Series of homocysteine responsive removal systems, and preparation method and application thereof

Abstract

The invention discloses a series of homocysteine responsive removal systems. The homocysteine responsive removal systems are obtained by carrying out a Schiff base reaction on a substance containing cystamine and / or selenocystamine and a multi-aldehyde monomer. A series of homocysteine responsive removal systems have high stability, can be uniformly and stably dispersed in an aqueous solution, and can specifically remove highly expressed homocysteine in depression patients, so that rapid and stable removal of blood risk factors is realized. According to the invention, a rapid, efficient and specific homocysteine removal effect is shown, and meanwhile, excellent biological safety is kept, which is crucial for ensuring the safety of a patient in a treatment process. Therefore, the COFs-based homocysteine responsive removal system is expected to become a novel efficient treatment means for treating homocysteine related diseases such as depression and the like, and revolutionary transformation is brought to research and clinical practice in related fields.

Description

Technical Field

[0001] The present invention relates to the fields of new material technology and biomedical pharmaceutical technology, and in particular to a series of homocysteine ​​responsive removal systems, preparation methods and uses thereof. Background Art

[0002] Covalent Organic Frameworks (COFs), as a porous material composed entirely of organic structural units, have attracted extensive attention in the fields of materials science and chemistry due to their unique pore structure, large specific surface area, low density, high stability, and easy-to-regulate functions. They have been listed as one of the hot research directions in the field of chemistry by the American Chemical Society. Since the first report of COF-1 by Omar M. Yaghi's research group at the University of California, Berkeley in 2005, the preparation and application research of COFs materials has entered a stage of rapid development and has become a highly anticipated research hotspot. [1] .

[0003] Since COFs are built from organic raw materials, they have a series of unique characteristics. First, COFs have unique designability, which is one of the most significant differences from other porous materials. Through the combination of different building blocks, materials with expected structures can be obtained, which provides unlimited possibilities for the customization and functionalization of COFs. Researchers can design and synthesize COFs materials with specific structures and functions according to actual needs to meet the application needs of different fields. Secondly, COFs are chemically unique. Through thermodynamically controlled reversible covalent bond connection, materials with crystalline structures can be obtained. This crystalline structure makes COFs significantly different from other porous materials in structure and properties, giving them unique physical and chemical properties. In addition, COFs also have the characteristics of regular pore structure, structural diversity and easy functionalization. These characteristics make COFs have broad application prospects in gas adsorption and separation, catalysis, optoelectronics and other fields. [2] .

[0004] Depression has become a common disease worldwide. Social frustration is one of the main causes of depression. With the acceleration of people's pace of life and the increase of social pressure, social frustration has caused more and more mental illnesses such as anxiety and depression. Social defeat stress is a form of social pressure based on the subordinate relationship between species. It causes frustrated individuals to have emotional and mental stress, thereby causing a series of diseases such as social avoidance, depression, anxiety, anhedonia, and reduced cognitive function. The occurrence of social defeat stress is often accompanied by alcohol and drug abuse, which seriously affects the patient's work and quality of life, and brings a heavy burden to the family and society.[3] .

[0005] Homocysteine ​​(Hcy) is a sulfur-containing amino acid and an important intermediate product produced in the metabolism of methionine and cysteine. When its detection value is greater than or equal to 10 micromol / L, it is clinically called "hyperhomocysteinemia" (high Hcy). Plasma homocysteine ​​levels are closely related to the severity of depression. It is not only the main clinical indicator for diagnosing depression, but also an important risk factor for myocardial infarction and stroke. [4] Homocysteine ​​can aggravate social isolation-induced depressive-like behavior in aged mice by inhibiting BDNF expression [5] , increases cortical excitability and exacerbates mechanical hyperalgesia and anxiety in a nitroglycerin-induced rat migraine model [6] , and can also exacerbate Aβ-induced cECDR4 / 5-mediated brain endothelial cell apoptosis, blood-brain barrier dysfunction, and angiogenesis defects [7] Folic acid is currently the main clinical drug for the treatment of homocystinemia. [8] However, folic acid has a short half-life in the body and is easily photolyzed by ultraviolet light in the skin. [9] , and long-term use will affect the absorption of zinc ions

[10] Therefore, developing a more efficient and stable treatment system is crucial to improving homocystinemia and its complications.

[0006] Cystamine is a straight-chain aliphatic diamine composed of disulfide bridges. It is produced by the oxidation of two cysteamine residues and is closely related to the metabolism of coenzyme A in tissues. In addition to being rapidly converted into the neuroactive substance cysteamine, cystamine can also be metabolized into endogenous cell components such as cysteine, hypotaurine and taurine in the body.

[11] Cystamine / cysteamine not only rescues the dopaminergic system, but also induces neurite dendrites in dopaminergic cells and exhibits neurorestorative properties in animal models of Parkinson's disease.

[12] It can also promote brain-derived neurotrophic factor (BDNF) levels and TrkB phosphorylation in the brain of mouse stroke models, and enhance neuronal progenitor cell proliferation, neuronal survival and plasticity through the BDNF / TrkB pathway

[13] . In a mouse model of major depression, cystamine / cysteamine can increase the levels of brain-derived neurotrophic factor (BDNF) in the brain and peripheral centers. Selenocystamine is a selenium substitute for cystamine. Selenium is usually unable to form a π bond, and its outer valence electrons are looser than those of sulfur. Therefore, compared with sulfur, selenium is a stronger nucleophile and reacts faster with reactive oxygen. Selenocystamine not only has glutathione peroxidase-like activity, but can also produce nitric oxide gas as a special coating on coronary stents to reduce the risk of vascular infarction.

[14] Therefore, constructing a new biomaterial treatment system through cystamine / selenocystamine is expected to achieve a new strategy for neuroprotective treatment. Summary of the invention

[0007] The purpose of the present invention is to provide a series of homocysteine ​​responsive removal systems, preparation methods and uses thereof, wherein the series of homocysteine ​​responsive removal systems are a COFs material based on cystamine and / or selenocystamine, which can be further applied to homocysteine ​​responsive removal. Based on the stimulus responsiveness of cystamine / selenocystamine to homocysteine, the present invention uses a variety of aldehyde-containing aggregation-induced emission / non-aggregation-induced emission groups as the skeleton to construct a series of novel stimulus-responsive covalent organic framework materials, and finally achieves a new treatment strategy for social frustration stress and anxiety-prone depressive-like behaviors based on covalent organic framework materials by synergizing the specific removal of homocysteine ​​in the blood circulation and the efficient protection of brain neurons. Specifically, the present invention adopts the following technical scheme:

[0008] First, a series of homocysteine ​​responsive removal systems of the present invention are COFs materials mainly obtained by reacting substances containing cystamine and / or selenocystamine with multi-aldehyde monomers through Schiff base, wherein the multi-aldehyde monomer contains more than 3 aldehyde groups and has a benzene ring as the skeleton.

[0009] Secondly, the present invention also provides a method for preparing the series of homocysteine ​​responsive removal systems, which comprises reacting a substance containing cystamine and / or selenocystamine with a multialdehyde monomer at a temperature of 100°C to 160°C by a solvent thermal method for 2 to 7 days; preferably reacting at 120-140°C for 3 days.

[0010] In the above-mentioned preparation method, preferably, the molar ratio of the polyaldehyde monomer to the substance containing cystamine and / or selenocystamine is 1:1 to 1:5, preferably 1:2.

[0011] In the preparation method described above, preferably, the substance containing cystamine and / or selenocystamine includes at least one of cystamine or its salt or its homologue, selenocystamine or its salt or its homologue. Among them, the salt of cystamine is preferably its dihydrochloride, and the salt of selenocystamine is preferably its dihydrochloride. The homologue of cystamine refers to a substance containing a cystamine structure, and the homologue of selenocystamine refers to a substance containing a selenocystamine structure. The multi-aldehyde monomer is an aldehyde monomer commonly used in the preparation of COFs, preferably containing more than 3 aldehyde groups and using a benzene ring as a skeleton, more preferably 3-6 aldehyde groups, most preferably 3-4 aldehyde groups, including but not limited to 1,2,4,5-benzene tetraaldehyde (1T1), 3,3',5,5'-tetraaldehyde biphenyl (1T2), 1,1':4',1"-terphenyl]-3,3",5,5"-tetraformaldehyde (1T3), 1,1':4',1":4",1"'-tetraphenyl quaternary ammonium salt]-3,3',5,5'-tetraacetaldehyde (1T4), trimesic acid (3T1), 1,3,5-tris(p-formylphenyl)benzene (3T2), 1,3,5-tris(4'-formyl[1,1'-biphenyl]-4-yl)benzene (3T3), tetraformyltetraphenylethylene (4T1), tetrakis-(4-formyl-(1,1-biphenyl))ethylene (4T2), and 1,3,6,8-tetrakis(4-formylphenyl)pyrene (4Tp).

[0012] In the preparation method of the COFs material described above, preferably, the solvent includes but is not limited to at least one of mesitylene, 1,4-dioxane, n-butanol, o-dichlorobenzene, acetonitrile, dimethylformamide, dimethylacetamide, and acetone, preferably mesitylene and 1,4-dioxane, with a volume ratio of 1:10-10:1, preferably 1:3-3:1. In addition, the main peak of the X-ray diffraction spectrum of a series of homocysteine ​​responsive scavenging systems obtained by the present invention in the range of 2Theta (2θ) angle 1 to 20° is before 12°.

[0013] Third, the series of homocysteine ​​responsive removal systems obtained by the present invention can be used in combination with homocysteine ​​response. Further, the series of homocysteine ​​responsive removal systems can be used to specifically remove homocysteine ​​in a liquid environment, without significantly removing its analog cysteine, and the liquid environment includes plasma, blood, and body fluids. In particular, homocysteine ​​in blood can be removed efficiently and specifically.

[0014] Furthermore, the series of homocysteine ​​responsive clearance systems can be used in the preparation of health products, foods or medicines for preventing, improving or treating hyperhomocysteinemia.

[0015] Furthermore, the series of homocysteine ​​responsive clearance systems can be used in the preparation of health products, foods or drugs for preventing, improving or treating cardiovascular and cerebrovascular diseases and mental and psychological diseases. Furthermore, the drug for treating mental and psychological diseases is an antidepressant drug.

[0016] In addition, the series of homocysteine ​​responsive removal systems can also improve the anxiety-like depressive behavior of animals in vivo, while also increasing the blood hydrogen sulfide content. The use methods of the series of homocysteine ​​responsive removal systems described in the present invention in the biomedical field include intravenous injection, nasal drops, etc.

[0017] The present invention obtains an innovative series of homocysteine ​​responsive clearance systems, which cleverly combines specific chemical structures with biological responsive mechanisms, and provides a new strategy for intervention against high homocysteine ​​levels in the treatment of depression patients. Specifically, the present invention has the following technical features:

[0018] 1. Architecture and composition

[0019] Backbone group: The present invention uses a class of compounds containing aldehyde groups as the backbone group, which includes but is not limited to aggregation-induced emission (AIE) and non-aggregation-induced emission groups. Aggregation-induced emission groups can significantly enhance the luminescence performance under certain conditions (such as aggregation state), which is helpful for in vivo and in vitro monitoring and tracking; while non-aggregation-induced emission groups may show advantages in other aspects (such as solubility and stability).

[0020] Homocysteine ​​responsive groups: The core of this system is to use the disulfide bond (SS) or diselenide bond (Se-Se) in cystamine dihydrochloride and selenocystamine dihydrochloride as the responsive group. These bonds are stable under physiological conditions, but can react specifically with homocysteine ​​to achieve homocysteine ​​removal. In particular, the diselenide bond in selenocystamine may have higher reactivity and selectivity than the disulfide bond, which is suitable for more efficient homocysteine ​​removal.

[0021] 2. Preparation method

[0022] The preparation process mainly involves the Schiff base chemical reaction between the aldehyde backbone group and cystamine dihydrochloride or selenocystamine dihydrochloride to form a stable covalent bond. This step ensures the high stability of the scavenging system and its uniform dispersion in aqueous solution, laying the foundation for subsequent biological applications.

[0023] 3. Uses and advantages

[0024] Specific removal of homocysteine: Depression patients are often accompanied by high homocysteine ​​levels, and high homocysteine ​​is a risk factor for a variety of cardiovascular diseases. The removal system of the present invention can specifically identify and remove Hcy, a high-risk factor for cardiovascular disease and depression, in the blood.

[0025] Fast and stable: The response groups in the system can quickly respond to the presence of homocysteine ​​and undergo chemical reactions, thereby achieving rapid removal. At the same time, the stability of the system ensures long-term effects in complex biological environments.

[0026] Biocompatibility and monitoring: Some backbone groups have AIE properties, which makes the system easy to track and monitor in vivo or in vitro experiments, helping to evaluate the clearance effect and adjust the treatment plan.

[0027] Potential clinical application: Based on the above advantages, the homocysteine ​​responsive clearance system of the present invention is expected to become an auxiliary treatment for hyperhomocysteinemia, providing new possibilities for improving the prognosis of patients.

[0028] Based on the above, the series of homocysteine ​​responsive clearance systems of the present invention are not only innovative in design, but also show great potential in biological applications, providing new ideas and methods for the treatment of related diseases.

[0029] A series of homocysteine ​​responsive removal systems of the present invention can specifically remove harmful components of homocysteine ​​in blood / serum samples, and play a therapeutic role in diseases with elevated homocysteine ​​such as depression. The preparation method of the homocysteine ​​responsive removal system provided by the present invention can synthesize a series of homocysteine ​​responsive removal systems based on COFs, and play a therapeutic role in animal models of hyperhomocysteinemia and depression. The preparation of the homocysteine ​​responsive removal system described in the present invention is based on Schiff base reaction and is synthesized by solvent thermal method. Its synthetic raw materials are aldehyde-containing skeleton groups and cystamine dihydrochloride or selenocystamine dihydrochloride shown in Table 1. Its homocysteine ​​scavenging group is a disulfide bond / diselenium bond contained in cystamine dihydrochloride / selenocystamine dihydrochloride, and some skeleton groups containing aldehyde groups have aggregation-induced emission characteristics (4T1, 4T2 and 4Tp). Table 1 shows the abbreviation, CAS number, Chinese full name and English full name of the aldehyde-containing skeleton raw materials in a series of COFs-based homocysteine ​​responsive removal systems.

[0030] Table 1

[0031]

[0032] The beneficial effects of the present invention are:

[0033] The series of homocysteine ​​responsive removal systems based on covalent organic frameworks (COFs) innovatively proposed in this application (Table 2) show excellent potential for biomedical applications. These systems not only showed high sensitivity and specific removal ability for homocysteine ​​(Hcy) in human blood samples in in vitro experiments, but also verified its effective intervention effect on animal models such as depression caused by elevated Hcy levels in a mouse model, a system that is closer to the real physiological environment. Specifically, the system can significantly reduce the Hcy level in mice, thereby improving their anxiety, depressive behavior and stress response, providing a new perspective for understanding and treating these diseases. Table 2 is a description of the raw materials and product abbreviations of a series of homocysteine ​​responsive removal systems based on COFs.

[0034] Table 2

[0035]

[0036] It is particularly worth emphasizing that the series of COFs-based homocysteine ​​responsive clearance systems described in this application are the first to directly target high concentrations of homocysteine ​​in the blood as a potential risk factor for clearance therapy, which is of great significance in the biomedical field. Its therapeutic effectiveness has not only been fully verified in in vitro experiments at the cellular or molecular level, but also demonstrated actual therapeutic effects in complex in vivo environments (such as mouse models), further confirming its wide application and reliability.

[0037] In addition, the system was designed with full consideration of cost-effectiveness and ease of preparation to ensure its feasibility in large-scale applications. More importantly, the system demonstrated rapid, efficient and specific homocysteine ​​removal effects, and it can efficiently remove Hcy in vitro in just 2 hours while maintaining excellent biosafety, which is crucial to ensuring the safety of patients during treatment. Therefore, the COFs-based homocysteine ​​responsive removal system is expected to become a new and efficient treatment for homocysteine-related diseases such as depression, bringing revolutionary changes to research and clinical practice in related fields. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 This is a series of XRD crystal structure characterization diagrams of homocysteine ​​responsive scavenging systems based on COFs.

[0039] Figure 2 It is a series of COFs-based homocysteine ​​responsive clearance systems for the relative clearance value ratio of homocysteine ​​and cysteine ​​in human blood.

[0040] Figure 3These are H&E staining images of the main organs of mice after injection of 4T1-S-COF, 4T1-Se-COF, 4Tp-S-COF, and 4Tp-Se-COF. The scale bar is 200μm.

[0041] Figure 4 In the cross-elevation test, 4T1-S-COF, 4T1-Se-COF, 4Tp-S-COF, and 4Tp-Se-COF treatment improved the anxiety-depression-like behavior of mice.

[0042] Figure 5 In the open field test, 4T1-S-COF, 4T1-Se-COF, 4Tp-S-COF, and 4Tp-Se-COF treatment improved the anxiety-depression-like behavior of mice.

[0043] Figure 6 The effects of injection of 4T1-S-COF, 4T1-Se-COF, 4Tp-S-COF, and 4Tp-Se-COF on serum cortisol, homocysteine, cysteine, and hydrogen sulfide in mice.

[0044] Figure 7 This is a schematic diagram of the preparation mechanism of a series of COFs-based homocysteine ​​responsive scavenging systems. DETAILED DESCRIPTION

[0045] Instruments and reagents

[0046] X-ray diffractometer (D8 Advance X-ray diffractometer (Bruker) with Cu Kα radiation, 40 kV, 40 mA, ); UV absorption spectrum (UV-1800, Mapada, China); thermogravimetric analysis (20-800°C, PerkinElmer TG:DTA6300); infrared spectrum (Vector-22 spectrometer, Bruker); fluorescence spectrum ((HORIBA Scientific, Japan). Transmission electron microscopy (JEM-1011, JEOL, Japan); dynamic light scattering (DLS) (BI-200SM (Brookhaven Instruments Corporation)); laser confocal microscopy (LSM-710, Zeiss Inc., Germany). All reagents were purchased from Sinopharm Chemical Reagent Co., Ltd.

[0047] The method for preparing a series of COFs-based homocysteine ​​responsive removal systems of the present invention comprises the following steps:

[0048] Step 1: Raw material mixing and preliminary processing

[0049] 1. In a clean glass sealed tube, weigh 0.05 mmol of a specific aldehyde-containing skeleton monomer (see Table 1), and then add 0.1 mmol of cystamine dihydrochloride or selenocystamine dihydrochloride as a homocysteine ​​response group.

[0050] 2. Add 1 ml of mesitylene and 1 ml of 1,4-dioxane as solvents into the sealed tube in sequence, and then place the mixture in an ultrasonic bath for 30 minutes to ensure that the raw materials are fully mixed.

[0051] 3. Slowly add 0.55 ml of glacial acetic acid (or add 0.35 ml of trifluoroacetic acid and 0.15 ml of trifluoroacetic acid) to the system and continue ultrasonic treatment for 15 minutes.

[0052] Step 2: Refrigeration-Vacuum Cycle Treatment

[0053] 1. After the ultrasonic treatment is completed, connect the glass tube to an inert gas environment filled with argon to exclude oxygen and other gases that may affect the reaction.

[0054] 2. Under this environment, the mixture in the sealed tube is thawed by three consecutive liquid nitrogen quick freezing-evacuation-thawing cycles. After each quick freezing, a 3-minute vacuum evacuation operation is immediately performed to remove dissolved gases and possible volatile by-products, and then the mixture is thawed. This cycle helps to further purify the reaction system.

[0055] Step 3: Sealing and high temperature reaction

[0056] 1. After completing the freezing-circulation vacuum cycle, immediately use an alcohol burner to seal the glass tube under vacuum to ensure that the reaction system remains airtight in the subsequent process.

[0057] 2. Place the sealed glass tube in an oven or heating device with a preset temperature of 120°C for a heating reaction for 3 days. This stage is intended to promote the polymerization reaction between the raw materials to form the target product.

[0058] Step 4: Product separation and purification

[0059] 1. After the reaction is completed, wait for the glass tube to cool to room temperature and perform suction filtration under vacuum conditions to separate the solid product and the remaining solvent and unreacted substances.

[0060] 2. Use appropriate amounts of tetrahydrofuran and 1,4-dioxane as washing solvents to repeatedly wash the product to remove impurities and residual solvents attached to the surface.

[0061] Finally, the washed product was placed in a desiccator and dried naturally at room temperature to a constant weight, thereby obtaining the final target product (as shown in Table 2).

[0062] Example 1

[0063] The preparation methods of a series of homocysteine ​​responsive scavenging systems based on COFs are as follows:

[0064] (1) 0.05 mmol of aldehyde skeleton monomer (as shown in Table 1) and 0.1 mmol of cystamine dihydrochloride or selenocystamine dihydrochloride were added to a glass sealed tube, followed by 1 ml of mesitylene and 1 ml of 1,4-dioxane, followed by ultrasonication for 30 minutes, followed by the addition of 0.55 ml of glacial acetic acid (or 0.35 ml of trifluoroacetic acid and 0.15 ml of trifluoroacetic acid) and continued ultrasonication for 15 minutes.

[0065] (2) After the ultrasound was completed, three cycles of liquid nitrogen quick freezing-vacuum pumping for 3 minutes-thawing were performed in an argon environment.

[0066] (3) The glass tube was sealed using an alcohol burner while vacuum evacuating, and then reacted at 120°C for 3 days.

[0067] (4) After the reaction is completed, vacuum filtration is performed, and the product is repeatedly washed with tetrahydrofuran and 1,4-dioxane and then dried to obtain the final product (as shown in Table 2).

[0068] (5) Use X-ray diffraction (XRD) to analyze the crystal structure of the material (such as Figure 1 shown).

[0069] Example 2

[0070] The in vitro performance evaluation methods of a series of COFs-based homocysteine ​​responsive removal systems are as follows:

[0071] (1) In accordance with clinical ethics requirements, after signing the relevant informed consent documents, blood samples with high homocysteine ​​levels were obtained from patients with depression. After coagulation, the samples were centrifuged at 3000 rpm / min for 15 minutes, and the supernatant was collected to obtain the patient serum samples.

[0072] (2) 200 μl of blood sample and 0.4 mg of a series of COFs materials (as shown in Table 2) were added to a centrifuge tube to make the material concentration 2 mg / ml. No material was added to the control group. After thorough mixing, the tube was incubated at 37°C for 2 h, followed by centrifugation at 14,000 rpm / min for 10 min to separate the material precipitate and collect the supernatant.

[0073] (3) The homocysteine ​​content in the supernatant of each group was detected using an ELISA kit, and the cysteine ​​content in the supernatant of each group was detected using a phosphotungstic acid reduction method to screen for groups with high sensitivity and specificity for homocysteine ​​removal (e.g. Figure 2 As shown in the figure, it was observed that each COFs material had a good scavenging effect on homocysteine, but had no obvious effect on cysteine; at the same time, it was also found that 4T1-S-COF, 4T1-Se-COF, 4Tp-S-COF, and 4Tp-Se-COF had a higher scavenging effect on homocysteine.

[0074] Example 3

[0075] Figure 3 The experimental operation process is as follows:

[0076] Mice were injected with 20 mg / ml 4T1-S-COF, 4T1-Se-COF, 4Tp-S-COF, and 4Tp-Se-COF through the tail vein, and the control group was injected with an equal amount of saline. After 24 hours of observation, the brain, heart, liver, spleen, lung, and kidney of the mice were obtained for H&E staining to detect the biosafety of the materials. Figure 3 It can be clearly seen that each group of materials has no pathological damage to major organs such as the brain (B), heart (H), liver (L), spleen (S), lung (Lu), and kidney (K), and has high biosafety.

[0077] Example 4

[0078] Figure 4 The experimental operation process is as follows:

[0079] After the mice in each group were injected with 20 mg / ml of 4T1-S-COF, 4T1-Se-COF, 4Tp-S-COF, and 4Tp-Se-COF through the tail vein (the control group was injected with the same amount of normal saline), the social defeat stress model of mice was established. Figure 4 The protective effect of COFs on anxiety-depression-like behaviors in mice was detected (as shown). The results showed that COFs intervention could significantly increase the time mice stayed in the open arms and reduce the time they stayed in the closed arms in the cross-elevation test, thus improving the anxiety-depression-like behaviors of mice caused by social frustration stress.

[0080] Example 5

[0081] Figure 5 The experimental operation process is as follows:

[0082] After the mice in each group were injected with 20 mg / ml of 4T1-S-COF, 4T1-Se-COF, 4Tp-S-COF, and 4Tp-Se-COF through the tail vein (the control group was injected with the same amount of saline), the social defeat stress model of mice was established. Figure 5 The protective effect of COFs on anxiety-depression-like behaviors in mice was detected (shown in Figure 2). The results showed that COFs intervention could significantly increase the time mice stayed in the central area and the number of crossings in the open field test, and improve the anxiety-depression-like behaviors of mice caused by social frustration stress.

[0083] Example 6

[0084] Figure 6 The experimental operation process is as follows:

[0085] The mice in each group were injected with 20 mg / ml of 4T1-S-COF, 4T1-Se-COF, 4Tp-S-COF, and 4Tp-Se-COF through the tail vein (the control group was injected with an equal amount of saline), and the social defeat stress model was established in mice. Then, the serum of mice was collected to detect the levels of cortisol, homocysteine, and hydrogen sulfide (such as Figure 6 The results showed that COFs intervention could significantly counteract the increase of serum cortisol in mice caused by social frustration stress and relieve the stress state of mice. COFs intervention could also improve the increase of serum homocysteine ​​level in mice caused by anxiety and depression, but had no significant effect on the beneficial amino acid cysteine ​​that the body normally needs.

[0086] The above animal experimental results show that the series of homocysteine ​​responsive removal systems based on COFs described in this application not only play a highly sensitive and highly specific homocysteine ​​removal effect in human blood samples in vitro, but also can play a role in removing homocysteine ​​and improving anxiety, depression and stress in mouse animal models with elevated homocysteine ​​such as depression. The series of homocysteine ​​responsive removal systems based on COFs described in this application have realized for the first time a scavenging treatment strategy for homocysteine, a high-risk factor in the blood, and its therapeutic effectiveness has been confirmed in both in vitro and in vivo experiments. In addition, the system is low in cost and easy to prepare. Most importantly, it has a rapid, efficient, specific removal of blood homocysteine ​​and excellent biosafety, providing a new and efficient treatment strategy for diseases with elevated homocysteine ​​such as depression.

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Claims

1. A series of homocysteine ​​responsive removal systems, which are COFs materials mainly obtained by reacting substances containing cystamine and / or selenocystamine with multi-aldehyde monomers through Schiff base reaction, wherein the multi-aldehyde monomers contain more than 3 aldehyde groups and have a benzene ring as the skeleton.

2. The method for preparing the removal system according to claim 1, characterized in that: The substance containing cystamine and / or selenocystamine is reacted with a multi-aldehyde monomer at a temperature of 100° C. to 160° C. by a solvent thermal method for 2 to 7 days.

3. The method for preparing the removal system according to claim 1, characterized in that: The molar ratio of the polyaldehyde monomer to the substance containing cystamine and / or selenocystamine is 1:1 to 1:5, preferably 1:

2.

4. The method for preparing the removal system according to claim 1, characterized in that: The substance containing cystamine and / or selenocystamine includes at least one of cystamine or its salt or homologues thereof, and selenocystamine or its salt or homologues thereof.

5. The method for preparing the removal system according to claim 1, characterized in that: The solvent includes at least one of mesitylene, 1,4-dioxane, n-butanol, o-dichlorobenzene, acetonitrile, dimethylformamide, dimethylacetamide, and acetone, preferably mesitylene and 1,4-dioxane.

6. The scavenging system according to claim 1 or obtained by the preparation method according to any one of claims 2 to 5 has a responsive binding application with homocysteine.

7. The use according to claim 6, characterized in that The removal system can specifically remove homocysteine ​​in a liquid environment, but has no significant removal effect on its analog cysteine.

8. Use of the scavenging system according to claim 1 or obtained by the preparation method according to any one of claims 2 to 5 in the preparation of health products, foods or medicines for preventing, improving or treating hyperhomocysteinemia.

9. Use of the scavenging system according to claim 1 or obtained by the preparation method according to any one of claims 2 to 5 in the preparation of health products, foods or medicines for preventing, improving or treating cardiovascular and cerebrovascular diseases and mental and psychological diseases.

10. The use according to claim 9, characterized in that The medicine for treating mental illness is an antidepressant.

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