), (3-chloropropyl)triethoxysilane, (3-methacryloxypropyl)trimethoxysilane (MAPTMS), (3-carboxypropyl)trimethoxysilane, (3-bromopropyl)trimethoxysilane, (3-isocyanatopropyl)trimethoxysilane (IPTMS), (3-vinyl)trimethoxysilane (VTMS), vinyltriethoxysilane (VTES), methyltrimethoxysilane (MTMS), vinyltris(2-methoxyethoxy)silane (VTMOEO), octyltriethoxysilane (OTES), (3-anilinopropyl)trimethoxysilane, 3-(2,3-epoxypropoxy)propyltrimethoxysilane, 11-aminoundecyltriethoxysilane, docosyltriethoxysilane, methyltrimethoxysilane, methyltriethoxysilane, n-octyltriethoxysilane, dodecyltrimethoxysilane, hexadecyltrimethoxysilane, octadecyltrimethoxysilane, aminoethylaminopropyltrimethoxysilane, 3-(trimethoxysilyl)propyldimethyloctadecylammonium chloride, phenylaminomethyltrimethoxysilane, 3-ureidopropyltrimethoxysilane.

3. The silica particles modified with the phenylboronic acid derivative according to claims 1 and 2, characterized in that: The substituents capable of reacting with the silane coupling agent are amino, carboxyl, mercapto, C3-C8 epoxy group, C2-C8 alkynyl group, azide group, hydroxyl group or aldehyde group.

4. The silica particles modified with the phenylboronic acid derivative according to claim 1, wherein: The phenylboronic acid derivative is one of the following compounds.

5. The silica particles modified with a phenylboronic acid derivative according to any one of claims 1-4, characterized in that: The particle is selected from any one of the following, 6. Use of the silica particles modified with the phenylboronic acid derivative according to claim 1, characterized in that: The application of the phenylboronic acid derivative-modified silica particles in the preparation of drugs, medical devices for preventing or treating hyperglycemia, hyperlipidemia and glycolipid metabolism disorders, or in the preparation of general foods, health foods, and foods for special medical purposes.

Images