Metal ion-carboxylic acid ligand molecule self-assembled nano-drug, injection as well as preparation method and application of metal ion-carboxylic acid ligand molecule self-assembled nano-drug

Abstract

The invention relates to a metal ion-carboxylic acid ligand molecule self-assembled nano-drug, an injection as well as a preparation method and application of the metal ion-carboxylic acid ligand molecule self-assembled nano-drug. The metal ion-carboxylic acid ligand molecule self-assembled nano-drug comprises a metal ion located at the center and a carboxylic acid ligand molecule linked with the metal ion through a coordinate bond, wherein the metal ions comprise at least one of Zn < 2 + >, Ce < 2 + >, Ce < 3 + >, Ce < 4 + >, Mn < 2 + > and Fe < 2 + >; the carboxylic acid ligand molecule comprises itaconic acid, fumaric acid, aconitic acid, citric acid or tricarboxylic acid.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical materials, and particularly relates to a metal ion-carboxylic acid ligand molecular self-assembled nano-drug, an injection, and their preparation methods and applications. Background Art

[0002] Itaconic acid (IA) is a metabolite catalyzed by an enzyme encoded by the immunity-related GTPase M (Irg1) in the mitochondrial matrix. In recent years, it has been widely regarded as an important immunometabolic regulator. Studies have shown that itaconic acid is significantly upregulated in immune cells (such as macrophages) and has multiple biological activities in aspects such as anti-inflammation, antioxidant, metabolic regulation, and antibacterial. These properties make it show great potential in the treatment of inflammatory diseases, metabolic disorders, and infectious diseases.

[0003] Although itaconic acid shows significant therapeutic effects in animal models and in vitro experiments, its clinical application is still in the exploratory stage. First of all, as a small molecule metabolite, itaconic acid is easily metabolized and cleared in the body, which may lead to insufficient local concentration or off-target effects due to systemic distribution. Therefore, developing efficient delivery systems (such as nanoparticles, liposomes, or cell-based delivery strategies) to enhance the targeting and stability of itaconic acid is one of the key points for future research. In addition, the biosafety and potential toxic side effects of itaconic acid still need to be comprehensively evaluated. Although animal models and in vitro experiments show its good biocompatibility, in the complex human environment, itaconic acid may have unpredictable effects on normal cell metabolism, immune homeostasis, or the microbiome. Therefore, future research should comprehensively evaluate its biological effects by combining multi-omics technologies and verify its safety and effectiveness through rigorous clinical trials. Therefore, how to improve the specific delivery of itaconic acid, optimize its pharmacokinetic properties, and verify its effectiveness and safety in the human body are the key issues to be urgently solved in future research and translational medicine. Future research should focus on developing efficient delivery systems, exploring the in-depth details of its mechanism of action, and verifying its therapeutic potential through clinical trials, so as to provide new treatment strategies for inflammatory diseases, metabolic diseases, and infectious diseases.

[0004] Transition metals play extremely important roles in modern chemical and biomedical research. Transition metals (such as iron, copper, manganese, etc.) and endogenous metal ions in the human body (such as zinc, magnesium, etc.) exhibit important application values in the fields of drug delivery and disease treatment due to their unique coordination abilities, redox properties, and catalytic activities. Metal ions not only play roles through catalytic reactions (such as the Fenton reaction), but also can achieve therapeutic purposes by regulating cell metabolism, immune responses, and signal pathways. For example, iron ions play a key role in regulating ferroptosis, copper ions can inhibit tumor progression by suppressing angiogenesis and regulating the functions of immune cells, while zinc ions play important roles in anti-inflammatory and antibacterial processes. In addition, manganese ions can enhance host defense capabilities by activating immune cells (such as macrophages). The multiple functions of these metal ions endow them with broad application potentials in tumor treatment, inflammatory diseases, infectious diseases, and neurodegenerative diseases.

[0005] Although transition metals and endogenous metal ions show significant advantages in drug delivery and treatment, their applications still face some challenges. For example, the non-specific distribution of metal ions may lead to off-target effects and toxicity, and their stability in complex biological environments also needs to be further optimized. Therefore, future research should focus on developing more efficient metal-based delivery systems, such as metal-organic frameworks (MOFs), transition metal coordination polymers, and metal ion-based nanoparticles. These materials can efficiently encapsulate drugs and achieve controlled release. By surface-modifying targeting ligands (such as antibodies, peptides, or aptamers) or designing stimulus-responsive materials (such as pH, redox, or enzyme-sensitive materials), these systems can achieve precise drug delivery, realizing long circulation and controlled release effects, thereby improving the therapeutic effect and reducing side effects. Summary of the Invention

[0006] Aiming at the above technical problems, the purpose of the present invention is to provide a nano-drug carrier material, an injection, and their preparation methods and applications that can increase the specific targeting, long circulation time, controlled release, and high biocompatibility of small molecule drugs.

[0007] In the first aspect, the present invention provides a metal ion-carboxylic acid ligand molecule self-assembled nano-drug, and the metal ion-carboxylic acid ligand molecule self-assembled nano-drug includes: a metal ion located at the center, and carboxylic acid ligand molecules linked to the metal ion through coordination bonds; Wherein: the metal ion includes Zn 2+ , Ce 2+ , Ce 3+ , Ce 4+ , Mn 2+ and Fe 2+ at least one of them; the carboxylic acid ligand molecules include itaconic acid, fumaric acid, aconitic acid, citric acid, or tricarboxylic acid.

[0008] Preferably, the particles of the metal ion-carboxylic acid ligand molecular self-assembled nano-drug have a spherical morphology, and the average particle size is 2-4 nm.

[0009] Preferably, the mass ratio of the metal ion in the metal ion-carboxylic acid ligand molecular self-assembled nano-drug is 5-10 wt%, and the mass ratio of the carboxylic acid ligand molecule is 40-95 wt%, preferably 90-95 wt%.

[0010] Preferably, the particle structure of the metal ion-carboxylic acid ligand molecular self-assembled nano-drug is amorphous.

[0011] Preferably, the metal ion-carboxylic acid ligand molecular self-assembled nano-drug has stability in the aqueous phase and physiological environment.

[0012] Preferably, the metal ion-carboxylic acid ligand molecular self-assembled nano-drug has the catalytic activity of scavenging reactive oxygen species.

[0013] In a second aspect, the present invention provides a preparation method of the above-mentioned metal ion-carboxylic acid ligand molecular self-assembled nano-drug, and the preparation method includes: adding a metal salt solution to a carboxylic acid ligand molecule solution and mixing, and maintaining condensation reflux; then, after washing and drying, the metal ion-carboxylic acid ligand molecular self-assembled nano-drug is obtained.

[0014] Preferably, the metal salt is an acetate of a metal ion; the concentration of the metal salt solution is 5-20 mg / mL.

[0015] Preferably, the concentration of the carboxylic acid ligand molecule solution is 10-25 mg / mL.

[0016] Preferably, the molar ratio of the carboxylic acid ligand molecule to the metal salt is 1:(1-1.5), preferably 1:1.

[0017] Preferably, the parameters of the condensation reflux include: rotation speed 300-400 rpm, temperature 110-125 °C, time 4-5 h; The washing liquid used for the washing is a mixed solution of water and ethanol, and the number of washing times is 2-3 times; The drying method is vacuum freeze-drying, the temperature is -90 to -70 °C, and the time is 6-12 h.

[0018] In a third aspect, the present invention provides an injection of the above-mentioned metal ion-carboxylic acid ligand molecular self-assembled nano-drug, and the injection of the metal ion-carboxylic acid ligand molecular self-assembled nano-drug includes: a biocompatible solution, and the above-mentioned metal ion-carboxylic acid ligand molecular self-assembled nano-drug dispersed in the biocompatible solution.

[0019] Preferably, the biocompatible solution is at least one of normal saline and phosphate buffer solution; The concentration of the metal ion-carboxylic acid ligand molecule self-assembled nano-drug in the injection solution is 10-40 mg / mL.

[0020] Fourthly, the present invention provides an application of the above-mentioned metal ion-carboxylic acid ligand molecule self-assembled nano-drug or the metal ion-carboxylic acid ligand molecule self-assembled nano-drug injection solution in the preparation of a drug for treating or preventing oxidative stress-related diseases.

[0021] Preferably, the oxidative stress-related diseases include neurodegenerative diseases, cardiovascular diseases, diabetes and its complications, inflammatory diseases, cancer or aging-related diseases.

[0022] Preferably, the oxidative stress-related disease can be kidney injury caused by platinum-based chemotherapeutic drugs.

[0023] Beneficial effects (1) The preparation process of the present invention is simple, pollution-free, high-yield, low-cost, easy for mass production. The obtained nano-drug material has good stability, high specific surface area, which is beneficial for the drug to penetrate various biological barriers, and can specifically and effectively accumulate at the lesion site, release controllably, and produce good therapeutic effects. It is one of the most promising treatment options for inflammatory lesions; (2) The metal ion-carboxylic acid ligand molecule self-assembled nano-drug material provided by the present invention can reach the inflammatory lesion site, respond and release metal ions and carboxylic acid ligand molecules such as itaconic acid, respectively play their specific biological functions, and reduce the production of ROS such as hydroxyl radicals and superoxide anions, thereby alleviating the damage to cells and achieving the effect of synergistically protecting cell damage; (3) The self-assembled nanoparticles provided by the present invention have an amorphous property, and have a faster degradation and release effect than crystalline materials (such as metal-organic framework nanoparticles). Description of the drawings

[0024] Figure 1 It is the TEM image of the itaconic acid cerium (IA-Ce) self-assembled nano-drug prepared in Example 1; Figure 2 It is the Mapping element distribution diagram and EDS energy spectrum analysis diagram of the IA-Ce self-assembled nano-drug prepared in Example 1; Figure 3 It is the XRD pattern of the IA-Ce self-assembled nano-drug prepared in Example 1; Figure 4 It is the Zeta potential analysis diagram of the IA-Ce self-assembled nano-drug prepared in Example 1; Figure 5FT-IR spectrum of the IA-Ce self-assembled nano-drug prepared in Example 1; Figure 6 XPS spectrum of the IA-Ce self-assembled nano-drug prepared in Example 1; Figure 7 Thermogravimetric curve of the IA-Ce self-assembled nano-drug prepared in Example 1; Figure 8 ESR test chart of the reaction scavenging system of the IA-Ce self-assembled nano-drug prepared in Example 1 with hydroxyl radicals; Figure 9 TEM image of the itaconic acid zinc (IA-Zn) self-assembled nano-drug prepared in Example 2; Figure 10 Mapping elemental distribution chart and EDS energy spectrum analysis chart of the IA-Zn self-assembled nano-drug prepared in Example 2; Figure 11 XRD pattern of the IA-Zn self-assembled nano-drug prepared in Example 2; Figure 12 Zeta potential analysis chart of the IA-Zn self-assembled nano-drug prepared in Example 2; Figure 13 FT-IR analysis chart of the IA-Zn self-assembled nano-drug prepared in Example 2; Figure 14 XPS spectrum of the IA-Zn self-assembled nano-drug prepared in Example 2; Figure 15 Thermogravimetric curve of the IA-Zn self-assembled nano-drug prepared in Example 2; Figure 16 ESR test chart of the reaction scavenging system of the IA-Zn self-assembled nano-drug prepared in Example 2 with hydroxyl radicals; Figure 17 TEM image of the drug material prepared in Comparative Example 1; Figure 18 TEM image of the IA-Zn self-assembled nano-drug prepared in Example 3; Figure 19 TEM image of the drug material prepared in Comparative Example 2; Figure 20 TEM image of the drug material prepared in Comparative Example 3; Figure 21 TEM image of the IA-Ce self-assembled nano-drug prepared in Example 4; Figure 22 TEM image of the drug material prepared in Comparative Example 4; Figure 23 TEM image of the drug material prepared in Comparative Example 5; Figure 24 TEM image of the drug material prepared in Comparative Example 6; Figure 25 TEM image of the drug material prepared in Comparative Example 7; Figure 26 Schematic diagram of the total SOD activity detection results of the IA-Ce self-assembled nano-drug prepared in Example 1; Figure 27 Cell viability of HK-2 cells after incubation with different concentrations of IA-Ce nano-drug for 24 hours and 48 hours respectively in the in vitro safety experiment of the IA-Ce self-assembled nano-drug prepared in Example 1; Figure 28 Cell viability of HK-2 cells after co-incubation with different concentrations of cisplatin (DDP) (100, 50, 25, 12.5, 6.25, 3.2 μM) for 12 hours and 24 hours respectively in the cytotoxicity experiment of the chemotherapeutic drug cisplatin DDP on HK-2 cells; Figure 29 Inhibitory effect of different concentrations of IA-Ce nano-materials on the toxic effect of cisplatin after 24 hours in the in vitro chemotherapeutic effect protection ability experiment of the IA-Ce self-assembled nano-drug prepared in Example 1; Figure 30 Curve of body weight change of mice in different treatment groups during 30 days in the safety evaluation experiment of the IA-Ce self-assembled nano-drug prepared in Example 1 on animal body weight in the long term (30 days); Figure 31 Blood routine and blood biochemical data of mice in different treatment groups after 30 days in the safety evaluation experiment of the IA-Ce self-assembled nano-drug prepared in Example 1 on animal blood under long-term treatment; Figure 32 HE sections of the main organs (heart, liver, spleen, lung, kidney) of mice in different treatment groups after 30 days in the safety evaluation experiment of the IA-Ce self-assembled nano-drug prepared in Example 1 on the main organs of animals under long-term exposure; Detailed implementation manners

[0025] The present invention is further illustrated by the following implementation manners. It should be understood that the following implementation manners are only used to illustrate the present invention and do not limit the present invention.

[0026] First, the present invention provides a metal ion-carboxylic acid ligand molecule self-assembled nano-drug. Wherein, the particles of the metal ion-carboxylic acid ligand molecule self-assembled nano-drug may include: a metal ion located at the center, and carboxylic acid ligand molecules linked to the metal ion through coordination bonds.

[0027] In some embodiments, the metal ions may include Zn 2+ , Ce 2+ , Ce 3+ , Ce 4+ , Mn 2+ and Fe 2+ or at least one of them. The above-mentioned transition metal ions used in the present invention can form stable coordination bonds with carboxylic acid ligands (such as itaconic acid), thereby constructing stable MOFs or coordination polymers; at the same time, the complexes formed by the metal ions and carboxylic acids have good biocompatibility, functionality and stability.

[0028] In some embodiments, the carboxylic acid ligand molecules may include itaconic acid (IA), fumaric acid, aconitic acid, citric acid or tricarboxylic acid.

[0029] In some embodiments, the particle structure of the metal ion-carboxylic acid ligand molecule self-assembled nano-drug is amorphous; preferably, the particles of the metal ion-carboxylic acid ligand molecule self-assembled nano-drug have a spherical morphology, and the average particle size can be 2-4 nm; more preferably, the average particle size of cerium itaconate (IA-Ce) is 2-3 nm, and the average particle size of zinc itaconate (IA-Zn) is 3-4 nm.

[0030] Among them, the control and selection of the particle size of the nano-drug particles are mainly to balance the drug delivery efficiency, stability, clearance rate and targeting. Too small or too large particle size may have different effects on the performance and application of the drug. The particle size of this material is controlled within 2-4 nm, mainly based on its application requirements in the research of related diseases such as the kidney. Research shows that particles with a particle size less than 10 nm can reach the renal tubules through the glomerular basement membrane, particles with a particle size between 10-100 nm are likely to deposit in the glomeruli, and particles larger than 400 nm will enter the renal tubules through the peripheral blood vessels. Therefore, a particle size range of 2-4 nm can effectively achieve the targeted delivery of drugs in the kidney.

[0031] In some embodiments, the mass ratio of the metal ions in the metal ion-carboxylic acid ligand molecule self-assembled nano-drug may be 5-10 wt%, and the mass ratio of the carboxylic acid ligand molecules may be 40-95 wt%, preferably 90-95 wt%.

[0032] By controlling the mass ratio of metal ions to carboxylic acid ligand molecules within an appropriate range, the functions of metal ions (such as functions of drug carriers, catalysis, imaging, etc.) and the requirements for the stability and structural integrity of the ligands can be balanced. Carboxylic acid ligand molecules are usually used to form coordination bonds with metal ions to form stable nanostructures. A higher proportion of ligands helps to enhance stability and avoid the disordered accumulation or aggregation of metal ions; however, an excessive amount of ligand molecules will increase the drug loading capacity, but at the same time, it is likely to affect the coordination effect between the ligand and the metal ion, resulting in a decrease in the drug release efficiency or targeting property. At the same time, if the content of metal ions is too large, it will cause toxicity to cells or the human body and increase side effects; if the content of metal ions is too small, it will affect its functions such as drug delivery, imaging, and catalysis, and at the same time, it will affect the therapeutic effect of the drug and reduce its multifunctionality.

[0033] It should also be noted that the metal ion-carboxylic acid ligand molecule self-assembled nano-drug provided by the present invention also has the following functions: (1) Solubilization function: significantly improving the dissolution and absorption of poorly soluble drugs and increasing the bioavailability; (2) Protection and barrier function: reducing the degradation of drugs in vivo and in vitro and increasing the drug stability; (3) Controlled release function: enabling the drug to have different environment-responsive release characteristics by utilizing the differences in the types and properties of the carrier materials and combining specific preparation processes; (4) Sustained release function: slowly releasing the drug, changing the in vivo half-life of the drug, and prolonging the action time; (5) Long-circulation function: prolonging the exposure time of the drug in the systemic circulation through the modification of hydrophilic materials and enhancing the drug efficacy.

[0034] In some embodiments, the particle structure of the metal ion-carboxylic acid ligand molecule self-assembled nano-drug can be in an amorphous state; the metal ion-carboxylic acid ligand molecule self-assembled nano-drug has stability in an aqueous phase and a physiological environment.

[0035] In some embodiments, the metal ion-carboxylic acid ligand molecule self-assembled nano-drug has the catalytic activity of scavenging reactive oxygen species.

[0036] Hereinafter, an exemplary description will be given of the preparation method of the above-mentioned metal ion-carboxylic acid ligand molecule self-assembled nano-drug provided by the present invention. Among them, the preparation method may include the following steps: adding a metal salt solution to a carboxylic acid ligand molecule solution and mixing, while maintaining a cold reflux; then, after washing and drying, the metal ion-carboxylic acid ligand molecule self-assembled nano-drug is obtained.

[0037] In some embodiments, the metal salt can be an acetate of a metal ion; preferably, the concentration of the metal salt solution can be 5-20 mg / mL, and the solvent can be water, ethanol, phosphate buffer solution (PBS).

[0038] It should be noted that the metal salt will affect the synthesis, morphology, size, drug release and other properties of the self-assembled nano-drug. Selecting a suitable metal salt is crucial for the efficacy of the drug. For example, the morphology, size and dimensions of the drug synthesized with ammonium cerium nitrate are not suitable for the selection of disease models. Treating diseases such as kidney diseases requires the drug to be effectively targeted and delivered to the kidney area, and the size and morphology of the nanoparticles have an important impact on their distribution, penetration and targeting ability in the body. The nano-drug synthesized with acetate is more likely to obtain smaller and uniform particle sizes, which helps the drug to pass through the kidney barrier and accumulate at the kidney lesion site.

[0039] In some embodiments, the concentration of the carboxylic acid ligand molecule solution can be 10-25 mg / mL, and the solvent can be water, ethanol, phosphate buffer solution (PBS).

[0040] In some embodiments, the molar ratio of the carboxylic acid ligand molecule to the metal salt can be 1:(1-1.5), preferably 1:1. Under the condition of this molar ratio, a metal ion-carboxylic acid ligand molecule self-assembled nano-drug with better regular shape and uniform metal ion distribution can be formed.

[0041] If the molar ratio of the two is too large (i.e., the ligand is in excess), the following problems will occur: (1) Affecting the coordination effect: If the molar ratio of the ligand is too high (e.g., exceeding 1.5), there may be too many ligand molecules, and metal ions cannot be fully coordinated to the ligand, or some metal ions are occupied by the excess ligand, forming a non-uniform coordination environment. This will lead to uneven distribution of metal ions in the nanoparticles, affecting the stability and functionality of the nano-drug; (2) Irregular morphology: Excess ligand molecules may cause the morphology of the nanoparticles to be irregular or form larger particles instead of the expected uniform small particles. This is because too many ligands may hinder the aggregation or self-assembly process of metal ions, resulting in deviations in morphology and size; (3) Drug loading problem: Too many ligands may increase the carrier capacity of the nano-drug, but such excessive ligands may cause changes in the drug release rate or weaken the targeting to the target area, especially when there are specific requirements in the design of the drug carrier. If the molar ratio of the two is too small (i.e., the metal salt is in excess), the following problems will occur: (1) Affecting the coordination stability: If the molar ratio of the metal salt is too large (e.g., exceeding 1), there may be an excessive presence of metal ions, and the ligand cannot provide enough coordination sites to stabilize the metal ions. This will lead to unstable coordination bonds of metal ions, possibly resulting in uneven distribution of metal ions in the nano-drug, and even dissolution or dissociation phenomena, affecting the functionality of the drug; (2) Non-uniform size of nanoparticles: Excessive metal ions may cause the growth rate of nanoparticles to be too fast, forming larger and irregularly shaped particles. Too many metal ions may cause aggregation or agglomeration of particles, thus affecting the uniformity of the final particle size and the biocompatibility of the drug; (3) Poor drug targeting: In the case of excess metal salt, although the presence of metal ions helps with some functions of the drug (such as targeted drug release, imaging, etc.), too many metal ions may affect the drug release mechanism and targeting, possibly reducing its effectiveness at specific targets (such as the kidney, tumor, etc.).

[0042] In some embodiments, the parameters of the condensation reflux may include: rotation speed 300 - 400 rpm, temperature 110 - 125 °C, and time 4 - 5 h.

[0043] By controlling the parameters of the condensation reflux within the above ranges, it is possible to ensure the full progress of the reaction while avoiding side reactions and excessive particle growth. Too high or too low temperature, too long or too short time may all have an adverse impact on the formation of the coordination bond between metal ions and carboxylic acid ligands and the successful preparation of nano-drugs. Therefore, strictly controlling these parameters is crucial for obtaining high-quality and stable nano-drugs.

[0044] In some embodiments, the washing liquid used for the washing may be a mixed solution of water and ethanol, and the volume ratio may be 2:5; the number of washing times may be 2 - 3 times.

[0045] In some embodiments, the drying method can be vacuum freeze-drying, the temperature can be -90 to -70 °C, and the time can be 6 to 12 h.

[0046] As an example, the method for preparing the metal ion-carboxylic acid ligand molecular self-assembled nanomedicine may include the following steps: Dissolve equimolar amounts of itaconic acid and metal salt in deionized water and ethanol liquids with a volume ratio of 2:5 respectively, and then add the metal salt solution to the itaconic acid solution system through a Pasteur pipette, and ultrasonically stir and mix at room temperature for 1 min to obtain a mixed solution; maintain condensation reflux (300 rpm, 120 °C, 4 h); then, wash 2-3 times with a mixed solution of water and ethanol, and vacuum freeze-dry to obtain the metal ion-itaconic acid self-assembled nanomedicine.

[0047] The synthesis process of the metal ion-carboxylic acid ligand molecular self-assembled nanomedicine material provided by the present invention is simple, pollution-free, high-yield, low-cost and easy for batch production, and has excellent clinical application prospects in the biomedical field.

[0048] In addition, the present invention also provides an injection of the above-mentioned metal ion-carboxylic acid ligand molecular self-assembled nanomedicine. Wherein, the injection of the metal ion-carboxylic acid ligand molecular self-assembled nanomedicine may include: a biocompatible solution, and the metal ion-carboxylic acid ligand molecular self-assembled nanomedicine dispersed in the biocompatible solution.

[0049] In some embodiments, the biocompatible solution can be at least one of normal saline and phosphate buffer solution.

[0050] In some embodiments, the concentration of the metal ion-carboxylic acid ligand molecular self-assembled nanomedicine in the injection can be 10 to 40 mg / mL.

[0051] By controlling the nanomedicine in the injection within the above range, the therapeutic effect and biocompatibility of the medicine can be effectively balanced. If the concentration is too high, it may increase toxicity and injection difficulty; while if the concentration is too low, it may lead to insufficient drug efficacy and even treatment failure. Therefore, controlling the appropriate concentration range is the key to ensuring the drug effect and safety.

[0052] The present invention combines carboxylic acid ligand molecules such as itaconic acid with functional nanocarriers (metal ions) to prepare a class of metal ion-carboxylic acid ligand molecular self-assembled nanomedicine materials with high specific surface area, high biocompatibility and multifunctional characteristics. In addition, the nanomedicine with kidney targeting and stimulus responsiveness constructed by using the nanomedicine material can significantly improve the enrichment and retention of itaconic acid and the like in the kidney, promote kidney repair, and enhance its therapeutic effect through sustained release, providing a new strategy for the treatment of kidney injury.

[0053] The metal ion-carboxylic acid ligand molecular self-assembled nano-drug or the metal ion-carboxylic acid ligand molecular self-assembled nano-drug injection solution provided by the present invention can be applied to the preparation of drugs for treating or preventing oxidative stress-related diseases. Among them, the oxidative stress-related diseases may include neurodegenerative diseases, cardiovascular diseases, diabetes and its complications, inflammatory diseases, cancers or aging-related diseases. In addition, the oxidative stress-related disease may also be kidney injury caused by platinum-based chemotherapeutic drugs.

[0054] The following further illustrates embodiments to detail the present invention. Similarly, it should be understood that the following embodiments are only used to further illustrate the present invention and cannot be construed as limiting the protection scope of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above content of the present invention fall within the protection scope of the present invention. The specific process parameters and the like in the following examples are only an example within a suitable range, that is, those skilled in the art can make selections within a suitable range through the description herein, rather than being limited to the specific values in the following examples.

[0055] Example 1 (1) Dissolve 0.2 g of itaconic acid in 20 mL of deionized water, and after mixing and stirring evenly, obtain an itaconic acid solution (10 mg / mL); dissolve 0.5 g of anhydrous cerium acetate in 50 mL of absolute ethanol, and after mixing and stirring evenly, obtain a cerium acetate solution (10 mg / mL); control the molar ratio of itaconic acid to cerium acetate to be 1:1, gradually add the cerium acetate solution to the itaconic acid solution, and ultrasonically stir and mix evenly at room temperature for 1 min; (2) Add the above mixture to a three-necked flask, place a magnetic stirrer, reflux and condense at 300 rpm and 120 °C for 4 h, wash 2-3 times with a water and ethanol mixture, centrifuge and collect the product at 12000 rpm for 15 min, and vacuum freeze-dry to obtain the cerium ion-itaconic acid self-assembled nano-drug (IA-Ce).

[0056] Example 2 (1) Dissolve 0.39 g of itaconic acid in 20 mL of deionized water, and after mixing and stirring evenly, obtain an itaconic acid solution (19.5 mg / mL); dissolve 0.6585 g of zinc acetate dihydrate in 50 mL of absolute ethanol, and after mixing and stirring evenly, obtain a zinc acetate solution (13.17 mg / mL); control the molar ratio of itaconic acid to zinc acetate dihydrate to be 1:1, gradually add the zinc acetate solution to the itaconic acid solution, and stir and mix evenly at room temperature for 1 min; (2) Add the above-mentioned mixed solution into a three-necked flask, place a magnetic stir bar, and carry out condensation reflux for 4 h under the conditions of 300 rpm and 120 °C. Then wash it with water and ethanol 2-3 times, collect the product by centrifugation at 12000 rpm for 15 min, and finally obtain the zinc ion-itaconic acid self-assembled nano-drug (IA-Zn) after vacuum freeze-drying.

[0057] Example 3 The preparation process of the zinc ion-itaconic acid self-assembled nano-drug (IA-Zn) provided in this example refers to Example 2, and the main difference is only that: In step (1), the molar ratio of itaconic acid to zinc acetate dihydrate is 1:1.5.

[0058] Example 4 The preparation process of the cerium ion-itaconic acid self-assembled nano-drug (IA-Ce) provided in this example refers to Example 1, and the main difference is only that: In step (1), the molar ratio of itaconic acid to cerium acetate is 1:1.5.

[0059] Comparative Example 1 The preparation process of the drug material provided in this comparative example refers to Example 2, and the main difference is only that: In step (1), the molar ratio of itaconic acid to zinc acetate dihydrate is 3:1.

[0060] Comparative Example 2 The preparation process of the drug material provided in this comparative example refers to Example 1, and the main difference is only that: In step (2), the heating time of itaconic acid and cerium acetate is reduced to 3 h.

[0061] Comparative Example 3 The preparation process of the drug material provided in this comparative example refers to Example 1, and the main difference is only that: In step (1), the molar ratio of itaconic acid to cerium acetate is 3:1.

[0062] Comparative Example 4 The preparation process of the drug material provided in this comparative example refers to Example 1, and the main difference is that: In step (1), ammonium cerium nitrate is used as the cerium salt, and the concentration of the ammonium cerium nitrate solution is 10 mg / mL; In step (2), the heating temperature is 60 °C.

[0063] Comparative Example 5 The preparation process of the drug material provided in this comparative example refers to Example 1, and the main difference is only that: In step (2), the molar ratio of itaconic acid to cerium acetate is 1:3.

[0064] Comparative Example 6 The preparation process of the drug material provided in this comparative example refers to Example 1, and the main difference is only that: In step (2), the heating time was extended to 8 h.

[0065] Comparative Example 7 The preparation process of the drug material provided in this comparative example refers to Example 1, and the main difference is only that: In step (2), the heating temperature was 140 °C.

[0066] Figure 1 It is the TEM image of the itaconic acid cerium (IA-Ce) self-assembled nano-drug prepared in Example 1. As can be seen from the figure, the itaconic acid cerium self-assembled nano-drug exhibits a relatively regular spherical morphology, uniform particle size and high dispersibility, and the average particle size is about 2 - 3 nm.

[0067] Figure 2 It is the Mapping elemental distribution map and EDS energy spectrum analysis map of the IA-Ce self-assembled nano-drug prepared in Example 1. As can be seen from the figure, the IA-Ce self-assembled nano-drug has a nano-particle morphology with uniformly distributed C, O, and Ce elements, indicating the successful preparation of the drug.

[0068] Figure 3 It is the XRD pattern of the IA-Ce self-assembled nano-drug prepared in Example 1. As can be seen from the figure, the structure synthesized by the IA-Ce self-assembled nano-drug is a self-assembled complex nano-particle of itaconic acid and metal cerium.

[0069] Figure 4 It is the Zeta potential analysis map of the IA-Ce self-assembled nano-drug prepared in Example 1. As can be seen from the Zeta potential information on the drug surface, the Zeta potentials of the IA-Ce nano-materials suspended in PBS (pH = 7.4) and DMEM high-glucose basal medium are -12.7 mV and -8.7 mV respectively, showing good physiological stability.

[0070] Figure 5 It is the Fourier transform infrared spectroscopy FT-IR pattern of the IA-Ce self-assembled nano-drug prepared in Example 1. As can be seen from the figure, the successful formation of the self-assembled nano-particles of the IA-Ce nano-material.

[0071] Figure 6 It is the X-ray photoelectron spectroscopy XPS pattern of the IA-Ce self-assembled nano-drug prepared in Example 1. As can be seen from the figure, the high-resolution XPS spectrum of Ce-3d confirms the valence state of cerium in itaconic acid cerium, and the binding energies located at 880.97 eV - 899.67 eV and 882.57 eV - 901.45 eV belong to Ce 3+, the binding energies at 885.58 eV - 904.29 eV and 898.07 eV - 915.9 eV are attributed to Ce 4+ .

[0072] Figure 7 is the thermogravimetric curve of the IA-Ce self-assembled nanodrug prepared in Example 1. It can be seen from the figure that the content of itaconic acid in the IA-Ce self-assembled nanodrug particles is 40.15%.

[0073] Figure 8 is the electron spin resonance (ESR) test diagram of the reaction scavenging system of the IA-Ce self-assembled nanodrug prepared in Example 1 with hydroxyl radicals. It can be seen from the figure that the IA-Ce self-assembled nanodrug can scavenge hydroxyl radicals, and there is a positive correlation with the applied concentration.

[0074] Figure 9 is the TEM image of the itaconic acid zinc (IA-Zn) self-assembled nanodrug prepared in Example 2. It can be seen from the figure that the IA-Zn self-assembled nanodrug presents a relatively regular spherical morphology, uniform particle size and high dispersibility, and the average particle size is about 3 - 4 nm.

[0075] Figure 10 is the Mapping element distribution diagram and EDS energy spectrum analysis diagram of the IA-Zn self-assembled nanodrug prepared in Example 2. It can be seen from the figure that the IA-Zn self-assembled nanodrug has a nanoparticle morphology with uniformly distributed C, O, and Zn elements, indicating that the nanodrug has been successfully prepared.

[0076] Figure 11 is the XRD pattern of the IA-Zn self-assembled nanodrug prepared in Example 2. It can be seen from the figure that the structure synthesized by the IA-Zn self-assembled nanodrug is a self-assembled complex nanoparticle of itaconic acid and metal zinc.

[0077] Figure 12 is the Zeta potential analysis diagram of the IA-Zn self-assembled nanodrug prepared in Example 2. The Zeta potential information on the drug surface shows that the Zeta potentials of the IA-Zn self-assembled nanodrug suspended in PBS (pH = 7.4) and DMEM high-glucose basal medium are -22.53 mV and -11.07 mV respectively, indicating good physiological stability.

[0078] Figure 13 is the Fourier transform infrared spectroscopy (FT-IR) analysis diagram of the IA-Zn self-assembled nanodrug prepared in Example 2. It can be seen from the figure that the self-assembled nanoparticles of the IA-Zn nanostructure are successfully formed.

[0079] Figure 14X-ray photoelectron spectroscopy (XPS) spectrum of the IA-Zn self-assembled nano-drug prepared in Example 2. As can be seen from the figure, the Zn 2p peak fitting confirms the valence state of zinc in zinc itaconate, indicating that Zn 2+ with binding energies at 1021.68 eV and 1044.65 eV is mainly present on the surface of zinc itaconate.

[0080] Figure 15 Thermogravimetric curve of the IA-Zn self-assembled nano-drug prepared in Example 2. As can be seen from the figure, the content of itaconic acid in the IA-Zn self-assembled nano-drug accounts for 46.87% of the total mass of the material.

[0081] Figure 16 Electron spin resonance (ESR) test graph of the reaction scavenging system of the IA-Zn self-assembled nano-drug prepared in Example 2 with hydroxyl radicals. As can be seen from the figure, the IA-Zn self-assembled nano-drug can scavenge hydroxyl radicals, and there is a positive correlation with the applied concentration.

[0082] Figure 17 Transmission electron microscopy (TEM) image of the drug material prepared in Comparative Example 1. As can be seen from the figure, the morphology of the material particles is irregular, the sizes are different, and there are many background impurities.

[0083] Figure 18 Transmission electron microscopy (TEM) image of the IA-Zn self-assembled nano-drug prepared in Example 3. As can be seen from the figure, the sizes of the material particles are relatively consistent, the dispersion is good, the sizes are uniform, and the background is clean.

[0084] Figure 19 Transmission electron microscopy (TEM) image of the drug material prepared in Comparative Example 2. As can be seen from the figure, the morphology of the material particles is irregular, the sizes are different, there are many large particles, and they are relatively easy to agglomerate.

[0085] Figure 20 Transmission electron microscopy (TEM) image of the drug material prepared in Comparative Example 3. As can be seen from the figure, the morphology of the material particles is irregular, the dispersion is poor, the sizes are different, and they are relatively easy to agglomerate.

[0086] Figure 21 Transmission electron microscopy (TEM) image of the IA-Ce self-assembled nano-drug prepared in Example 4. As can be seen from the figure, the sizes of the material particles are relatively consistent, the dispersion is good, the sizes are uniform, and the background is clean.

[0087] Figure 22 Transmission electron microscopy (TEM) image of the drug material prepared in Comparative Example 4. As can be seen from the figure, there is no particle distribution in the material, the dispersion is poor, and they are agglomerated together.

[0088] Figure 23TEM image of the drug material prepared in Comparative Example 5. It can be seen from the figure that the material particles have irregular morphologies, different sizes, and a large number of large particles, making it relatively easy to agglomerate.

[0089] Figure 24 TEM image of the drug material prepared in Comparative Example 6. It can be seen from the figure that the material particles have irregular morphologies, different sizes, and a large number of large particles, making it relatively easy to agglomerate.

[0090] Figure 25 TEM image of the drug material prepared in Comparative Example 7. It can be seen from the figure that there is no particle distribution in the material, the dispersion is poor, and the particles are agglomerated together.

[0091] Figure 26 Schematic diagram of the total SOD activity detection results of the IA-Ce self-assembled nano-drug prepared in Example 1. It can be seen from the figure that the IA-Ce self-assembled nano-drug has good SOD-like enzyme activity and good ability to scavenge superoxide anions.

[0092] Next, an in vitro safety experiment of the IA-Ce self-assembled nano-drug prepared in Example 1 was carried out: Human renal proximal tubular cells HK-2 (Catalog No. SCSP-511) were purchased from the Cell Bank of the Chinese Academy of Sciences Committee for Type Culture Collection; The culture medium was prepared with DMEM / F12 high-glucose medium (RPMI 1640, 89%), fetal bovine serum (FBS, 10%) and penicillin-streptomycin solution (1000 U / mL, 1%), and cultured in an incubator (37 °C, 5% carbon dioxide); The HK-2 cells were seeded into a 96-well plate at a density of 8000 cells per well and incubated overnight to allow them to adhere; The cells were rinsed 2-3 times with fresh PBS, and then cultured with fresh medium containing different concentrations of IA-Ce nano-materials (200, 100, 50, 25, 12, 0 μg / mL) for 24 h and 48 h respectively. The HK-2 cells treated differently were processed using a standard CCK-8 kit; After co-incubating the cells with fresh medium containing 10% CCK for 1 hour, the absorbance of the solution at 450 nm was measured using a microplate reader.

[0093] Figure 27 Cell viability of HK-2 cells after incubation with different concentrations of the IA-Ce self-assembled nano-drug for 24 hours and 48 hours respectively in the in vitro safety experiment of the IA-Ce self-assembled nano-drug prepared in Example 1. It can be seen from the figure that through the cell viability detection of human renal proximal tubular cells (HK-2), the IA-Ce self-assembled nano-drug did not show obvious cytotoxicity at different concentrations, indicating that the IA-Ce material has good cell biocompatibility.

[0094] Next, a cytotoxicity experiment of the chemotherapeutic drug cisplatin (DDP) on HK-2 cells was carried out: Human renal proximal tubular cells HK-2 (Catalog number SCSP-511) were purchased from the Cell Bank of the Chinese Academy of Sciences Committee for Type Culture Collection; They were cultured in a culture medium prepared with DMEM / F12 high-glucose medium (RPMI 1640, 89%), fetal bovine serum (FBS, 10%) and penicillin-streptomycin solution (1000 U / mL, 1%) in an incubator (37 °C, 5% carbon dioxide); HK-2 cells were seeded into 96-well plates at a density of 10,000 cells per well and incubated overnight to allow them to adhere; The cells were rinsed 2-3 times with fresh PBS and then cultured with fresh medium containing different concentrations of the chemotherapeutic drug cisplatin (DDP) (100, 50, 25, 12.5, 6.25, 3.2 μM) prepared with DMF for 12 h and 24 h respectively, and the HK-2 cells treated differently were processed using a standard CCK-8 kit; After the cells were co-incubated with fresh medium containing 10% CCK for 1 hour, the absorbance of the solution at 450 nm was measured using a microplate reader.

[0095] Figure 28 Cell viability after HK-2 cells were co-incubated with different concentrations of cisplatin (DDP) (100, 50, 25, 12.5, 6.25, 3.2 μM) for 12 hours and 24 hours respectively in the cytotoxicity experiment of the chemotherapeutic drug cisplatin (DDP) on HK-2 cells. It can be seen from the figure that as the concentration of cisplatin increased, the survival rate of HK-2 cells decreased significantly, indicating that cisplatin had an obvious toxic effect on HK-2 cells at different concentrations.

[0096] Next, an experiment on the protective ability of the IA-Ce self-assembled nanodrug prepared in Example 1 against in vitro chemotherapy effects was carried out: Human renal proximal tubular cells HK-2 (Catalog number SCSP-511) were purchased from the Cell Bank of the Chinese Academy of Sciences Committee for Type Culture Collection; They were cultured in a culture medium prepared with DMEM / F12 high-glucose medium (RPMI 1640, 89%), fetal bovine serum (FBS, 10%) and penicillin-streptomycin solution (1000 U / mL, 1%) in an incubator (37 °C, 5% carbon dioxide); HK-2 cells were seeded into 96-well plates at a density of 10,000 cells per well and incubated overnight to allow them to adhere; The cells were rinsed 2-3 times with fresh PBS and then co-incubated with fresh medium containing different concentrations of IA-Ce nanomaterials (100, 50, 12.5, 6.25, 3.13 μg / mL) and cisplatin (25 μM) for 24 h respectively, and the HK-2 cells treated differently were processed using a standard CCK-8 kit; After the cells were co-incubated with fresh medium containing 10% CCK for 1 hour, the absorbance of the solution at 450 nm was measured using a microplate reader.

[0097] Figure 29In the experiment on the protective ability of the IA-Ce self-assembled nanodrug prepared in Example 1 against the in vitro chemotherapy effect, the inhibitory effects of IA-Ce nanomaterials at different concentrations on the toxicity of cisplatin after 24 hours were studied. As can be seen from the figure, with the increase in the concentration of the IA-Ce material, the toxic effect of cisplatin on HK-2 cells was significantly weakened, and the cell survival rate was significantly increased. This result indicates that the IA-Ce material can effectively inhibit the cytotoxicity induced by cisplatin and exhibits good chemotherapy protection effect.

[0098] Next, the safety evaluation experiment of the IA-Ce self-assembled nanodrug prepared in Example 1 on the body weight of animals over a long period of time (30 days) was carried out: The in vivo animal experiment was carried out in accordance with the guidelines of the Animal Ethics Committee of the North Campus of Tongji University. ICR mice (7-8 weeks old, female) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Twenty 7-8-week-old ICR mice were randomly divided into 4 groups and received intraperitoneal injection of 0, 7.5, 15, and 30 mg / kg of IA-Ce injection solution (dispersed in PBS), respectively. The body weight of the mice was recorded every three days.

[0099] Figure 30 In the safety evaluation experiment of the IA-Ce self-assembled nanodrug prepared in Example 1 on the body weight of animals over a long period of time (30 days), the body weight change curves of mice in different treatment groups during the 30-day period were shown. As can be seen from the figure, the body weight of the experimental animals was always maintained within a safe range during the long-term treatment, without significant decrease or abnormal fluctuation. This result indicates that the IA-Ce material still has good biosafety after long-term exposure in animals, providing an important basis for its safety in clinical applications.

[0100] Next, the safety evaluation experiment of the IA-Ce self-assembled nanodrug prepared in Example 1 on the blood in animals under long-term treatment was carried out: The in vivo animal experiment was carried out in accordance with the guidelines of the Animal Ethics Committee of the North Campus of Tongji University. ICR mice (7-8 weeks old, female) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Twenty 7-8-week-old ICR mice were randomly divided into 4 groups and received intraperitoneal injection of 0, 7.5, 15, and 30 mg / kg of IA-Ce injection solution (dispersed in PBS), respectively. After 30 days, the mice were euthanized and blood samples were taken for routine blood and blood biochemical analyses.

[0101] Figure 31Blood routine and blood biochemical data of mice in different treatment groups after 30 days in the safety evaluation experiment of IA-Ce self-assembled nano-drugs prepared in Example 1 under long-term treatment on animal blood. As can be seen from the figure, the blood routine and blood biochemical indexes of the experimental animals are all within the normal range, and no significant abnormalities are found. This result indicates that the IA-Ce material still has good biosafety after long-term exposure in animals, providing an important basis for its safety in clinical applications.

[0102] Next, a safety evaluation experiment of the IA-Ce self-assembled nano-drugs prepared in Example 1 on the main organs (heart, liver, spleen, lung, kidney) of animals under long-term exposure was carried out: The in-vivo animal experiment was carried out in accordance with the guidelines of the Animal Ethics Committee of the North Campus of Tongji University. ICR mice (7-8 weeks old, female) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.; 20 ICR mice at 7-8 weeks old were randomly divided into 4 groups and received intraperitoneal injection of 0, 7.5, 15, and 30 mg / kg of IA-Ce injection (dispersed in PBS); after 30 days, the mice were euthanized, and the main internal organs (heart, liver, spleen, lung, kidney) were taken for pathological section analysis.

[0103] Figure 32 HE sections of the main organs (heart, liver, spleen, lung, kidney) of mice in different treatment groups after 30 days in the safety evaluation experiment of the IA-Ce self-assembled nano-drugs prepared in Example 1 under long-term exposure to the main organs (heart, liver, spleen, lung, kidney) of animals. As can be seen from the HE section results of the organs in the figure, no obvious pathological abnormalities or tissue structure damage were found in the main organs of the animals. This result indicates that the IA-Ce material still has good biosafety after long-term exposure in animals, providing further support for its safety in clinical applications.

[0104] In addition, under the same weight fraction, the present invention also carried out experimental explorations on the antioxidant properties of the molar ratios of itaconic acid and Ce salt and Zn salt being 1:1 and 1:1.5 respectively. The experimental results show that when the molar ratio of itaconic acid to metal salt is 1:1, the performance of the material is relatively better.

Claims

1. A metal ion-carboxylic acid ligand molecular self-assembled nano-drug, characterized in that, The metal ion-carboxylic acid ligand molecular self-assembled nano-drug includes: a metal ion located at the center, and carboxylic acid ligand molecules linked to the metal ion through coordination bonds; Wherein: the metal ions include Zn 2+ , Ce 2+ , Ce 3+ , Ce 4+ , Mn 2+ and Fe 2+ and at least one of them; the carboxylic acid ligand molecules include itaconic acid, fumaric acid, aconitic acid, citric acid or tricarboxylic acid.

2. The metal ion-carboxylic acid ligand molecular self-assembled nano-drug according to claim 1, wherein The particles of the metal ion-carboxylic acid ligand molecular self-assembled nano-drug have a spherical morphology, and the average particle size is 2-4 nm.

3. The metal ion-carboxylic acid ligand molecular self-assembled nano-drug according to claim 1 or 2, characterized in that, In the metal ion-carboxylic acid ligand molecular self-assembled nano-drug, the mass percentage of the metal ion is 5-10 wt%, and the mass percentage of the carboxylic acid ligand molecule is 40-95 wt%, preferably 90-95 wt%.

4. The metal ion-carboxylic acid ligand molecular self-assembled nano-drug according to any one of claims 1-3, characterized in that, The particle structure of the metal ion-carboxylic acid ligand molecular self-assembled nano-drug is amorphous.

5. The metal ion-carboxylic acid ligand molecular self-assembled nano-drug according to any one of claims 1-4, characterized in that, The metal ion-carboxylic acid ligand molecular self-assembled nano-drug has stability in the aqueous phase and physiological environment.

6. The metal ion-carboxylic acid ligand molecular self-assembled nano-drug according to any one of claims 1-5, characterized in that, The metal ion-carboxylic acid ligand molecular self-assembled nano-drug has the catalytic activity of scavenging reactive oxygen species.

7. A method for preparing a metal ion-carboxylic acid ligand molecular self-assembled nano-drug according to any one of claims 1-6, characterized in that, The preparation method includes: adding a metal salt solution to a carboxylic acid ligand molecule solution and mixing, while maintaining condensation reflux; then, after washing and drying, the metal ion-carboxylic acid ligand molecular self-assembled nano-drug is obtained.

8. The preparation method according to claim 7, wherein, The metal salt is an acetate salt of a metal ion; the concentration of the metal salt solution is 5-20 mg / mL.

9. The preparation method according to claim 7 or 8, characterized in that, The concentration of the carboxylic acid ligand molecule solution is 10-25 mg / mL.

10. The preparation method according to any one of claims 7-9, characterized in that, The molar ratio of the carboxylic acid ligand molecule to the metal salt is 1:(1-1.5), preferably 1:

1.

11. The preparation method according to any one of claims 7 to 10, characterized in that, The parameters of the condensation reflux include: The rotation speed is 300-400 rpm, the temperature is 110-125 °C, and the time is 4-5 h; The washing liquid used for washing is a mixed solution of water and ethanol, and the number of washing times is 2-3 times; The drying method is vacuum freeze-drying, the temperature is -90 to -70 °C, and the time is 6-12 h.

12. A metal ion-carboxylic acid ligand molecular self-assembled nano-drug injection, characterized in that, The metal ion-carboxylic acid ligand molecular self-assembled nano-drug injection includes: a biocompatible solution, and the metal ion-carboxylic acid ligand molecular self-assembled nano-drug according to any one of claims 1-3 dispersed in the biocompatible solution.

13. The metal ion-carboxylic acid ligand molecular self-assembled nano-drug injection according to claim 12, characterized in that, The biocompatible solution is at least one of physiological saline and phosphate buffer solution; The concentration of the metal ion-carboxylic acid ligand molecular self-assembled nano-drug in the injection is 10-40 mg / mL.

14. Use of the metal ion-carboxylic acid ligand molecular self-assembled nano-drug according to any one of claims 1-6 or the metal ion-carboxylic acid ligand molecular self-assembled nano-drug injection according to claim 12 or 13 in the preparation of a drug for treating or preventing oxidative stress-related diseases.

15. The application according to claim 14, wherein The oxidative stress-related diseases include neurodegenerative diseases, cardiovascular diseases, diabetes and its complications, inflammatory diseases, cancer or aging-related diseases.

16. The application according to claim 14 or 15, characterized in that The oxidative stress-related disease is kidney injury caused by platinum-based chemotherapy drugs.

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