A series of homocysteine-responsive scavenging systems, methods of making and uses thereof

Abstract

The application discloses a series of homocysteine responsive scavenging systems, which are obtained by Schiff base reaction of a material containing cystamine and / or selenocystamine and a polyaldehyde monomer. The series of homocysteine responsive scavenging systems have high stability, can be uniformly and stably dispersed in an aqueous solution, and can specifically scavenge homocysteine which is highly expressed in patients with depression, so that rapid and stable blood risk factor scavenging is realized. The application exhibits rapid, efficient and specific homocysteine scavenging effect, while maintaining excellent biological safety, which is crucial for guaranteeing the safety of patients in the treatment process. Therefore, the COFs-based homocysteine responsive scavenging system is expected to become a new and efficient treatment method for treating depression and other homocysteine-related diseases, and bring revolutionary changes to the research and clinical practice in the related field.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of new materials and biomedical medicine, in particular to a series of homocysteine-responsive clearance systems, a preparation method and a use thereof. BACKGROUND

[0002] Covalent organic framework materials (Covalent Organic Frameworks, COFs) as a kind of porous material composed of organic structural units, due to its unique pore structure, large specific surface area, low density, high stability and easy to control function, etc. Significant advantages, in the field of materials science and chemistry has been widely concerned, and was listed as one of the hot research directions in the field of chemistry by the American Chemical Society. Since 2005, Omar M. Yaghi group of University of California at Berkeley first reported COF-1, the preparation and application of COFs materials has entered a stage of rapid development, and has become a research hotspot .

[0003] Because COFs are constructed from organic raw materials, they have a series of unique characteristics. First, COFs have unique designability, which is one of the most significant differences between them and 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 requirements of different fields. Second, COFs have chemical uniqueness. Through the reversible covalent bond connection controlled by thermodynamics, materials with crystal structure can be obtained. This crystal 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 regular pore structure, structural diversity and easy functionalization. These characteristics make COFs have wide application prospects in gas adsorption and separation, catalysis, optoelectronics and other fields .

[0004] Depression has become a common disease worldwide, and social frustration is one of the main causes of depression. With the acceleration of people's life rhythm and the increase of social pressure, social frustration causes anxiety, depression and other mental illnesses to gradually increase. Social defeat stress is a social pressure mode based on the subordinate relationship between species, which causes emotional and mental stress in the defeated individual, leading to social avoidance, emotional depression, anxiety, lack of pleasure, reduced cognitive function and a series of diseases. The occurrence of social defeat stress is often accompanied by alcohol and drug abuse, which seriously affects the quality of life of patients, and brings heavy burden to families and society .

[0005] Homocysteine (Hcy) is a sulfur-containing amino acid, which is an important intermediate product in the metabolism of methionine and cysteine. When its detection value is greater than or equal to 10 micromole / liter, it is clinically referred to as "hyperhomocysteinemia" (high Hcy). Plasma homocysteine levels are closely related to the severity of depression, not only a major clinical indicator for the diagnosis of depression, but also an important risk factor for myocardial infarction and stroke . Homocysteine can aggravate the depressive-like behavior induced by social isolation in old mice by inhibiting BDNF expression , and increase cortical excitability and exacerbate mechanical hyperalgesia and anxiety in a rat migraine model induced by nitroglycerin , and can also exacerbate Aβ-induced cECDR4 / 5-mediated brain endothelial cell apoptosis, blood-brain barrier dysfunction, and angiogenesis defects Folic acid is the main clinical drug for the treatment of homocysteine emia at present, however, its half-life in the body is short, and it is easily photolyzed by ultraviolet light in the skin , and long-term use can affect zinc ion absorption . Therefore, the development of more efficient and stable treatment systems is crucial for improving homocysteine and its complications.

[0006] Cystamine is a straight-chain aliphatic diamine composed of a disulfide bridge, which is oxidized from two cystamine residues and is closely related to the metabolism of coenzyme A in tissues. In the body, cystamine is rapidly converted into the neuroactive substance cystamine, and can also be metabolized into endogenous cellular components such as homocysteine, hypotaurine, and taurine . Cystamine / cystamine not only rescues the dopaminergic system and induces neurite outgrowth of dopaminergic cells, showing neurorestorative properties in animal models of Parkinson's disease , but also promotes brain-derived neurotrophic factor (BDNF) levels and TrkB phosphorylation in a mouse stroke model, enhancing neuronal progenitor cell proliferation, neuron survival, and plasticity through the BDNF / TrkB pathway In a severe depression mouse model, cystamine / cysteamine can increase the level of brain-derived neurotrophic factor (BDNF) in the brain and peripheral central. Selenocystamine is a selenium substitute of cystamine, selenium generally cannot form a pi bond, and its outer valence electron is looser than that of sulfur, so compared with sulfur, selenium is a stronger nucleophile and reacts with active oxygen faster. Selenocystamine not only has glutathione peroxidase-like activity, but also produces nitric oxide gas as a special coating on the coronary stent to reduce the risk of vascular infarction Therefore, by constructing a new biomaterial treatment system with cystamine / selenocystamine, a new strategy for neuroprotective treatment is expected to be realized. SUMMARY

[0007] The purpose of the present application is to provide a series of homocysteine-responsive clearance systems, a preparation method and uses thereof, which is a COFs material based on cystamine and / or selenocystamine, and can be further applied to homocysteine-responsive clearance. The present application is based on the stimulation responsiveness of cystamine / selenocystamine to homocysteine, and a series of new stimulus-responsive covalent organic framework materials are constructed with a variety of aldehyde-containing aggregation-induced emission / non-aggregation-induced emission groups as the skeleton. Through the specific clearance of homocysteine in blood circulation and the efficient protection of brain neurons, a new treatment strategy for social frustration stress and anxiety-prone depression-like behavior based on covalent organic framework materials is ultimately realized. Specifically, the technical solutions adopted by the present application are as follows:

[0008] Firstly, the series of homocysteine-responsive clearance systems of the present application are COFs materials obtained by Schiff base reaction of a substance containing cystamine and / or selenocystamine and a polyaldehyde monomer, wherein the polyaldehyde monomer contains more than 3 aldehyde groups and has a benzene ring as the skeleton.

[0009] Secondly, the present application also provides a preparation method of the series of homocysteine-responsive clearance systems, which is to react a substance containing cystamine and / or selenocystamine with a polyaldehyde monomer at a temperature of 100-160 DEG C for 2-7 days by a solvothermal method; preferably, the reaction is carried out at 120-140 DEG 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 1:1-1:5, 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 homologue, selenocystamine or its salt or homologue. Preferably, the salt of cystamine is its dihydrochloride, and the salt of selenocystamine is its dihydrochloride. Homologues of cystamine refer to substances containing a cystamine structure, and homologues of selenocystamine refer to substances containing a selenocystamine structure. The polyaldehyde monomer is an aldehyde monomer commonly used in the preparation of COFs, preferably containing 3 or more aldehyde groups with a benzene ring as the backbone, more preferably 3-6 aldehyde groups, and most preferably 3-4 aldehyde groups, including but not limited to 1,2,4,5-benzyltetraaldehyde (1T1), 3,3',5,5'-tetraaldehyde biphenyl (1T2), 1,1':4',1''-terphenyl]-3,3'',5,5''-tetracarboxaldehyde (1T3), 1,1':4',1”:4”,1”'-tetraphenyl At least one of the following: [quaternary ammonium salt]-3,3',5,5'-tetraacetaldehyde (1T4), pyromellitic triacetaldehyde (3T1), 1,3,5-tris(p-formylphenyl)benzene (3T2), 1,3,5-tris(4'-aldehyde[1,1'-biphenyl]-4-yl)benzene (3T3), tetraaldehyde tetrastyrene (4T1), tetra-(4-aldehyde-(1,1-biphenyl))ethylene (4T2), and 1,3,6,8-tetra(4-formylphenyl)pyrene (4Tp).

[0012] In the above-described method for preparing COFs materials, 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. Furthermore, the main peak value of the X-ray diffraction patterns of the series of homocysteine-responsive scavenging systems obtained in this invention in the 2Theta (2θ) angle range of 1~20° is before 12°.

[0013] Thirdly, the series of homocysteine-responsive scavenging systems obtained in this invention can be applied in conjunction with homocysteine ​​responses. Furthermore, these systems can be used to specifically remove homocysteine ​​from liquid environments, while showing no significant removal of its analogues, such as cysteine. The liquid environment includes plasma, blood, and body fluids. In particular, they can efficiently and specifically remove homocysteine ​​from blood.

[0014] Furthermore, the aforementioned series of homocysteine-responsive clearance systems can be used in the preparation of drugs for the prevention, improvement, or treatment of hyperhomocysteinemia.

[0015] Furthermore, the aforementioned series of homocysteine-responsive clearance systems can be used in the preparation of drugs for the prevention, improvement, or treatment of cardiovascular and cerebrovascular diseases and mental illnesses. Even further, the drug for treating mental illnesses is an antidepressant.

[0016] Furthermore, the aforementioned series of homocysteine-responsive clearance systems can improve anxiety- and depression-like behaviors in living animals while also increasing blood hydrogen sulfide levels. The biomedical applications of the aforementioned series of homocysteine-responsive clearance systems include intravenous injection and nasal drops.

[0017] This invention provides an innovative series of homocysteine-responsive clearance systems. This system ingeniously combines specific chemical structures with biological responsive mechanisms, offering a new strategy for interventions targeting high homocysteine ​​levels, particularly in the treatment of depression. Specifically, this invention has the following technical features:

[0018] 1. System Architecture and Components

[0019] Skeletal Groups: This invention employs a class of compounds containing aldehyde groups as skeletal groups, including but not limited to aggregation-induced emission (AIE) and non-aggregation-induced emission groups. Aggregation-induced emission groups can significantly enhance luminescence performance under specific conditions (such as aggregated state), which is helpful for in vivo and in vitro monitoring and tracking; while non-aggregation-induced emission groups may exhibit advantages in other aspects (such as solubility and stability).

[0020] Homocysteine ​​responsive groups: The core of this system lies in utilizing the disulfide (SS) or diselenyl (Se-Se) bonds in cystamine dihydrochloride and selenocystamine dihydrochloride as responsive groups. These bonds are stable under physiological conditions but can specifically react with homocysteine, thereby achieving homocysteine ​​scavenging. In particular, the diselenyl bond in selenocysteine ​​may have higher reactivity and selectivity than the disulfide bond, making it suitable for more efficient homocysteine ​​scavenging.

[0021] 2. Preparation method

[0022] The preparation process mainly involves a Schiff base chemical reaction between the aldehyde backbone group and cystamine dihydrochloride or selenocystamine dihydrochloride, forming 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 clearance of homocysteine: Patients with depression often have high homocysteine ​​levels, and high homocysteine ​​is a risk factor for various cardiovascular diseases. The clearance system of this invention can specifically identify and clear homocysteine ​​(Hcy), a high-risk factor for cardiovascular disease and depression, from the blood.

[0025] Rapid and stable: The responsive groups in the system can respond rapidly to the presence of homocysteine ​​and undergo chemical reactions, thereby achieving rapid clearance. Simultaneously, the system's stability ensures long-term effectiveness in complex biological environments.

[0026] Biocompatibility and monitoring: Some skeletal groups have AIE properties, making the system easy to track and monitor in vivo or in vitro experiments, which helps to assess clearance effects and adjust treatment plans.

[0027] Potential Clinical Applications: Based on the above advantages, the homocysteine-responsive clearance system of this invention holds promise as an adjunctive treatment for hyperhomocysteinemia, offering new possibilities for improving patient prognosis.

[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] This invention discloses a series of homocysteine-responsive scavenging systems that specifically remove harmful homocysteine ​​from blood / serum samples and exert therapeutic effects in diseases with elevated homocysteine ​​levels, such as depression. The invention also provides a method for preparing these homocysteine-responsive scavenging systems, which can synthesize a series of COF-based homocysteine-responsive scavenging systems and exert therapeutic effects in animal models of hyperhomocysteinemia and depression. The homocysteine-responsive scavenging systems of this invention are prepared based on the Schiff base reaction and synthesized via a solvothermal method. The raw materials are aldehyde-containing backbone groups and cystamine dihydrochloride or selenocystamine dihydrochloride, as shown in Table 1. The homocysteine ​​scavenging groups are the disulfide / diselenobonds contained in cystamine dihydrochloride / selenocystamine dihydrochloride, and some of the aldehyde-containing backbone groups exhibit aggregation-induced emission properties (4T1, 4T2, and 4Tp). Table 1 lists the abbreviations, CAS numbers, full Chinese names, and full English names of aldehyde-containing backbone materials in a series of COF-based homocysteine ​​responsive scavenging systems.

[0030] Table 1

[0031]

[0032] The beneficial effects of this invention are as follows:

[0033] This application innovatively proposes a series of homocysteine-responsive scavenging systems based on covalent organic frameworks (COFs) (Table 2), demonstrating excellent potential for biomedical applications. These systems not only exhibited high sensitivity and specificity in clearing homocysteine ​​(Hcy) from human blood samples in in vitro experiments, but also demonstrated effective intervention in animal models of depression and other diseases caused by elevated Hcy levels in mouse models—a system more closely resembling the real physiological environment. Specifically, this system significantly reduced Hcy levels in mice, thereby improving their anxiety, depressive behaviors, and stress responses, providing a new perspective for understanding and treating these diseases. Table 2 provides a description of the raw materials and abbreviations of the products for a series of COF-based homocysteine-responsive scavenging systems.

[0034] Table 2

[0035]

[0036] Of particular note is the series of homocysteine-responsive clearance systems based on COFs described in this application. This pioneering treatment strategy directly targets high concentrations of homocysteine ​​in the blood, a potential risk factor, and is of significant importance in the biomedical field. Its therapeutic efficacy has been fully validated not only in in vitro experiments at the cellular or molecular level but also in complex in vivo biological environments (such as mouse models), further demonstrating its broad applicability and reliability.

[0037] Furthermore, the system's design fully considers cost-effectiveness and ease of preparation, ensuring its feasibility for large-scale application. More importantly, the system exhibits rapid, efficient, and specific homocysteine ​​clearance, effectively clearing Hcy in vitro in just 2 hours while maintaining excellent biosafety, which is crucial for ensuring patient safety during treatment. Therefore, this COFs-based homocysteine-responsive clearance system holds promise as a novel and highly effective treatment for homocysteine-related diseases such as depression, bringing revolutionary changes to research and clinical practice in related fields. Attached Figure Description

[0038] Figure 1 These are XRD crystal structure characterization diagrams of a series of homocysteine-responsive scavenging systems based on COFs.

[0039] Figure 2 It is a series of COF-based homocysteine-responsive clearance systems that achieve relative clearance ratios of homocysteine ​​and cysteine ​​in human blood.

[0040] Figure 3These are H&E staining images of major organs in mice after injection with 4T1-S-COF, 4T1-Se-COF, 4Tp-S-COF, and 4Tp-Se-COF, with a scale bar of 200 μm.

[0041] Figure 4 The study investigated the effects of 4T1-S-COF, 4T1-Se-COF, 4Tp-S-COF, and 4Tp-Se-COF treatments on improving anxiety-depressive-like behaviors in mice during the cruciate sac test.

[0042] Figure 5 The study investigated the effects of 4T1-S-COF, 4T1-Se-COF, 4Tp-S-COF, and 4Tp-Se-COF treatments on improving anxiety-depressive-like behaviors in mice during an open field experiment.

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

[0044] Figure 7 This is a schematic diagram illustrating the preparation mechanism of a series of COFs-based homocysteine-responsive scavenging systems. Detailed Implementation

[0045] Instruments and reagents

[0046] X-ray diffractometer (D8 Advance X-ray diffractometer (Bruker) with Cu Kα radiation, 40 kV, 40 mA, λ = 1.54051 Å); UV absorption spectroscopy (UV-1800, Mapada, China); thermogravimetric analysis (20-800 °C, PerkinElmer TG: DTA6300); infrared spectroscopy (Vector-22 spectrometer, Bruker); fluorescence spectroscopy (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 homocysteine-responsive scavenging systems based on COFs, as described in this invention, includes the following steps:

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

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

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

[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) dropwise to the system, and continue sonication for 15 minutes.

[0052] Step 2: Freezing-vacuum circulation treatment

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

[0054] 2. Under this environment, the mixture in the sealed tube was subjected to three consecutive cycles of liquid nitrogen rapid freezing-evacuation-thawing. Immediately after each rapid freezing, a 3-minute vacuum evacuation was performed to remove dissolved gases and any volatile byproducts that might be generated, followed by thawing of the mixture. This cycle helps to further purify the reaction system.

[0055] Step 3: Sealing and high-temperature reaction

[0056] 1. After completing the freeze-circulation and vacuum cycle, immediately use an alcohol torch to seal the glass tube under vacuum to ensure that the reaction system remains sealed in subsequent processes.

[0057] 2. Place the sealed glass tube in an oven or heating device at a preset temperature of 120℃ for a heating reaction lasting 3 days. This stage aims 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 complete, wait for the glass tube to cool to room temperature, and then perform a vacuum filtration operation to separate the solid product, the remaining solvent, and the 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 adhering to the surface.

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

[0062] Example 1

[0063] The following are methods for preparing a series of COF-based homocysteine-responsive scavenging systems:

[0064] (1) Add 0.05 mmol of aldehyde backbone monomer (as shown in Table 1) and 0.1 mmol of cystamine dihydrochloride or selenocystamine dihydrochloride to a glass sealing tube, add 1 ml of trimethylbenzene and 1 ml of 1,4-dioxane, and sonicate for 30 minutes. Then add 0.55 ml of glacial acetic acid (or 0.35 ml of trifluoroacetic acid and 0.15 ml of trifluoroacetic acid) and continue sonicating for 15 minutes.

[0065] (2) After the ultrasound, the liquid nitrogen quick-freezing-vacuum pumping for 3 minutes-thawing cycle was performed three times in an argon atmosphere.

[0066] (3) While vacuuming, seal the glass tube with an alcohol torch, and then react 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) Analyzing the crystal structure of materials using X-ray diffraction (XRD) (e.g.) Figure 1 (As shown).

[0069] Example 2

[0070] The following are methods for evaluating the in vitro performance of COF-based homocysteine-responsive scavenging systems:

[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's serum samples.

[0072] (2) Add 200 μl of blood sample and 0.4 mg of a series of COFs materials (as shown in Table 2) to a centrifuge tube to make the material concentration 2 mg / ml. No material was added to the control group. After thorough mixing, incubate at 37°C for 2 hours, then centrifuge at 14000 rpm / min for 10 minutes 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 homocysteine ​​content in the supernatant of each group was detected using the phosphotungstic acid reduction method. Groups with high sensitivity and specificity for homocysteine ​​clearance were screened (e.g., Figure 2 As shown in the figure, it was observed that each COF material had a good scavenging effect on homocysteine, but no significant 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 high scavenging effect on homocysteine.

[0074] Example 3

[0075] Figure 3 The experimental procedure is as follows:

[0076] Mice were injected intravenously with 20 mg / ml of 4T1-S-COF, 4T1-Se-COF, 4Tp-S-COF, and 4Tp-Se-COF, respectively, while the control group was injected with an equal volume of physiological saline. After 24 hours of observation, mouse brains, hearts, livers, spleens, lungs, and kidneys were collected for H&E staining to assess the biocompatibility of the materials. Figure 3 It is evident from the results that each group of materials did not cause pathological damage to major organs such as the brain (B), heart (H), liver (L), spleen (S), lungs (Lu), and kidneys (K), demonstrating high biocompatibility.

[0077] Example 4

[0078] Figure 4 The experimental procedure is as follows:

[0079] Mice in each group were injected intravenously with 20 mg / ml of 4T1-S-COF, 4T1-Se-COF, 4Tp-S-COF, and 4Tp-Se-COF (the control group received an equal volume of saline) to establish a mouse model of social frustration stress. The cruciate pedestal test (e.g., Figure 4 (As shown) The protective effect of COFs on anxiety-depression-like behavior in mice was examined. The results showed that COF intervention significantly increased the time mice spent in the open arm and decreased the time spent in the closed arm in the cruciate trek test, thus improving anxiety-depression-like behavior induced by social frustration in mice.

[0080] Example 5

[0081] Figure 5 The experimental procedure is as follows:

[0082] Mice in each group were injected intravenously with 20 mg / ml of 4T1-S-COF, 4T1-Se-COF, 4Tp-S-COF, and 4Tp-Se-COF (the control group received an equal volume of saline) to establish a mouse model of social frustration stress. The open field test (e.g., ...) was then used to assess the stress. Figure 5 (As shown) The protective effect of COFs on anxiety-depression-like behavior in mice was examined. The results showed that COF intervention significantly increased the time mice spent in the central region and the number of crossings in the open field test, and improved anxiety-depression-like behavior induced by social frustration stress in mice.

[0083] Example 6

[0084] Figure 6 The experimental procedure is as follows:

[0085] Mice in each group were injected intravenously with 20 mg / ml of 4T1-S-COF, 4T1-Se-COF, 4Tp-S-COF, and 4Tp-Se-COF (the control group received an equal volume of saline) to establish a mouse model of social frustration. Subsequently, serum samples were collected to measure the levels of cortisol, homocysteine, and hydrogen sulfide (e.g.,...). Figure 6 (As shown in the image). The results showed that COF intervention could significantly counteract the increase in serum cortisol induced by social frustration stress in mice and alleviate the stress state in mice. COF intervention could also improve the increase in serum homocysteine ​​levels in mice induced by anxiety and depression, but had no significant effect on homocysteine, a beneficial amino acid required by the body.

[0086] The above animal experimental results demonstrate that the series of COF-based homocysteine-responsive clearance systems described in this application not only exhibit highly sensitive and specific homocysteine ​​clearance in human blood samples in vitro, but also demonstrate homocysteine ​​clearance, improvement of anxiety and depression behaviors, and stress reduction in mouse animal models of elevated homocysteine ​​levels, such as depression. This series of COF-based homocysteine-responsive clearance systems represents the first realization of a clearance treatment strategy targeting high-risk homocysteine ​​levels in the blood, and its therapeutic efficacy has been confirmed in both in vitro and in vivo experiments. Furthermore, this system is low-cost, easy to prepare, and most importantly, possesses rapid, efficient, and specific homocysteine ​​clearance effects with excellent biosafety, providing a new and highly effective treatment strategy for diseases with elevated homocysteine ​​levels, such as depression.

[0087] References:

[0088] [1] COTE A P, BENIN A I, OCKWIG N W, et al. Porous, crystalline,covalent organic frameworks [J]. Science, 2005, 310(5751): 1166-70.

[0089] [2] SHI Y, YANG J, GAO F, et al. Covalent Organic Frameworks: RecentProgress in Biomedical Applications [J]. ACS Nano, 2023, 17(3): 1879-905.

[0090] [3] NEWMAN E L, LEONARD M Z, ARENA D T, et al. Social defeat stressand escalation of cocaine and alcohol consumption: Focus on CRF [J].Neurobiol Stress, 2018, 9: 151-65.

[0091] [4]WU D-F, YIN R-X, DENG J-L. Homocysteine, hyperhomocysteinemia andH-type hypertension [J]. Eur J Prev Cardiol, 2024.

[0092] [5]WEI M D, HUANG Y Y, ZENG Y, et al. Homocysteine Modulates SocialIsolation-Induced Depressive-Like Behaviors Through BDNF in Aged Mice [J].Mol Neurobiol, 2023, 60(9): 4924-34.

[0093] [6]GERASIMOVA E, YAKOVLEVA O, ENIKEEV D, et al. HyperhomocysteinemiaIncreases Cortical Excitability and Aggravates Mechanical Hyperalgesia andAnxiety in a Nitroglycerine-Induced Migraine Model in Rats [J]. Biomolecules,2022, 12(5).

[0094] [7]CAREY A, PARODI-RULLAN R, VAZQUEZ-TORRES R, et al. Homocysteinepotentiates amyloid -induced death receptor 4- and 5-mediated cerebralendothelial cell apoptosis, blood brain barrier dysfunction and angiogenicimpairment [J]. Aging Cell, 2024: e14106.

[0095] [8]LIWINSKI T, LANG U E. Folate and Its Significance in DepressiveDisorders and Suicidality: A Comprehensive Narrative Review [J]. Nutrients,2023, 15(17).

[0096] [9]TANG J S, CAIT A, WHITE R M, et al. MR1-dependence ofunmetabolized folic acid side-effects [J]. Front Immunol, 2022, 13: 946713.

[0097]

[10] CHIPLONKAR S A, AGTE V V. Predicting bioavailable zinc from lowerphytate forms, folic Acid and their interactions with zinc in vegetarianmeals [J]. J Am Coll Nutr, 2006, 25(1): 26-33.

[0098]

[11] GIBRAT C, CICCHETTI F. Potential of cystamine and cysteamine inthe treatment of neurodegenerative diseases [J]. Prog Neuro-PsychopharmacolBiol Psychiatry, 2011, 35(2): 380-9.

[0099]

[12] CISBANI G, DROUIN-OUELLET J, GIBRAT C, et al. Cystamine / cysteamine rescues the dopaminergic system and shows neurorestorativeproperties in an animal model of Parkinson's disease [J]. Neurobiol Dis,2015, 82: 430-44.

[0100]

[13] LI P-C, JIAO Y, DING J, et al. Cystamine improves functionalrecovery via axon remodeling and neuroprotection after stroke in mice [J].CNS Neurosci Ther, 2015, 21(3): 231-40.

[0101]

[14] PáLLA T, MIRZAHOSSEINI A, NOSZáL B. Properties of Selenolate-Diselenide Redox Equilibria in View of Their Thiolate-Disulfide Counterparts[J]. Antioxidants (Basel), 2023, 12(4).

Claims

1. A homocysteine-responsive scavenging material, which is a COF material obtained by reacting cystamine and / or selenocystamine with a polyaldehyde monomer via a Schiff base reaction, wherein the polyaldehyde monomer is at least one of tetraaldehyde tetraphenylethylene and 1,3,6,8-tetra(4-formylphenyl)pyrene.

2. The method for preparing the cleaning material according to claim 1, characterized in that, Cystamine and / or selenocystamine are reacted with polyaldehyde monomers at a temperature of 100℃~160℃ for 2~7 days using a solvothermal method.

3. The method for preparing the cleaning material as described in claim 2, characterized in that, The molar ratio of the polyaldehyde monomer to cystamine and / or selenocystamine is 1:1 to 1:

5.

4. The method for preparing the cleaning material as described in claim 3, characterized in that, The molar ratio of the polyaldehyde monomer to cystamine and / or selenocystamine is 1:

2.

5. The method for preparing the cleaning material as described in claim 2, characterized in that, The cystamine and / or selenocystamine include at least one of cystamine or its salts, selenocystamine or its salts.

6. The method for preparing the scavenging system as described in claim 2, characterized in that, The solvent includes at least one of the following: mesitylene, 1,4-dioxane, n-butanol, o-dichlorobenzene, acetonitrile, dimethylformamide, dimethylacetamide, and acetone.

7. The method for preparing the cleaning material as described in claim 6, characterized in that, The solvent is mesitylene and 1,4-dioxane.

8. The use of the scavenging material according to claim 1 or obtained by any one of claims 2-7 in the preparation of a medicament for the prevention, improvement or treatment of hyperhomocysteinemia.

9. The use of the scavenging material according to claim 1 or obtained by any one of claims 2-7 in the preparation of a medicament for the prevention, improvement or treatment of depression.

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