Double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles and preparation method thereof

Abstract

A double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticle and a preparation method thereof, using multiple tumor therapeutic drug molecules as ligands and transition metal ions as coordination center atoms, respectively coordinating the metal ions with the two ligands to form two different infinite coordination polymer nanoparticles, and then assembling the two different infinite coordination polymer nanoparticles into anti-tumor composite nanoparticles with a double-layer structure through electrostatic adsorption. The present invention prepares two infinite coordination polymer nanoparticles through the mechanism of coordination polymerization and assembles them into double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles. By optimizing the drug ratio, the best drug synergistic system can be screened, and the invention has important application prospects.

Description

Technical Field

[0001] The present invention relates to a preparation method of an infinite coordination polymer, and in particular to a double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticle and a preparation method thereof, which are determined through an innovative assembly strategy. Background Art

[0002] Curcumin (Cur), doxorubicin (Dox), aquinone dihydrochloride (AQ4N), epigallocatechin gallate (EGCG), gossypol, and combretin (CA4) are currently frequently used drugs in cancer treatment regimens. 2,2'-Azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH) is a thermodynamic tumor therapeutic agent. Curcumin (Cur) is a polyphenol extracted from the traditional Chinese medicine Curcuma longa. It possesses numerous significant biological activities, including anti-inflammatory, antitumor, antioxidant, antibacterial, and hepatoprotective properties. It is particularly considered a promising new drug for cancer treatment. However, in practice, curcumin (Cur) suffers from low solubility, poor stability, and low absorption rate. It is easily converted to glucuronic and sulfonic acids in the intestine. Furthermore, its rapid metabolism, short half-life, and low bioavailability limit its application in pharmaceuticals. Doxorubicin (Dox), aquinoline dihydrochloride (AQ4N), epigallocatechin gallate (EGCG), and gossypol have been shown to have promising therapeutic effects in cancer treatment. Dox, in particular, has been approved by the FDA for clinical use for many years. Researchers have found that combining these drugs has a greater synergistic therapeutic effect than administering them individually (Application No.: CN201811401834.8). For example, Jin Zhulie et al. proposed a drug combination for cancer treatment containing gossypol and phenformin as active ingredients (Application No.: CN201580020573.3); Yao Jing et al. proposed a multifunctional synergistic drug combination system based on doxorubicin (Dox) and its construction method (Application No.: CN201711188300.7); and Fang Xiaohong et al. reported a case study of the combined use of gossypol acetate and a chemotherapeutic drug (Application No.: CN201910340195.7). While multidrug combinations demonstrate superior tumor therapeutic efficacy compared to single agents, their combined use suffers from significant differences in drug performance, preventing simultaneous delivery of the drug molecules to the tumor site. Furthermore, differences in water solubility and metabolic stability among these drugs limit their combined application. Therefore, carriers are needed to co-load these drug molecules and achieve simultaneous delivery of the different drug molecules to the tumor site.

[0003] With the continuous development of nanotechnology, many cases of composite nanocarriers loaded with multiple drug molecules have emerged. For example, Liu Zhidong et al. reported a folic acid-targeted modified nanostructured lipid carrier formulation co-loaded with doxorubicin hydrochloride and gambogic acid and its preparation method (Application No.: CN201810707409.5); Fang Chao et al. reported the preparation and application of cRGDfK peptide-modified multifunctional nanoparticles co-loaded with verteporfin (VP) and AQ4N (Application No.: CN201710473609.4); Shao et al. prepared a liposome containing Erianin and doxorubicin (Application No.: CN202011005803.8); and Zhang Xueqiong et al. prepared a nano-delivery system for doxorubicin and glycyrrhetinic acid (Application No.: CN201910247307.4). While the introduction of carriers in the aforementioned cases can address the issue of simultaneous drug delivery, they still suffer from the following drawbacks: 1. The introduction of carrier materials results in a low drug loading capacity; 2. Carrier materials have specific requirements for drug molecules; for example, some carriers can only load water-soluble or fat-soluble drug molecules, while carrier materials capable of simultaneously loading both water-soluble and fat-soluble drugs are rare; and 3. Large amounts of carrier materials introduced into the body can pose biosafety issues. These drawbacks make it difficult for drug molecules to maximize their tumor therapeutic effects, making the development of carrier-free, multi-drug composite nanosystems with excellent synergistic effects particularly important.

[0004] Infinite coordination polymers are carrier-free nanoparticle systems formed by coordination self-assembly of metal ions and drug molecules. Composite nanoparticles prepared through infinite coordination of different drugs offer numerous advantages for tumor treatment: 1. High drug loading capacity and effective multidrug synergy; 2. No carrier material, low in vivo side effects, and excellent stability; 3. The ability to combine different drugs and expand functional capabilities. Therefore, these infinite coordination polymer nanoparticles offer significant advantages and promising prospects for tumor treatment. Coordination polymer drug carrier systems have been reported, for example: Hou Zhenqing et al. prepared coordination polymers with methotrexate and metals for tumor treatment and diagnosis (Application No. CN201910970581.4); Zhou Wenhu et al. prepared coordination polymer nanoparticles with sodium disulfide and copper through coordination and applied them to tumor treatment (Application No. CN201910805848.4); and Zhang Qi et al. prepared hydrogen peroxide-responsive metal-polyphenol coordination polymer nanoparticles (Application No. CN202010174613.2). It should be noted that these coordination polymer drug delivery systems only coordinate a single drug molecule with a metal ion, which can easily lead to drug resistance during tumor treatment and lack the effect of synergistic tumor treatment. Wu Daocheng et al. proposed a method for preparing a dual-drug coordination polymer anti-tuberculosis nanodrug (application number: CN201811519280.1), which can significantly improve the drug's resistance to drug resistance. After long-term research, we have proposed a method for preparing a double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticle. These composite nanoparticles can achieve a synergistic anti-tumor effect of chemotherapy drugs, thermodynamic agents, and vascular inhibitors. Summary of the Invention

[0005] To further enhance the efficacy of multi-drug synergistic tumor therapy and address the shortcomings of current multi-drug nanoparticles in tumor synergistic therapy, such as asynchronous release, poor synergistic effect, and uneven distribution, the present invention proposes a method for preparing double-layered multi-drug infinite coordination polymer anti-tumor composite nanoparticles. Curcumin (Cur), doxorubicin (Dox), benoxanthraquinone dihydrochloride (AQ4N), epigallocatechin gallate (EGCG), gossypol, combretin (CA4), and 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH) are used as ligands. Two different drugs are coordinated with metal ions to form two different infinite coordination polymer nanoparticles. The two different infinite coordination polymer nanoparticles are then assembled into double-layered multi-drug infinite coordination polymer anti-tumor composite nanoparticles. The ratio of different drug molecules in this method can be controlled within a certain range. Through optimized design, these drugs can complement each other to achieve the goal of synergistic tumor therapy with multiple drugs. The preparation method of the present invention is simple and efficient, and can solve the delivery problem of drugs with large differences in properties that cannot be loaded at the same time. The prepared composite nanoparticles have the advantages of high drug encapsulation rate, multiple functions, and good synergistic effect.

[0006] In order to achieve the above object, the technical solution of the present invention is:

[0007] A double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticle, wherein the inner core coordination drug molecules are selected from: curcumin (Cur), doxorubicin (Dox), banoanthraquinone dihydrochloride (AQ4N), epigallocatechin gallate (EGCG) and 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH), and when preparing the inner core, two inner core coordination drugs are arbitrarily selected to coordinate with metal ions to form different positively charged infinite coordination polymer nanoparticles; the outer shell drug molecules are selected from: gossypol (Gossypol) and compretin (CA4), and when preparing the outer shell, gossypol (Gossypol) and compretin (CA4) are coordinated with metal ions to form negatively charged infinite coordination polymer nanoparticles; the inner core and outer shell infinite coordination polymer nanoparticles with different charges are assembled into a double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticle.

[0008] The mass ratio of the two core coordination drugs selected when preparing the core is (0.5-5.0): (0.5-5.0).

[0009] When preparing the shell, the mass ratio of gossypol (Gossypol) and combretin (CA4) is (0.5-5.0): (0.5-5.0).

[0010] The mass ratio of the core and shell infinite coordination polymer nanoparticles with different charges is 1:(1-10).

[0011] The preparation method of the above-mentioned double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles includes the following steps:

[0012] Step 1: Preparation of mixed stock solution of core infinite coordination polymer nanoparticles:

[0013] 0.5-5.0 mg of any two core coordination drug molecules were dissolved in 1.5 mL of solvent and dispersed under 50 kHz ultrasound for 10 minutes to prepare coordination drug mixed stock solution A;

[0014] The solvents include: anhydrous ethanol, a mixed solvent of anhydrous ethanol-water, and a mixed solvent of water ethanol-dimethyl sulfoxide; the volume ratio of the mixed solvent is between 1:5 and 5:1;

[0015] The core-coordinated drug molecules are selected from any two of the following different molecules: curcumin (Cur), doxorubicin (Dox), banoanthraquinone dihydrochloride (AQ4N), epigallocatechin gallate (EGCG) and 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH);

[0016] Step 2: Preparation of core coordination drug-metal ion pre-reaction mixture:

[0017] Take 10-20 mg mL -1 20-200 μL of the transition metal chloride ethanol solution is rapidly added dropwise to the coordination drug mixed solution A described in step 1 at a rate of 100-200 drops / min, with magnetic stirring at 600 rpm during the process, and stirring is continued for 10 minutes after the addition is completed;

[0018] The transition metal chloride salts include: cupric chloride dihydrate, ferric chloride hexahydrate, and ferrous chloride;

[0019] Step 3: Preparation of core infinite coordination polymer nanoparticles:

[0020] Adding a mixed solution of an alkaline buffer solution and a surfactant to the core coordination drug-metal ion pre-reaction mixture of step 2, adjusting the solution pH to 7.4-8.5, maintaining magnetic stirring at 1800 rpm during this process, and stirring in the dark for 72 hours after the addition to obtain positively charged core infinite coordination polymer nanoparticles;

[0021] The alkaline buffer solution includes: 10 mmol·L -1 Tris-hydrochloric acid buffer solution, 0.001 mol·L -1 Sodium hydroxide, 0.1% (w / w) triethylamine solution, 0.2 mol·L -1Potassium dihydrogen phosphate-sodium hydroxide buffer solution, 0.2 mol·L -1 Boric acid-borax buffer solution; the pH value of the alkaline buffer solution is 7.5-8.5.

[0022] The surfactant includes: Pluronic F127, cetyltrimethylammonium chloride; the content of the surfactant is 0.2% (w / w);

[0023] Step 4: Preparation of mixed stock solution of shell infinite coordination polymer nanoparticles:

[0024] 0.5-5.0 mg of gossypol and CA4 were dissolved in 1.5 mL of solvent respectively, and dispersed under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixed stock solution B;

[0025] The solvent includes: anhydrous ethanol, a mixed solvent of anhydrous ethanol-water, and a mixed solvent of anhydrous ethanol-dimethyl sulfoxide; the volume ratio of the mixed solvent is between (1:5) and (5:1);

[0026] Step 5: Preparation of shell coordination drug-metal ion pre-reaction mixture:

[0027] Take 10-20 mg mL -1 20-200 μL of the transition metal chloride ethanol solution is added dropwise to the coordination drug mixed solution B described in step 4 at a rate of 100-200 drops / min, with magnetic stirring at 600 rpm during the process, and stirring is maintained for 10 minutes after the addition is completed;

[0028] The transition metal chloride salts include: cupric chloride dihydrate, ferric chloride hexahydrate, and ferrous chloride;

[0029] Step 6: Preparation of shell infinite coordination polymer nanoparticles:

[0030] Adding a mixed solution of an alkaline buffer solution and a surfactant to the pre-reaction mixture of the shell-coordinated drug and the metal ion described in step 5, adjusting the pH of the solution to 7.4-8.5, maintaining magnetic stirring at 1800 rpm; stirring in the dark for 72 hours after the addition, to obtain negatively charged shell-infinite coordination polymer nanoparticles;

[0031] The alkaline buffer solution includes: 10 mmol·L -1 Tris-hydrochloric acid buffer solution, 0.001 mol·L -1 Sodium hydroxide, 0.1% (w / w) triethylamine solution, 0.2 mol·L -1 Potassium dihydrogen phosphate-sodium hydroxide buffer solution, 0.2 mol·L -1Boric acid-borax buffer solution; the pH value of the alkaline buffer solution is 7.5-8.5.

[0032] The surfactant includes: Pluronic F127 and cetyltrimethylammonium chloride; the content of the surfactant is 0.2% (w / w).

[0033] Step 7: Preparation of double-layer multi-drug unlimited coordination polymer composite nanoparticles:

[0034] The inner core infinite coordination polymer nanoparticles obtained in step 3 and the outer shell infinite coordination polymer nanoparticles obtained in step 6 are mixed in water at a mass ratio of 1:(1-10), and stirred for 8 hours to obtain double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles.

[0035] Advantages of the present invention:

[0036] 1. The present invention first prepares a plurality of drug molecules by pre-preparing a certain proportion of a core coordination drug mixed solution A and a shell coordination drug mixed solution B, then adds a metal ion solution as a coordination to the two solutions, and then adds an alkaline buffer solution to adjust the pH value. After a period of self-assembly and coordination, positively charged core infinite coordination polymer nanoparticles and negatively charged shell infinite coordination polymer nanoparticles are obtained. In order to achieve the purpose of simultaneous delivery of multiple drugs, the prepared core and shell infinite coordination polymer nanoparticles with opposite charges are mixed, and after a period of stirring, a double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticle is finally formed.

[0037] 2. The system of the present invention overcomes the problem of complex instability caused by the simultaneous coordination and competition of multiple drug molecules. It not only allows for the adjustment of the drug loading ratio of the infinite-coordination polymer nanoparticles, but also allows for the adjustment of the multi-drug ratio by combining two infinite-coordination polymer nanoparticles. Ultimately, this results in a double-layered, multi-drug infinite-coordination polymer anti-tumor composite nanoparticle with adjustable multi-drug ratios within a certain range. The double-layered, multi-drug infinite-coordination polymer anti-tumor composite nanoparticles proposed by the present invention will achieve optimal synergistic therapeutic effects in the field of tumor treatment, with excellent broad-spectrum potential and clinical translation advantages. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 The preparation process of double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles (taking Example 1 as an example).

[0039] Figure 2 This is a transmission electron microscope photograph of the double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles of Example 1.

[0040] Figure 3 The characterization results of the double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles obtained in Example 1 are shown in FIG. Figure 3 A / B are the X-ray diffraction results of the double-layered multi-drug infinite coordination polymer anti-tumor composite nanoparticles of Example 1, showing that the double-layered multi-drug infinite coordination polymer anti-tumor composite nanoparticles obtained in this example are amorphous nanoparticles without obvious crystal structure. Figure 3 C1-3 is a comparison of the Fourier transform infrared absorption spectra of the double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles obtained in Example 1 and the inner core and outer shell infinite coordination polymer nanoparticles.

[0041] Figure 3 D1-3 is the high-resolution XPS spectrum analysis and core / shell XPS spectrum analysis of the double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles obtained in Example 1. DETAILED DESCRIPTION

[0042] The present invention will be described below in conjunction with specific embodiments:

[0043] Example 1

[0044] Reference process Figure 1 , this example includes the following steps:

[0045] Step 1: 1.0 mg of benoxanthraquinone dihydrochloride (AQ4N) and 1.0 mg of 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH) were dissolved in 1.5 mL of anhydrous ethanol and dispersed under 50 kHz ultrasound for 10 minutes to prepare a coordination drug mixed stock solution A;

[0046] Step 2: Take 10 mg mL -1 20 μL of copper chloride dihydrate ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution A in step 1 at a rate of 150 drops / min. During this process, magnetic stirring was performed at 600 rpm. After the addition was completed, stirring was maintained for 10 minutes;

[0047] Step 3: Rapidly add 10 mmol·L of 0.2% (w / w) Pluronic F127 to the core coordination drug-metal ion pre-reaction mixture in step 2. -1 Tris(OH)-HCl buffer solution was added to adjust the solution pH to 7.4. During this process, magnetic stirring was maintained at 1800 rpm. After addition, stirring was performed in the dark for 72 hours to obtain positively charged core infinite coordination polymer nanoparticles.

[0048] Step 4: 0.5 mg of gossypol and 5.0 mg of CA4 were dissolved in 1.5 mL of anhydrous ethanol and dispersed under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixed stock solution B;

[0049] Step 5: Take 10 mg mL -1 20 μL of copper chloride dihydrate ethanol solution was rapidly added dropwise to the coordinated drug mixed stock solution B in step 4 at a rate of 150 drops / min. During this process, magnetic stirring was performed at 600 rpm. After the addition was completed, stirring was maintained for 10 minutes;

[0050] Step 6: Rapidly add 10 mmol·L of 0.2% (w / w) Pluronic F127 to the core coordination drug-metal ion pre-reaction mixture described in step 5. -1 Tris(OH)-HCl buffer solution was added to adjust the solution pH to 7.4. During this process, magnetic stirring was maintained at 1800 rpm. After addition, stirring was performed in the dark for 72 hours to obtain negatively charged shell-infinite coordination polymer nanoparticles.

[0051] Step 7: Mix the inner core infinite coordination polymer nanoparticles obtained in step 3 and the outer shell infinite coordination polymer nanoparticles obtained in step 6 in water at a mass ratio of 1:1, and stir for 8 hours to obtain double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles.

[0052] Figure 2 This is a transmission electron microscope photograph of Example 1, showing the morphology of the product obtained in this example. Figure 2 A is a transmission electron micrograph of the core infinite coordination polymer nanoparticles obtained in this case, showing a size of 115.5±8.4nm. Figure 2 B is a transmission electron microscopy image of the shell infinite coordination polymer nanoparticles, showing a size of 8.5±5.2 nm. Figure 2 C is a double-layer multi-drug coordination polymer anti-tumor composite nanoparticle with a size of 138.1±13.7nm. Figure 2 D / E is the hydrated particle size and potential data of double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles and their components.

[0053] Figure 3 A / B are the X-ray diffraction results of Example 1, which show that the double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles obtained in this example are amorphous nanoparticles without obvious crystal structure. Figure 3 C1-3 is a comparison of the Fourier transform infrared absorption spectra of the double-layer infinite coordination polymer composite nanoparticles obtained in Example 1 and the single-layer infinite coordination polymer nanoparticles. Figure 3 D1-3 is the high-resolution XPS spectrum analysis and single-layer XPS spectrum analysis of the double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles obtained in Example 1. The above characterization results prove that the process of drug molecules and metal ions forming nanoparticles is coordination-induced self-assembly.

[0054] Table 1 shows the raw materials in Example 1 and the electron binding energies of key elements in the preparation of double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles.

[0055] Table 1 Raw materials and preparation ICPs The electron binding energy of the key elements in

[0056]

[0057] Example 2

[0058] This example includes the following steps:

[0059] Step 1: 0.5 mg of curcumin (Cur) and 5.0 mg of doxorubicin (Dox) were dissolved in 1.5 mL of anhydrous ethanol-water mixture with a volume ratio of 1:5, and dispersed under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixed stock solution A;

[0060] Step 2: Take 15 mg mL -1 40 μL of copper chloride dihydrate ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution A in step 1 at a rate of 100 drops / min. During this process, magnetic stirring was performed at 600 rpm. After the addition was completed, stirring was maintained for 10 minutes;

[0061] Step 3: Rapidly add 0.001 mol·L of 0.2% (w / w) Pluronic F127 to the core coordination drug-metal ion pre-reaction mixture in step 2. -1 The sodium hydroxide buffer solution was added to adjust the solution pH to 7.8. During this process, magnetic stirring was maintained at 1800 rpm. After addition, stirring was performed in the dark for 72 hours to obtain positively charged core infinite coordination polymer nanoparticles.

[0062] Step 4: Dissolve 0.5 mg of gossypol and 0.5 mg of CA4 in 1.5 mL of a 1:5 ethanol-water mixture, and disperse under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixture stock solution B.

[0063] Step 5: Take 15 mg mL -1 40 μL of copper chloride dihydrate ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution B in step 1 at a rate of 100 drops / min. During this process, magnetic stirring was performed at 600 rpm. After the addition was completed, stirring was maintained for 10 minutes;

[0064] Step 6: Rapidly add 0.001 mol·L of 0.2% (w / w) Pluronic F127 to the pre-reaction mixture of the shell coordination drug and metal ion described in step 5. -1The sodium hydroxide buffer solution was added to adjust the solution pH to 7.8. During this process, magnetic stirring was maintained at 1800 rpm. After addition, stirring was performed in the dark for 72 hours to obtain negatively charged shell infinite coordination polymer nanoparticles.

[0065] Step 7: The core infinite coordination polymer nanoparticles obtained in step 3 and the shell infinite coordination polymer nanoparticles obtained in step 6 are mixed in water at a mass ratio of 1:2, and stirred for 8 hours to obtain double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles.

[0066] The size of the inner core infinite coordination polymer nanoparticles obtained in this example was 135.5±8.4 nm, the outer shell infinite coordination polymer nanoparticles showed a size of 7.5±3.9 nm, and the size of the double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles was 150.1±13.8 nm.

[0067] Example 3

[0068] This example includes the following steps:

[0069] Step 1: 5.0 mg of curcumin (Cur) and 1.0 mg of aquinone dihydrochloride (AQ4N) were dissolved in 1.5 mL of a 5:1 anhydrous ethanol-water mixed solution and dispersed under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixed stock solution A;

[0070] Step 2: Take 20 mg mL -1 60 μL of copper chloride dihydrate ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution A in step 1 at a rate of 200 drops / min. During this process, magnetic stirring was performed at 600 rpm. After the addition was completed, stirring was maintained for 10 minutes;

[0071] Step 3: Rapidly add 0.2% (w / w) Pluronic F127 in 0.1% (w / w) triethylamine buffer to the core-coordinated drug-metal ion pre-reaction mixture described in Step 2, adjusting the solution pH to 8.5. Maintain magnetic stirring at 1800 rpm during this process. After addition, stir in the dark for 72 hours to obtain positively charged core-infinite coordination polymer nanoparticles.

[0072] Step 4: 5.0 mg of gossypol and 0.5 mg of CA4 were dissolved in 1.5 mL of a 5:1 anhydrous ethanol-water mixture, and dispersed under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixture stock solution B.

[0073] Step 5: Take 20 mg mL -160 μL of copper chloride dihydrate ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution B in step 1 at a rate of 200 drops / min. During this process, magnetic stirring was performed at 600 rpm. After the addition was completed, stirring was maintained for 10 minutes;

[0074] Step 6: Rapidly add 0.2% (w / w) Pluronic F127 in 0.1% (w / w) triethylamine buffer to the core-coordinated drug-metal ion pre-reaction mixture described in Step 5, adjusting the solution pH to 8.5. Maintain magnetic stirring at 1800 rpm during this process. After addition, stir in the dark for 72 hours to obtain negatively charged shell-infinite coordination polymer nanoparticles.

[0075] Step 7: Mix the core infinite coordination polymer nanoparticles obtained in step 3 and the shell infinite coordination polymer nanoparticles obtained in step 6 in water at a mass ratio of 1:3, and stir for 8 hours to obtain double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles.

[0076] The size of the inner core infinite coordination polymer nanoparticles obtained in this example was 130.5±8.4 nm, the outer shell infinite coordination polymer nanoparticles showed a size of 4.4±2.9 nm, and the size of the double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles was 150±10.7 nm.

[0077] Example 4

[0078] This example includes the following steps:

[0079] Step 1: 2.0 mg of curcumin (Cur) and 1.0 mg of epigallocatechin gallate (EGCG) were dissolved in 1.5 mL of anhydrous ethanol-water mixture with a volume ratio of 2:3, and dispersed under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixed stock solution A;

[0080] Step 2: Take 10 mg mL -1 80 μL of ferric chloride hexahydrate ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution A in step 1 at a rate of 100 drops / min. During this process, magnetic stirring was performed at 600 rpm. After the addition was completed, stirring was maintained for 10 minutes;

[0081] Step 3: Rapidly add 0.2 mol·L of 0.2% (w / w) Pluronic F127 to the core coordination drug-metal ion pre-reaction mixture in step 2. -1 Potassium dihydrogen phosphate-sodium hydroxide buffer solution was added to adjust the solution pH to 7.4. During this process, magnetic stirring was maintained at 1800 rpm. After addition, the mixture was stirred in the dark for 72 hours to obtain positively charged core infinite coordination polymer nanoparticles.

[0082] Step 4: 1.0 mg of gossypol and 2.0 mg of CA4 were dissolved in 1.5 mL of a 2:3 anhydrous ethanol-water mixture, and dispersed under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixture stock solution B;

[0083] Step 5: Take 10 mg mL -1 80 μL of ferric chloride hexahydrate ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution B in step 4 at a rate of 100 drops per minute. During this process, magnetic stirring was performed at 600 rpm. After the addition was completed, stirring was maintained for 10 minutes;

[0084] Step 6: Rapidly add 0.2 mol·L of Pluronic F127 containing 0.2% (w / w) to the shell coordination drug-metal ion pre-reaction mixture in step 5. -1 Potassium dihydrogen phosphate-sodium hydroxide buffer solution was added to adjust the solution pH to 7.4. During this process, magnetic stirring was maintained at 1800 rpm. After addition, the mixture was stirred in the dark for 72 hours to obtain negatively charged shell infinite coordination polymer nanoparticles.

[0085] Step 7: The core infinite coordination polymer nanoparticles obtained in step 3 and the shell infinite coordination polymer nanoparticles obtained in step 6 are mixed in water at a mass ratio of 1:4, and stirred for 8 hours to obtain double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles.

[0086] The size of the inner core infinite coordination polymer nanoparticles obtained in this example was 135.5±8.4 nm, the outer shell infinite coordination polymer nanoparticles showed a size of 7.4±3.9 nm, and the size of the double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles was 160.1±13.7 nm.

[0087] Example 5

[0088] This example includes the following steps:

[0089] Step 1: 2.0 mg of curcumin (Cur) and 5.0 mg of 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH) were dissolved in 1.5 mL of a 3:2 anhydrous ethanol-water mixed solution and dispersed under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixed stock solution A;

[0090] Step 2: Take 15 mg mL -1 100 μL of ferric chloride hexahydrate ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution A in step 1 at a rate of 150 drops / min. During this process, magnetic stirring was performed at 600 rpm. After the addition was completed, stirring was maintained for 10 minutes;

[0091] Step 3: Rapidly add 0.2 mol·L of 0.2% (w / w) Pluronic F127 to the core coordination drug-metal ion pre-reaction mixture in step 2. -1 Boric acid-borax buffer solution was added to adjust the solution pH to 7.4. During this process, magnetic stirring was maintained at 1800 rpm. After addition, the mixture was stirred in the dark for 72 hours to obtain positively charged core infinite coordination polymer nanoparticles.

[0092] Step 4: Dissolve 0.5 mg of gossypol and 2 mg of CA4 in 1.5 mL of a 3:2 ethanol-water mixture, and disperse under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixture stock solution B.

[0093] Step 5: Take 15 mg mL -1 100 μL of ferric chloride hexahydrate ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution B in step 4 at a rate of 150 drops / min. During this process, magnetic stirring was performed at 600 rpm, and stirring was maintained for 10 minutes after the addition was completed;

[0094] Step 6: Rapidly add 0.2 mol·L of Pluronic F127 containing 0.2% (w / w) to the shell coordination drug-metal ion pre-reaction mixture in step 5. -1 Boric acid-borax buffer solution was added to adjust the solution pH to 7.4. During this process, magnetic stirring was maintained at 1800 rpm. After addition, the mixture was stirred in the dark for 72 hours to obtain negatively charged shell-infinite coordination polymer nanoparticles.

[0095] Step 7: The core infinite coordination polymer nanoparticles obtained in step 3 and the shell infinite coordination polymer nanoparticles obtained in step 6 are mixed in water at a mass ratio of 1:5, and stirred for 8 hours to obtain double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles.

[0096] The size of the inner core infinite coordination polymer nanoparticles obtained in this example was 125.5±8.4 nm, the outer shell infinite coordination polymer nanoparticles showed a size of 5.9±3.7 nm, and the size of the double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles was 155.1±10.7 nm.

[0097] Example 6

[0098] This example includes the following steps:

[0099] Step 1: Dissolve 1.0 mg of benoxanthraquinone dihydrochloride (AQ4N) and 2.0 mg of doxorubicin (Dox) in 1.5 mL of a 1:5 volume ratio of anhydrous ethanol-dimethyl sulfoxide mixture, and disperse under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixture stock solution A.

[0100] Step 2: Take 20 mg mL -1 120 μL of ferric chloride hexahydrate ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution A in step 1 at a rate of 200 drops / min. During this process, magnetic stirring was performed at 600 rpm. After the addition was completed, stirring was maintained for 10 minutes;

[0101] Step 3: Rapidly add a tris(hydroxymethyl)methane-hydrochloric acid buffer solution containing 0.2% (w / w) hexadecyltrimethylammonium chloride to the pre-reaction mixture of the core-coordinated drug and the metal ion described in Step 2, and adjust the solution pH to 8.5. Maintain magnetic stirring at 1800 rpm during this process. After addition, stir in the dark for 72 hours to obtain positively charged core-infinite coordination polymer nanoparticles.

[0102] Step 4: 3.0 mg of gossypol and 0.5 mg of CA4 were dissolved in 1.5 mL of a 1:5 volume ratio of anhydrous ethanol-dimethyl sulfoxide mixture, and dispersed under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixture stock solution B;

[0103] Step 5: Take 20 mg mL -1 120 μL of ferric chloride hexahydrate ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution B in step 4 at a rate of 200 drops / min. During this process, magnetic stirring was performed at 600 rpm. After the addition was completed, stirring was maintained for 10 minutes;

[0104] Step 6: Rapidly add a tris(hydroxymethyl)methane-hydrochloric acid buffer solution containing 0.2% (w / w) hexadecyltrimethylammonium chloride to the pre-reaction mixture of the shell-coordinated drug and the metal ion described in Step 5, and adjust the solution pH to 8.5. Maintain magnetic stirring at 1800 rpm during this process. After addition, stir in the dark for 72 hours to obtain negatively charged shell-infinite coordination polymer nanoparticles.

[0105] Step 7: The core infinite coordination polymer nanoparticles obtained in step 3 and the shell infinite coordination polymer nanoparticles obtained in step 6 are mixed in water at a mass ratio of 1:6, and stirred for 8 hours to obtain double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles.

[0106] The size of the inner core infinite coordination polymer nanoparticles obtained in this example was 100±10.4 nm, the outer shell infinite coordination polymer nanoparticles showed a size of 10.2±4.6 nm, and the size of the double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles was 130.1±15.7 nm.

[0107] Example 7

[0108] This example includes the following steps:

[0109] Step 1: 1.0 mg of doxorubicin (Dox) and 0.5 mg of epigallocatechin gallate (EGCG) were dissolved in 1.5 mL of a 5:1 ethanol-dimethyl sulfoxide mixture and dispersed under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixture stock solution A.

[0110] Step 2: Take 10 mg mL -1 140 μL of ferrous chloride ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution A in step 1 at a rate of 100 drops / min. During this process, magnetic stirring was performed at 600 rpm. After the addition was completed, stirring was maintained for 10 minutes;

[0111] Step 3: Rapidly add 0.001 mol·L of 0.2% (w / w) hexadecyltrimethylammonium chloride to the core coordination drug-metal ion pre-reaction mixture in step 2. -1 Sodium hydroxide buffer solution was added and the pH was adjusted to 7.4. During this process, magnetic stirring was maintained at 1800 rpm. After addition, the mixture was stirred in the dark for 72 hours to obtain positively charged core infinite coordination polymer nanoparticles.

[0112] Step 4: 1.0 mg of gossypol and 2.0 mg of CA4 were dissolved in 1.5 mL of a 5:1 mixed solution of anhydrous ethanol and dimethyl sulfoxide, and dispersed under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixed stock solution B;

[0113] Step 5: Take 10 mg mL -1 140 μL of ferrous chloride ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution B in step 4 at a rate of 100 drops / min. During this process, magnetic stirring was performed at 600 rpm, and stirring was maintained for 10 minutes after the addition was completed;

[0114] Step 6: Rapidly add 0.001 mol·L of 0.2% (w / w) hexadecyltrimethylammonium chloride to the pre-reaction mixture of the shell coordination drug and metal ion in step 5. -1Sodium hydroxide buffer solution was added to adjust the solution pH to 7.4. During this process, magnetic stirring was maintained at 1800 rpm. After addition, the mixture was stirred in the dark for 72 hours to obtain negatively charged shell infinite coordination polymer nanoparticles.

[0115] Step 7: The core infinite coordination polymer nanoparticles obtained in step 3 and the shell infinite coordination polymer nanoparticles obtained in step 6 are mixed in water at a mass ratio of 1:7, and stirred for 8 hours to obtain double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles.

[0116] The size of the inner core infinite coordination polymer nanoparticles obtained in this example was 140±10.4 nm, the outer shell infinite coordination polymer nanoparticles showed a size of 13.2±4.6 nm, and the size of the double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles was 175.1±17.7 nm.

[0117] Example 8

[0118] This example includes the following steps:

[0119] Step 1: Dissolve 1.0 mg of doxorubicin (Dox) and 5.0 mg of 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH) in 1.5 mL of a 2:3 mixture of anhydrous ethanol and dimethyl sulfoxide (DMSO) and disperse under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixture stock solution A.

[0120] Step 2: Take 15 mg mL -1 160 μL of ferrous chloride ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution A in step 1 at a rate of 200 drops / min. During this process, magnetic stirring was performed at 600 rpm. After the addition was completed, stirring was maintained for 10 minutes;

[0121] Step 3: Rapidly add 0.2% (w / w) hexadecyltrimethylammonium chloride in 0.1% triethylamine buffer to the core-coordinated drug-metal ion pre-reaction mixture described in Step 2, adjusting the solution pH to 7.4. Maintain magnetic stirring at 1800 rpm during this process. After addition, stir in the dark for 72 hours to obtain positively charged core-infinite coordination polymer nanoparticles.

[0122] Step 4: Dissolve 2.0 mg of gossypol and 3.0 mg of CA4 in 1.5 mL of a 2:3 mixed solution of anhydrous ethanol and dimethyl sulfoxide, and disperse them under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixed stock solution B.

[0123] Step 5: Take 15 mg mL -1160 μL of ferrous chloride ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution B in step 4 at a rate of 200 drops / min. During this process, magnetic stirring was performed at 600 rpm, and stirring was maintained for 10 minutes after the addition was completed;

[0124] Step 6: Rapidly add 0.2% (w / w) hexadecyltrimethylammonium chloride in 0.1% triethylamine buffer to the pre-reaction mixture of the shell-coordinated drug and metal ion described in Step 5, adjusting the pH to 7.4. Maintain magnetic stirring at 1800 rpm during this process. After addition, stir in the dark for 72 hours to obtain negatively charged shell-infinite coordination polymer nanoparticles.

[0125] Step 7: The core infinite coordination polymer nanoparticles obtained in step 3 and the shell infinite coordination polymer nanoparticles obtained in step 6 are mixed in water at a mass ratio of 1:8, and stirred for 8 hours to obtain double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles.

[0126] The size of the inner core infinite coordination polymer nanoparticles obtained in this example was 130±10.4 nm, the outer shell infinite coordination polymer nanoparticles showed a size of 12.2±4.7 nm, and the size of the double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles was 150.1±16.3 nm.

[0127] Embodiment 9

[0128] This example includes the following steps:

[0129] Step 1: 2.0 mg of epigallocatechin gallate (EGCG) and 0.5 mg of aquinone dihydrochloride (AQ4N) were dissolved in 1.5 mL of a 3:2 volume ratio of anhydrous ethanol-dimethyl sulfoxide mixture, and dispersed under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixture stock solution A;

[0130] Step 2: Take 20 mg mL -1 180 μL of ferrous chloride ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution A in step 1 at a rate of 150 drops / min. During this process, magnetic stirring was performed at 600 rpm. After the addition was completed, stirring was maintained for 10 minutes;

[0131] Step 3: Rapidly add 0.2 mol·L of 0.2% (w / w) hexadecyltrimethylammonium chloride to the core coordination drug-metal ion pre-reaction mixture in step 2. -1 Potassium dihydrogen phosphate-sodium hydroxide buffer solution was added to adjust the solution pH to 8.5. During this process, magnetic stirring was maintained at 1800 rpm. After addition, the mixture was stirred in the dark for 72 hours to obtain positively charged core infinite coordination polymer nanoparticles.

[0132] Step 4: 1.0 mg of gossypol and 3.0 mg of CA4 were dissolved in 1.5 mL of a 3:2 volume ratio of anhydrous ethanol-dimethyl sulfoxide mixture, and dispersed under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixture stock solution B;

[0133] Step 5: Take 20 mg mL -1 180 μL of ferrous chloride ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution B in step 4 at a rate of 150 drops / min. During this process, magnetic stirring was performed at 600 rpm. After the addition was completed, stirring was maintained for 10 minutes;

[0134] Step 6: Rapidly add 0.2 mol·L of 0.2% (w / w) hexadecyltrimethylammonium chloride to the pre-reaction mixture of the shell-coordinated drug and the metal ion in step 5. -1 Potassium dihydrogen phosphate-sodium hydroxide buffer solution was added to adjust the solution pH to 8.5. During this process, magnetic stirring was maintained at 1800 rpm. After addition, the mixture was stirred in the dark for 72 hours to obtain negatively charged shell infinite coordination polymer nanoparticles.

[0135] Step 7: The core infinite coordination polymer nanoparticles obtained in step 3 and the shell infinite coordination polymer nanoparticles obtained in step 6 are mixed in water at a mass ratio of 1:9, and stirred for 8 hours to obtain double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles.

[0136] The size of the inner core infinite coordination polymer nanoparticles obtained in this example was 120±10.4 nm, the outer shell infinite coordination polymer nanoparticles showed a size of 16.2±5.3 nm, and the size of the double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles was 153.1±17.4 nm.

[0137] Example 10

[0138] This example includes the following steps:

[0139] Step 1: 5.0 mg of epigallocatechin gallate (EGCG) and 0.5 mg of 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH) were dissolved in 1.5 mL of a 4:1 mixed solution of anhydrous ethanol and dimethyl sulfoxide, and dispersed under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixed stock solution A;

[0140] Step 2: Take 15 mg mL -1200 μL of copper chloride dihydrate ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution A in step 1 at a rate of 150 drops / min. During this process, magnetic stirring was performed at 600 rpm. After the addition was completed, stirring was maintained for 10 minutes;

[0141] Step 3: Rapidly add 0.2 mol·L of 0.2% (w / w) hexadecyltrimethylammonium chloride to the core coordination drug-metal ion pre-reaction mixture in step 2. -1 Boric acid-borax buffer solution was added to adjust the solution pH to 7.4. During this process, magnetic stirring was maintained at 1800 rpm. After addition, the mixture was stirred in the dark for 72 hours to obtain positively charged core infinite coordination polymer nanoparticles.

[0142] Step 4: 3.0 mg of gossypol and 1.0 mg of CA4 were dissolved in 1.5 mL of a 4:1 mixed solution of anhydrous ethanol and dimethyl sulfoxide, and dispersed under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixed stock solution B;

[0143] Step 5: Take 15 mg mL -1 200 μL of copper chloride dihydrate ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution B in step 1 at a rate of 150 drops / min. During this process, magnetic stirring was performed at 600 rpm. After the addition was completed, stirring was maintained for 10 minutes;

[0144] Step 6: Rapidly add 0.2 mol·L of 0.2% (w / w) hexadecyltrimethylammonium chloride to the pre-reaction mixture of the shell-coordinated drug and the metal ion in step 5. -1 Boric acid-borax buffer solution, adjusted to pH 7.4. During this process, magnetic stirring was maintained at 1800 rpm; after addition, the mixture was stirred in the dark for 72 hours to obtain negatively charged shell infinite coordination polymer nanoparticles;

[0145] Step 7: Mix the inner core infinite coordination polymer nanoparticles obtained in step 3 and the outer shell infinite coordination polymer nanoparticles obtained in step 6 in water at a mass ratio of 1:10, and stir for 8 hours to obtain double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles.

[0146] The size of the inner core infinite coordination polymer nanoparticles obtained in this example was 120±10.4 nm, the outer shell infinite coordination polymer nanoparticles showed a size of 14.0±5.6 nm, and the size of the double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles was 152±16.8 nm.

[0147] In summary, the present invention first dissolves the drug in a solvent such as ethanol according to a specific example to prepare a core coordination drug mixed solution A and a shell coordination drug mixed solution B, then quickly adds a transition metal chloride ethanol solution to the core coordination drug mixed solution A and the shell coordination drug mixed solution B, respectively, then adds an alkaline solution containing a surfactant to the core coordination drug mixed solution A and the shell coordination drug mixed solution B to adjust the pH, and reacts at room temperature; finally, the two nanoparticles are combined in different proportions to ultimately obtain a double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticle.

Claims

1. A double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticle, characterized in that: The core coordination drug molecules are selected from: curcumin (Cur), doxorubicin (Dox), banoanthraquinone dihydrochloride (AQ4N), epigallocatechin gallate (EGCG) and 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH). When preparing the core, two core coordination drugs are arbitrarily selected to coordinate with metal ions to form different positively charged infinite coordination polymer nanoparticles; the shell drug molecules are selected from: gossypol (Gossypol) and compretin (CA4). When preparing the shell, gossypol (Gossypol) and compretin (CA4) are coordinated with metal ions to form negatively charged infinite coordination polymer nanoparticles; the core and shell infinite coordination polymer nanoparticles with different charges are assembled into double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles.

2. The double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticle according to claim 1, characterized in that: The mass ratio of the two core coordination drugs selected when preparing the core is (0.5-5.0): (0.5-5.0).

3. The double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticle according to claim 1, characterized in that: When preparing the shell, the mass ratio of gossypol (Gossypol) and combretin (CA4) is (0.5-5.0): (0.5-5.0).

4. The double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticle according to claim 1, characterized in that: The mass ratio of the core and shell infinite coordination polymer nanoparticles with different charges is 1:(1-10).

5. The double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticle according to claim 1, characterized in that: The amount of metal ions added is sufficient to ensure excess reaction.

6. A method for preparing double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles, characterized in that: It includes the following steps: Step 1: Preparation of mixed stock solution of core infinite coordination polymer nanoparticles: 0.5-5.0 mg of any two core coordination drug molecules were dissolved in 1.5 mL of solvent and dispersed under 50 kHz ultrasound for 10 minutes to prepare coordination drug mixed stock solution A; The solvents include: anhydrous ethanol, a mixed solvent of anhydrous ethanol and water, and a mixed solvent of anhydrous ethanol and dimethyl sulfoxide; the volume ratio of the mixed solvent is between 1:5 and 5:1; The core-coordinated drug molecules are selected from any two of the following different molecules: curcumin (Cur), doxorubicin (Dox), banoanthraquinone dihydrochloride (AQ4N), epigallocatechin gallate (EGCG) and 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH); Step 2: Preparation of core coordination drug-metal ion pre-reaction mixture: Take 10-20 mg mL -1 20-200 μL of the transition metal chloride ethanol solution is rapidly added dropwise to the coordination drug mixed solution A described in step 1 at a rate of 100-200 drops / min, with magnetic stirring at 600 rpm during the process, and stirring is continued for 10 minutes after the addition is completed; The transition metal chloride salts include: cupric chloride dihydrate, ferric chloride hexahydrate, and ferrous chloride; Step 3: Preparation of core infinite coordination polymer nanoparticles: Adding a mixed solution of an alkaline buffer solution and a surfactant to the core coordination drug-metal ion pre-reaction mixture of step 2, adjusting the solution pH to 7.4-8.5, maintaining magnetic stirring at 1800 rpm during this process, and stirring in the dark for 72 hours after the addition to obtain positively charged core infinite coordination polymer nanoparticles; The alkaline buffer solution includes: 10 mmol·L -1 Tris-hydrochloric acid buffer solution, 0.001 mol·L -1 Sodium hydroxide, 0.1% (w / w) triethylamine solution, 0.2 mol·L -1 Potassium dihydrogen phosphate-sodium hydroxide buffer solution, 0.2 mol·L -1 Boric acid-borax buffer solution; the pH of the alkaline buffer solution is 7.5-8.5; The surfactant includes: Pluronic F127, cetyltrimethylammonium chloride; the content of the surfactant is 0.2% (w / w); Step 4: Preparation of mixed stock solution of shell infinite coordination polymer nanoparticles: 0.5-5.0 mg of gossypol and CA4 were dissolved in 1.5 mL of solvent respectively, and dispersed under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixed stock solution B; The solvent includes: anhydrous ethanol, a mixed solvent of anhydrous ethanol-water, and a mixed solvent of anhydrous ethanol-dimethyl sulfoxide; the volume ratio of the mixed solvent is between (1:5) and (5:1); Step 5: Preparation of shell coordination drug-metal ion pre-reaction mixture: Take 10-20 mg mL -1 20-200 μL of the transition metal chloride ethanol solution is added dropwise to the coordination drug mixed solution B described in step 4 at a rate of 100-200 drops / min, with magnetic stirring at 600 rpm during the process, and stirring is maintained for 10 minutes after the addition is completed; The transition metal chloride salts include: cupric chloride dihydrate, ferric chloride hexahydrate, and ferrous chloride; Step 6: Preparation of shell infinite coordination polymer nanoparticles: Adding a mixed solution of an alkaline buffer solution and a surfactant to the pre-reaction mixture of the shell-coordinated drug and the metal ion described in step 5, adjusting the pH of the solution to 7.4-8.5, maintaining magnetic stirring at 1800 rpm; stirring in the dark for 72 hours after the addition, to obtain negatively charged shell-infinite coordination polymer nanoparticles; The alkaline buffer solution includes: 10 mmol·L -1 Tris-hydrochloric acid buffer solution, 0.001 mol·L -1 Sodium hydroxide, 0.1% (w / w) triethylamine solution, 0.2 mol·L -1 Potassium dihydrogen phosphate-sodium hydroxide buffer solution, 0.2 mol·L -1 Boric acid-borax buffer solution; the pH of the alkaline buffer solution is 7.5-8.5; The surfactant includes: Pluronic F127, cetyltrimethylammonium chloride; the content of the surfactant is 0.2% (w / w); Step 7: Preparation of double-layer multi-drug unlimited coordination polymer composite nanoparticles: The inner core infinite coordination polymer nanoparticles obtained in step 3 and the outer shell infinite coordination polymer nanoparticles obtained in step 6 are mixed in water at a mass ratio of 1:(1-10), and stirred for 8 hours to obtain double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles.

7. The method for preparing a double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticle according to claim 6, characterized in that: The following steps are involved: Step 1: 1.0 mg of benoxanthraquinone dihydrochloride (AQ4N) and 1.0 mg of 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH) were dissolved in 1.5 mL of anhydrous ethanol and dispersed under 50 kHz ultrasound for 10 minutes to prepare a coordination drug mixed stock solution A; Step 2: Take 10 mg mL -1 20 μL of copper chloride dihydrate ethanol solution was rapidly added dropwise to the coordination drug mixed stock solution A in step 1 at a rate of 150 drops / min; during this process, magnetic stirring was performed at 600 rpm, and stirring was maintained for 10 minutes after the addition was completed; Step 3: Rapidly add 10 mmol·L of 0.2% (w / w) Pluronic F127 to the core coordination drug-metal ion pre-reaction mixture in step 2. -1 Tris(hydroxymethylaminomethane)-hydrochloric acid buffer solution was added to adjust the solution pH to 7.4; during this process, magnetic stirring was maintained at 1800 rpm; after addition, stirring was performed in the dark for 72 hours to obtain positively charged core infinite coordination polymer nanoparticles; Step 4: 0.5 mg of gossypol and 5.0 mg of CA4 were dissolved in 1.5 mL of anhydrous ethanol and dispersed under 50 kHz ultrasound for 10 minutes to prepare a coordinated drug mixed stock solution B; Step 5: Take 10 mg mL -1 20 μL of copper chloride dihydrate ethanol solution was rapidly added dropwise to the coordinated drug mixed solution B in step 4 at a rate of 150 drops / min; during this process, magnetic stirring was performed at 600 rpm, and stirring was maintained for 10 minutes after the addition was completed; Step 6: Rapidly add 10 mmol·L of 0.2% (w / w) Pluronic F127 to the core coordination drug-metal ion pre-reaction mixture described in step 5. -1 Tris(OH)-hydrochloric acid buffer solution was added to adjust the solution pH to 7.4; during this process, magnetic stirring was maintained at 1800 rpm; after addition, stirring was performed in the dark for 72 hours to obtain negatively charged shell infinite coordination polymer nanoparticles; Step 7: Mix the inner core infinite coordination polymer nanoparticles obtained in step 3 and the outer shell infinite coordination polymer nanoparticles obtained in step 6 in water at a mass ratio of 1:1, and stir for 8 hours to obtain double-layer multi-drug infinite coordination polymer anti-tumor composite nanoparticles.

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