WO2018133687A1

WO2018133687A1 - Preparation and application of amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy

Info

Publication number: WO2018133687A1
Application number: PCT/CN2018/071741
Authority: WO
Inventors: Shuting XU; Deyue Yan; Wei Huang; Xinyuan Zhu; Yongfeng ZHOU
Original assignee: Shanghai Jiaotong University
Priority date: 2017-01-18
Filing date: 2018-01-08
Publication date: 2018-07-26
Also published as: CN106860872A; CN106860872B

Abstract

An amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy, which is formed through coordination of a histone deacetylase inhibitor with a platinum-based antitumor agent and self-assembly in water. After entering tumor cells, the amphiphilic drug-drug nanoparticle can hydrolyze to release two drug agents. The amphiphilic complex can self-assemble into nanoparticles in water without any carriers, and the complex can realize drug delivery by itself. At the meantime, the amphiphilic drug-drug nanoparticle can effectively enter tumor cells, reduce the blocking effect of sulfur-containing ligands in blood on cisplatin, and decrease the toxic and side effects towards normal cells. It can also be hydrolyzed to release the histone deacetylase inhibitor and platinum-based antitumor active agents, thereby achieving the synergistic effect for reversing platinum-based drug resistance in cancer therapy and the purpose of cancer treatment.

Description

Preparation and Application of Amphiphilic Drug-Drug Nanoparticle for Reversing Platinum-Based Anticancer Drug Resistance in Cancer Therapy

Technical Field

The present invention belongs to the technical field of antitumor drugs, and in particular to the preparation and application of an amphiphilic drug-drug nanoparticle for reversing multi-drug resistance in tumor therapy towards platinum-based anticancer drug.

Background

Malignant tumors (cancers) have been the leading cause of rising mortality in all countries of the world. Therefore, how to effectively treat malignant tumors has become one of the most urgent problems around the world. Currently, cancer treatments include the following approaches: surgical resection, chemotherapy, radiotherapy, ablation, immunotherapy and biotherapy. Among these, chemotherapy is one of the most convenient and extensive applied treatments, in which platinum-based anticancer drugs are the most widely used.

However, most of platinum-based antitumor agents have the following problems, for example, poor solubility, no selectivity, large side effects on normal tissues, tendency of being removed from the blood, and high risk of causing multi-drug resistance after administration for a certain period of time, and even some tumors (such as colon cancer and non-small cell lung cancer) have intrinsic resistance to cisplatin. In the existing technology, in order to solve the problems of poor solubility and short blood retention time, a large number of literatures have reported the use of nano-scale materials as the carrier of antitumor drugs. The carriers can deliver drugs into cancer cells to achieve the purpose of killing cancer cells, and specifically include water-soluble polymers (Advanced Drug Delivery Reviews 2009, 61 (13) , 1214-1219) , liposomes (Anticancer Research 2006, 26 (2B) , 1489-1493) , vesicles (Journal of the American Chemical Society 2005, 127 (23) , 8236-8237) , polymer nanoparticles (Bioconjugate Chemistry 2010, 21 (2) , 328-337) , inorganic materials (ACS Nano 2008, 2 (10) , 2057-2064; Journal of the American Chemical Society 2008, 130 (34) , 11467-11476) , and so on. However, these nano-sized carriers, after delivering the drug into cancer cells, fail to effectively overcome multi-drug resistance of cancer cells towards the platinum-based anticancer drug. At the meantime, the carrier itself needs to be excreted through organs such as the kidneys, resulting in renal inflammations or other disorders.

Summary

The first object of the present invention is to provide an amphiphilic drug-drug nanoparticle for reversing multi-drug resistance in cancer therapy, so as to solve the problems in the prior technique, for example, platinum-based anticancer drug-resistance of tumors and high risk of renal inflammations or other disorders caused by nano-carrier excretion through organs such as the kidneys after drug delivery.

The second object of the present invention is to provide a method for preparing the amphiphilic drug-drug nanoparticle, so as to solve the problems in the prior technique, for example, platinum-based anticancer drug resistance of tumors and high risk of renal inflammations or other disorders caused by nano-carrier excretion through organs such as the kidneys after drug delivery. The third object of the present invention is to provide applications of the amphiphilic drug-drug nanoparticle, so as to solve the problems in the prior technique, for example, platinum-based anticancer drug resistance of tumors and high risk of renal inflammations or other disorders caused by nano-carrier excretion through organs such as the kidneys after drug delivery.

The technical solution provided by the present invention is as follows:

An amphiphilic drug-drug nanoparticle, which can reverse platinum-based anticancer drug resistance in cancer therapy, is formed by a coordination reaction of a histone deacetylase inhibitor with a platinum-based antitumor agent and self-assembly in water; and after entering tumor cells, the amphiphilic drug-drug nanoparticle is hydrolyzed to release the histone deacetylase inhibitor and the platinum-based antitumor active agent.

Further preferably, the amphiphilic drug-drug nanoparticle has a particle size less than 100 nm. Further preferably, the histone deacetylase inhibitor is hydrophobic and may be one selected from vorinostat, trichostatin A, N-hydroxy-N'-3-pyridinyloctanediamide (pyroxamide) , 2-propenamide, 3, 4-dihydroxybenzohydroxamic acid (Dido) , 4-phenylbutyric acid, 2-propylpentanoic acid, N-butyric acid, sodium phenylbutyrate, sodium 2-propylpentanoate or sodium buntanoate.

Further preferably, the platinum-based antitumor agent may be one selected from cisplatin, transplatin, trans-dichlorodipridine platinum (trans- [PtCl ₂ (py) ₂] ) or picoplatin.

This invention also discloses a method of preparing the amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy, including the following steps:

(1) coordinating the histone deacetylase inhibitor with the platinum-based antitumor agent to obtain an amphiphilic drug-drug complex;

(2) dissolving the amphiphilic drug-drug complex in an organic solvent, adding the resulting solution dropwise into water at room temperature, removing the organic solvent to obtain an aqueous solution of amphiphilic drug-drug nanoparticle, and performing post-treatment to obtain the amphiphilic drug-drug nanoparticle. The organic solvent is selected from N, N'-dimethylformamide, dimethyl sulfoxide and methanol.

Further preferably, the coordination reaction in step (1) is one selected from the following two processes:

process 1: dissolving the platinum-based antitumor agent together with silver nitrate in an organic solvent, allowing the reaction to take place, removing precipitation of silver chloride, and collecting the supernatant as solution 1; mixing and dispersing the histone deacetylase inhibitor and alkali in an organic solvent, allowing the reaction to take place, removing insoluble matter, and collecting the supernatant as solution 2; then, mixing the solution 1 and solution 2 for reaction, removing the organic solvents and extracting to obtain the amphiphilic drug-drug complex;

process 2: dissolving the platinum-based anticancer drug together with silver nitrate in water, allowing the reaction to take place, removing precipitation of silver chloride, and collecting the supernatant as solution 3; then, adding the histone deacetylase inhibitor into the solution 3 for reaction, removing water and settling in ether to obtain the amphiphilic drug-drug complex.

Further preferably, in the process 1, the molar ratio of platinum-based antitumor agent to histone deacetylase inhibitor to silver nitrate is 1: 0.25-0.5: 0.95-1.05.

Further preferably, in the process 2, the molar ratio of platinum-based antitumor agent to histone deacetylase inhibitor to silver nitrate is 1: 2-3: 0.95-1.05.

Further preferably, the organic solvent is one of N, N'-dimethylformamide, dimethylsulfoxide or methanol; and the alkali is one of sodium hydroxide or sodium carbonate.

This invention also disclosed the usage of the amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy for preparing anticancer drug or anti-tumor-resistant drug.

As compared to the prior technique, the present invention has benefits as follows:

1. According to the amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy of the invention, the histone deacetylase inhibitor and the platinum-based antitumor agent are bonded via coordination bonds to provide the synergistic effect on antitumor treatment with simple preparation method, high yield and obvious effectiveness;

2. the amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy of the invention can self-assemble in water to form nanoparticles with a particle size less than 100 nm, which can achieve drug delivery without any carriers. Because of the enhanced penetration to tumor tissues and the retention effect, this drug-drug nanoparticle can accumulate in the tumor tissues, enter tumor cells more effectively, reduce the blocking effect of sulfur-containing ligands in the blood on cisplatin, and reduce the side effects on normal cells. After the nanoparticles enter tumor cells, the complex can be hydrolyzed to release the histone deacetylase inhibitor (HDACi) and platinum-based antitumor agent under the weakly acid environment in tumor tissues, which in turn provide the synergistic effect of reversing platinum-based drug resistance in cancer therapy and achieve the purpose of anticancer treatment. It should be understood that any product of the present invention may be implemented without needing to achieve all the above advantages at the same time.

Brief Description of the Drawings

Fig. 1 is the ¹H-NMR spectrum of the amphiphilic drug-drug complex of example 1;

Fig. 2 is the mass spectrum of the amphiphilic drug-drug complex of example 1;

Fig. 3 is the infrared spectrum of the amphiphilic drug-drug complex of example 1;

Fig. 4 is the dynamic light scattering and transmission electron microscopy photo of the amphiphilic drug-drug nanoparticle of example 1;

Fig. 5 is the growth inhibiting effect of the amphiphilic drug-drug nanoparticle (example 1) towards the tumor cell;

Fig. 6 schematically shows the mechanism of reversing drug resistance by the amphiphilic drug-drug nanoparticle (example 1) ;

Fig. 7 schematically shows the anticancer effect of the amphiphilic drug-drug complex (example 1) towards drug-resistant tumor.

Detailed Description of the Invention

The present invention will be described below with reference to specific embodiments. It should be understood that these embodiments are merely illustrative of the present invention, and not intended to limit the scope of the present invention. Modifications and changes made by those skilled in the technique according to the present invention in practical applications are still falling within the scope of the present invention.

Example 1

Disclosed in this example is a method for preparing an amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy, specifically including the following steps:

(1) firstly, dissolving 300 mg cisplatin (CDDP for short) and 169.87 mg silver nitrate in 10 mL N, N'-dimethylformamide, allowing the reaction to take place for 24h, removing precipitated silver chloride, and collecting the supernatant as solution 1; secondly, mixing and dispersing 88.1 mg vorinostat (SAHA for short) and 13.3 mg sodium hydroxide in 5 mL methanol, allowing the reaction to take place, removing insoluble matter, and collecting the supernatant as solution 2; and at last, mixing the solution 1 and solution 2, allowing the reaction to take place for 48 h, removing the organic solvents, dissolving in methanol, removing excessive CDDP and recrystallizing to obtain an amphiphilic drug-drug complex; the structural formula I is shown as below:

The ¹H-NMR spectrum, mass spectrum and infrared spectrum of the structural formula I are shown in Fig. 1, Fig. 2 and Fig. 3, respectively. ¹H NMR (400 MHz, DMSO-d6) δ (ppm) : 9.83 (1H, Ar-NH-C=O) , 7.55 (2H, -CH=C-NH) , 7.25 (2H, -CHCH=C-NH) , 6.98 (1H, -CH=CHCH=C-NH) , 3.94 (6H, Pt-NH ₃) , 2.28 (2H, -NH-O=C-CH ₂-CH ₂) , 1.91 (2H, -CH ₂-C=O-N) , 1.55 (4H, -CH ₂-CH ₂-CH ₂-CH ₂-) , 1.28 (4H, -CH ₂-CH ₂-CH ₂-CH ₂-) ; IRν _max/cm ^-1 1660vs (amide C=O) , 1599 s (hydroxamate C=O) , 1543vs (hydroxamate C-N) ; MS: 755.13 m/z.

(2) dissolving the obtained amphiphilic drug-drug complex in dimethylsulfoxide, adding the resulting solution dropwise into water at room temperature, removing dimethylsulfoxide to obtain an aqueous solution of amphiphilic drug-drug nanoparticles. The dynamic light scattering and transmission electron microscopy photo of the nanoparticles based on vorinostat-cisplatin complex obtained in this example is shown in Fig. 4, with the average size about 50 nm.

Example 2

(1) firstly, dissolving 391 mg picoplatin and 169.87 mg silver nitrate in 10 mL N, N'-dimethylformamide, allowing the reaction to take place for 24 h, removing precipitated silver chloride and collecting the supernatant as solution 1; secondly, mixing and dispersing 100.7 mg trichostatin A and 35.3 mg sodium carbonate in 5 mL methanol, allowing the reaction to take place, removing insoluble matter, and collecting the supernatant as solution 2; and at last, mixing the solution 1 and solution 2, allowing the reaction to take place for 48 h, removing the organic solvents, removing excessive picoplatin by dissolving with methanol, and recrystallizing to obtain an amphiphilic drug-drug complex; the structural formula II is shown as below:

(2) dissolving the obtained amphiphilic drug-drug complex in methanol, adding the resulting solution dropwise into water at room temperature, removing methanol to obtain an aqueous solution of amphiphilic drug-drug nanoparticles. The average size of the nanoparticles based on trichostatin A-picoplatin complex obtained in this example is about 80 nm.

Example 3

(1) firstly, dissolving 300 mg cisplatin and 169.87 mg silver nitrate in 10 mL N, N'-dimethylformamide, allowing the reaction to take place for 24 h, removing precipitated silver chloride, and collecting the supernatant as solution 1; secondly, mixing and dispersing 42.3 mg Dido and 35.3 mg sodium carbonate in 5 mL N, N'-dimethylformamide, allowing the reaction to take place, removing insoluble matter, and collecting the supernatant as solution 2; and at last mixing the solution 1 and solution 2, allowing the reaction to take place for 48 h, removing the organic solvents, dissolving in methanol, removing excessive cisplatin and recrystallizing to obtain an amphiphilic drug-drug complex; the structural formula III is shown as below:

(2) dissolving the obtained amphiphilic drug-drug complex in dimethylsulfoxide, adding the resulting solution dropwise into water at room temperature, removing dimethylsulfoxide to obtain an aqueous solution of amphiphilic drug-drug nanoparticles. The average size of the nanoparticles based on Dido-cisplatin complex obtained in this example is about 40 nm.

Example 4

(1) firstly, dissolving 300 mg cisplatin and 169.87 mg silver nitrate in 20 mL water, allowing the reaction to take place for 24 h, removing precipitated silver chloride, and collecting the supernatant as solution 3; secondly, adding 332 mg sodium 2-propylpentanoate into the solution 3, allowing the reaction to take place for 48 h, removing water, settling in ether to obtain an amphiphilic drug-drug complex; the structural formula IV is shown as below:

(2) dissolving the obtained amphiphilic drug-drug complex in dimethylsulfoxide, adding the resulting solution dropwise into water at room temperature, removing dimethylsulfoxide to obtain an aqueous solution of amphiphilic drug-drug nanoparticle, and performing post-treatment to obtain an amphiphilic drug-drug nanoparticle. The average particle size of the nanoparticles based on sodium 2-propylpentanoate-cisplatin complex obtained in this example is about 45 nm.

Example 5

(1) firstly, dissolving 391 mg picoplatin and 169.87 mg silver nitrate in 10 mL N, N'-dimethylformamide, allowing the reaction to take place for 24 h, removing precipitated silver chloride, and collecting the supernatant as solution 1; secondly, mixing 42.3 mg Dido and 80 mg sodium hydroxide, allowing the reaction to take place, removing insoluble matter, and collecting the supernatant as solution 2; and at last, mixing the solutions 1 and 2, allowing the reaction to take place for 48 h, removing the organic solvents, removing excessive picoplatin by dissolving with methanol, and recrystallizing to obtain an amphiphilic drug-drug complex; the structural formula V is shown as below:

(2) dissolving the obtained amphiphilic drug-drug complex in methanol, adding the resulting solution dropwise into water at room temperature, removing methanol to obtain an aqueous solution of amphiphilic drug-drug nanoparticles. The average size of the nanoparticles based on Dido-picoplatin complex obtained in this example is about 60 nm.

Shown below are the in vitro anticancer experiments of an amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy of the invention towards cell of non-small cell lung cancer.

Example 6

The amphiphilic drug-drug nanoparticle (CDDP-SAHA for short) obtained in example 1 (cisplatin/vorinostat in the molar ratio of 2) and cisplatin were respectively mixed with culture medium to form solutions with cisplatin concentrations of 0, 2.5, 5, 10, 20, 40, 80 μmol/L and corresponding vorinostat concentrations of 0, 1.25, 2.5, 5, 10, 20, 40 μmol/L. Then, A549 cells (non-small cell lung cancer) and A549/CDDP cells (cisplatin-resistant non-small cell lung cancer) were cultured in the solutions for 72 h, the cell viability was detected by MTT method and the results were shown in Fig. 5. It was shown that, as compared to free drug, the amphiphilic drug-drug nanoparticles exhibited significant cytotoxicity towards the common cancer cells. Furthermore, free cisplatin was substantially ineffective towards cisplatin-resistant non-small cell lung cancer cells. While, the amphiphilic drug-drug nanoparticles exhibits a significant effect towards both cells. Therefore, the amphiphilic drug-drug nanoparticle of the present invention has potential applications in reversing platinum-based anticancer drug resistance in cancer therapy. Shown below are the experiments on mechanism of an amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy of the invention.

Example 7

The amphiphilic drug-drug nanoparticle obtained in example 1 (2 μM) and cisplatin (4 μM) were co-cultured with A549 and A549/CDDP cells for 24 h, the content of platinum and the content of DNA-Pt adduct in the cells were measured by ICP-MS. As Figure 6a shown, CDDP-SAHA nano-drug can conspicuously improve the cellular uptake of cisplatin in both A549 and A549/DR cells (25-49 fold) , while little free cisplatin was internalized. The results in Figure 6b revealed that the cells treated with CDDP-SAHA nano-drug exhibited higher cellular DNA-bound platinum concentration than that treated with free CDDP for both A549 and A549/DR cells (4-4.2 fold) . These results suggested that CDDP-SAHA nano-drug could enhance the accumulation and internalization of CDDP in both A549 and A549/DR cells. This is the first explanation of CDDP-SAHA nano-drug overcoming drug-resistance of NSCLC.

Also, the amphiphilic drug-drug nanoparticle obtained in Example 1 (0, 4, 8μM) was co-cultured with A549/CDDP cells for 48 h, and the content of reduced glutathione in the cells was measured by using GSH and GSSG Assay Kit. As shown in Figure 6c, when A549/DR cells incubated with higher concentration of CDDP-SAHA nano-drug, the amount of intracellular reduced GSH decreased. The previous studies demonstrated that drug resistance mediated from over-expression of anti-apoptotic protein BCL-2 is associated with increased glutathione concentration. We incubated A549/DR cells with CDDP (8 μM) , SAHA (4 μM) , MIX (8 μM CDDP and 4 μM SAHA) and CDDP-SAHA nano-drug (4 μM) for 48 h. Then we used western blot technique to analyze the expression of BCL-2 and MRP1 proteins. As Figure 6d shown, the expression of BCL-2 and MRP1 proteins in nano-drug group was quite low compared to free CDDP. Attributing to the presence of SAHA, CDDP-SAHA nano-drug can prominently decrease intracellular GSH concentration and down-regulate anti-apoptotic protein BCL-2 and MRP1 proteins. This is the second molecular mechanism for reversing CDDP resistance by CDDP-SAHA nano-drug.

In brief, the possible mechanism of reversing CDDP resistance by CDDP-SAHA nano-drug includes two main aspects: enhanced uptake of CDDP and promoted CDDP-DNA adduct; decreased the reduced GSH concentration and down-expression of BCL-2 and MRP1 proteins. Which is shown below are experiments of growth inhibition effects of an amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy of the invention on A549/CDDP tumor.

Example 8

The tumor masses of tumor-bearing mice inoculated with A549/CDDP and A549 cells were stripped for detection the expression of Ctr1 protein, and it was found that the expression of Ctr1 protein in A549/CDDP tumor was significantly lower than that in A549 tumor, indicating the successful inoculation of cisplatin-resistant non-small cell lung cancer model. Since the molar ratio of cisplatin to vorinostat in the drug-drug nanoparticle is 2, the tumor-bearing mice were divided into seven groups: normal saline group, cisplatin (4 mg/kg) group, vorinostat (1.8 mg/kg) group, cisplatin-vorinostat mixture (4 mg/kg cisplatin + 1.8 mg/kg vorinostat) group, drug-drug nanoparticle obtained in example 1 (5 mg/kg, equivalent to 4 mg/kg cisplatin and 1.8 mg/kg vorinostat) group, drug-drug nanoparticle obtained in example 1 (7.5 mg/kg, equivalent to 6 mg/kg cisplatin and 2.7 mg/kg vorinostat) group, drug-drug nanoparticle obtained in example 1 (10 mg/kg, equivalent to 8 mg/kg cisplatin and 3.6 mg/kg vorinostat ) group. The mice were injected once every three days at the dosage of 200 μL, the mice were weighed and the tumor masses were measured. As shown in Fig. 7, free cisplatin had no inhibitory effect on cisplatin-resistant tumor, while the anticancer effect of nanoparticle group enhanced with increasing concentration, along with negligible effect on the weight of mice (Fig. 7b) . It is important that: in the case of injecting 10 mg/kg drug-drug nanoparticle, two of five mice were healed and the others showed minimized volume of tumor masses on Day 30. After treatments, the tumor masses were sampled and weighed (Fig. 7c) . The weight of tumor treated with 10 mg/kg amphiphilic drug-drug nanoparticle was the lowest. These results indicated that the amphiphilic drug-drug nanoparticle has potential applications in reversing platinum-based anticancer drug resistance in cancer therapy.

The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. The preferred embodiments are not described in all details, and the invention is not intended to be limited by the particular embodiments. Obviously, many modifications and variations are made in light of the teachings of the present invention. The embodiments are chosen and described in detail in this description to best explain the principles and practical applications of the invention, so that those skilled in the art could well understand and utilize the invention. The present invention is limited only by the claims and entirety and equivalents thereof.

Claims

An amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy, wherein the amphiphilic drug-drug nanoparticle is formed through coordination of a histone deacetylase inhibitor with a platinum-based antitumor agent and self-assembly in water; and after entering tumor cells, the amphiphilic drug-drug nanoparticle is hydrolyzed to release the histone deacetylase inhibitor and the platinum-based antitumor active agent.
The amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy of claim 1, wherein the amphiphilic drug-drug nanoparticle has a particle size less than 100 nm.
The amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy of claim 1, wherein the histone deacetylase inhibitor is one of vorinostat, trichostatin A, N-hydroxy-N’-3-pyridinyloctanediamide (pyroxamide) , 2-propenamide, 3, 4-dihydroxybenzohydroxamic acid (Dido) , 4-phenylbutyric acid, 2-propylpentanoic acid, N-butyric acid, sodium phenylbutyrate, sodium 2-propylpentanoate or sodium buntanoate.
The amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy of claim 1, wherein the platinum-based antitumor agent is one of cisplatin, trans-platin, trans-dichlorodipridine platinum (trans- [PtCl ₂ (py) ₂] ) or picoplatin.
A method for preparing the amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy of any one of claims 1-4, wherein the method includes the following steps:

(1) coordinating the histone deacetylase inhibitor with the platinum-based antitumor agent to obtain an amphiphilic drug-drug complex;

(2) dissolving the amphiphilic drug-drug complex in an organic solvent, adding the resulting solution dropwise into water at room temperature, removing the organic solvent to obtain an aqueous solution of amphiphilic drug-drug nanoparticle, and performing post-treatment to obtain the amphiphilic drug-drug nanoparticle.
The method for preparing the amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy of claim 5, wherein the coordination reaction in step (1) is one selected from the following two processes:

process 1: dissolving the platinum-based antitumor agent together with silver nitrate in an organic solvent, allowing the reaction to take place, removing precipitation of silver chloride, and collecting a supernatant as solution 1; mixing and dispersing the histone deacetylase inhibitor and alkali in an organic solvent, allowing the reaction to take place, removing insoluble matter, and collecting a supernatant as solution 2; and mixing the solution 1 and solution 2 for reaction, removing the organic solvents, and extracting to obtain the amphiphilic drug-drug complex;

process 2: dissolving the platinum-based antitumor agent together with silver nitrate in water, allowing the reaction to take place, removing precipitation of silver chloride, and collecting a supernatant as solution 3; and adding the histone deacetylase inhibitor into the solution 3 for reaction, removing water, and settling in ether, to obtain the amphiphilic drug-drug complex.
The method for preparing the amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy of claim 6, wherein in the process 1, a molar ratio of the platinum-based antitumor agent to the histone deacetylase inhibitor to the silver nitrate is 1: 0.25-0.5: 0.95-1.05.
The method for preparing the amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy of claim 6, wherein in the process 2, a molar ratio of the platinum-based antitumor agent to the histone deacetylase inhibitor to the silver nitrate is 1: 2-3: 0.95-1.05.
The method for preparing the amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy of claim 6, wherein the organic solvent is one of N, N'-dimethylformamide, dimethylsulfoxide or methanol; and the alkali is one of sodium hydroxide or sodium carbonate.
Use of the amphiphilic drug-drug nanoparticle for reversing platinum-based anticancer drug resistance in cancer therapy of any one of claims 1-4 for preparing anticancer drug or anti-tumor-resistant drug.