Preparation and application of amphiphilic polymer prodrug loaded with non-steroidal anti-inflammatory drug and platinum drug

Abstract

The invention relates to the technical field of medicines, and discloses preparation and application of an amphiphilic polymer prodrug loaded with a non-steroidal anti-inflammatory drug and a platinum drug. The polymer prodrug provided by the invention simultaneously loads the non-body anti-inflammatory drug and the tetravalent platinum drug, so that the convenience of simultaneous administration of the non-body anti-inflammatory drug and the tetravalent platinum drug is improved, and through a specially designed nano-drug delivery system, targeted delivery of drug molecules can be realized, side effects are reduced, and meanwhile, the drug delivery efficiency is improved. The GSH of the tumor microenvironment is utilized to realize the effect of degrading and releasing the drug, and the tumor cell internalization and permeation of the platinum drug and the non-body anti-inflammatory drug loaded in the drug molecules are enhanced.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to the preparation and application of an amphiphilic polymer prodrug loaded with a non-steroidal anti-inflammatory drug and a platinum drug. Background Art

[0002] Platinum drugs are one of the most widely used anti-cancer chemotherapy drugs. In order to alleviate the problems of high toxicity and drug resistance of traditional platinum drugs, researchers have found through long-term research that since the content of reducing substances such as glutathione (GSH) in normal cells is much lower than that in tumor cells, the use of tetravalent platinum for treatment can significantly reduce the toxic side effects of platinum drugs on normal cells.

[0003] Researchers have found that inhibiting the expression of cyclooxygenase 2 (COX-2) can significantly improve the ability of chemotherapy drugs (such as platinum drugs, etc.) to activate the body's immunity and enhance the efficacy of chemotherapy drugs. For example, the nonsteroidal anti-inflammatory drug indomethacin is a nonspecific COX-2 inhibitor that can effectively inhibit COX-2 activity and then inhibit the synthesis of downstream prostaglandin E2 (PGE2). Current studies have shown that the combination therapy of indomethacin and quadrivalent platinum drugs can optimize the clinical efficacy of platinum drugs.

[0004] However, both small molecule nonsteroidal anti-inflammatory drugs such as indomethacin and tetravalent platinum drugs have problems such as poor solubility and low bioavailability, which limit their clinical application. Moreover, current research is limited to the co-administration of indomethacin and tetravalent platinum drugs, and this mode of administration also has certain inconveniences. Therefore, the development of new drug molecules that can simultaneously load indomethacin and tetravalent platinum drugs and have better solubility and bioavailability is of great significance for targeted cancer treatment. Summary of the invention

[0005] The purpose of the present invention is to overcome the poor solubility and low bioavailability of non-steroidal anti-inflammatory drugs (such as indomethacin, etc.) and tetravalent platinum drugs in the prior art. Although co-administration can improve the clinical efficacy of platinum drugs, the way of administering indomethacin and platinum drugs separately is not convenient. The preparation and application of amphiphilic polymer prodrugs loaded with non-steroidal anti-inflammatory drugs and platinum are provided. The drug molecules provided by the present invention simultaneously load indomethacin and tetravalent platinum drugs, realize the administration of indomethacin and tetravalent platinum drugs in the same drug molecule, and improve the convenience and synergistic effect of drug administration. Moreover, the present invention also designs a unique nano drug delivery system for the drug molecule, which can realize the degradation and release of drugs by using GSH in the tumor microenvironment while realizing the targeted delivery of drug molecules to reduce side effects, and enhance the tumor cell internalization and penetration of platinum drugs and indomethacin loaded in drug molecules.

[0006] In order to achieve the above object, the present invention provides a method for preparing an amphiphilic drug molecule simultaneously loaded with a non-steroidal anti-inflammatory drug and a platinum drug, the method comprising:

[0007] (1) Providing nonsteroidal anti-inflammatory drug prodrugs and platinum drug prodrugs;

[0008] (2) providing a connection framework;

[0009] (3) The nonsteroidal anti-inflammatory drug prodrug and the platinum drug prodrug are bonded to the connecting skeleton through a condensation reaction.

[0010] The second aspect of the present invention provides an amphiphilic drug molecule that simultaneously carries a nonsteroidal anti-inflammatory drug and a platinum drug, and the drug molecule is prepared by the method described in the first aspect;

[0011] Alternatively, the structural units constituting the drug molecule include a connecting skeleton and a non-steroidal anti-inflammatory drug prodrug and a platinum drug prodrug bonded to the connecting skeleton through a condensation reaction.

[0012] The third aspect of the present invention provides an intermediate product obtained by the method according to the first aspect.

[0013] The fourth aspect of the present invention provides a targeted drug composition with anti-tumor function, wherein the active component in the drug composition contains the drug molecule described in the second aspect and / or the intermediate product described in the third aspect.

[0014] The fifth aspect of the present invention provides a method for preparing a targeted drug composition with anti-tumor function, the method comprising preparing nanoparticles containing the drug molecules described in the second aspect and / or the intermediate product described in the third aspect.

[0015] The sixth aspect of the present invention provides nanoparticles prepared by the method described in the fifth aspect.

[0016] The seventh aspect of the present invention provides the use of the drug molecule described in the second aspect, the intermediate product described in the third aspect, the pharmaceutical composition described in the fourth aspect, or the nanoparticles described in the sixth aspect in the preparation of anti-tumor targeted drugs.

[0017] Through the above technical solution, the present invention can at least achieve the following beneficial effects:

[0018] (1) The present invention realizes the bonding of the fetisol anti-inflammatory drug prodrug and the platinum drug prodrug on the connecting skeleton by designing specific fetisol anti-inflammatory drug prodrugs, platinum drug prodrugs and connecting skeletons, thereby forming an amphiphilic drug molecule having the efficacy of both fetisol anti-inflammatory drugs and platinum drugs, thereby improving the convenience of administration of the above two drugs.

[0019] (2) The amphiphilic drug molecules provided by the present invention have good solubility, GSH responsiveness, and can self-assemble to form nanoparticles that can utilize the GSH in the tumor microenvironment to achieve degradation and release of drugs, thereby improving the bioavailability of non-steroidal anti-inflammatory drugs (such as indomethacin) and quadrivalent platinum drugs loaded in the drug molecules. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is the H NMR spectrum of the indomethacin prodrug pre-indo obtained in Example 1.

[0021] Figure 2 This is the nuclear magnetic hydrogen spectrum of the carbon dodecamonocarboxy cisplatin C12-CISPt(IV)-COOH obtained in Example 1.

[0022] Figure 3 is the H NMR spectrum of the polymer PHDT obtained in Example 1.

[0023] Figure 4 This is the H NMR spectrum of the polymer PHDT-OH obtained in Example 1.

[0024] Figure 5 This is the H NMR spectrum of the polymer PHDT-PT obtained in Example 1.

[0025] Figure 6 This is the H NMR spectrum of the polymer INDO-PHDT-PT obtained in Example 1.

[0026] Figure 7 In Example 2, (a) a schematic diagram of the process of preparing nanoparticles Pt NP and a schematic diagram of the structure of nanoparticles Pt NP; (b) a schematic diagram of the process of preparing nanoparticles Pt-In NP and a schematic diagram of the structure of nanoparticles Pt-In NP.

[0027] Figure 8 (a) The particle size comparison diagram of Pt NP and Pt-In NP obtained by DLS detection in Test Example 1; (b) The Zeta potential analysis comparison diagram of Pt NP and Pt-InNP.

[0028] Fig. 9 This is a comparison chart of the killing effects of cisplatin, indomethacin, C12-CISPt(IV)-COOH, Pt NP and Pt-In NP on cancer cells miapaca-2 and pan02 obtained by MTT method in Test Example 2.

[0029] Fig.10 This is a comparison chart of the daily changes in tumor volume of mice in the PBS, cisplatin, Pt NP and Pt-In NP treatment groups in Test Example 2.

[0030] Fig.11 This is a comparison chart of tumor weight and volume of mice in the PBS, cisplatin, PtNP and Pt-InNP treatment groups in Test Example 2. DETAILED DESCRIPTION

[0031] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0032] In the present invention, unless otherwise specified, "DMF" is an abbreviation of "N,N-dimethylformamide", which has the same meaning; "pre-indo" is an abbreviation of "indomethacin prodrug", which has the same meaning; "CISPt(IV)" is an abbreviation of "tetravalent cisplatin", which has the same meaning as "HO-CISPt(IV)-OH" and "HO-CIS(IV)-OH"; "CISPt(IV)-COOH" and "CIS(IV)-COOH" are abbreviations of "monocarboxy cisplatin". formula, they have the same meaning; "dodecyl isocyanate" and "dodecyl isocyanate" have the same meaning; "HPMDA" is the abbreviation of "1,2,4,5-cyclohexanetetracarboxylic dianhydride", they have the same meaning; "PEG" is the abbreviation of "polyethylene glycol", they have the same meaning; "EDCI" is the abbreviation of "1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride", they have the same meaning; "DMAP" is the abbreviation of "4-dimethylaminopyridine", they have the same meaning; the above groups of terms with the same meaning can be used interchangeably.

[0033] In the present invention, unless otherwise specified, "eq" means "equivalent", and one equivalent (1eq) is the amount of a compound corresponding to gaining / losing one electron.

[0034] In the present invention, the numbers of operations, reagents, etc. (e.g., "first purification", "reagent A", "organic solvent I", "alcohol solvent I", etc.) are only used to facilitate the distinction of corresponding operations and reagents in different steps in the description, and have no limiting effect on the specific reagent selection and the order / method / conditions of operation. Operations / reagents with different numbers in different steps may be the same or different.

[0035] The inventors of the present invention cleverly designed and synthesized prodrug molecules with the activity of fezoid anti-inflammatory drugs and (quadrivalent) platinum drugs in their research, and designed and synthesized linker skeleton molecules that can simultaneously load them thereon through condensation reactions based on the characteristics of these prodrug molecules, thereby achieving the purpose of having the activity of fezoid anti-inflammatory drugs and platinum drugs on the same drug molecule. In addition, the inventors also cleverly designed the drug molecules to have GSH responsiveness and good oil-water amphiphilicity, thereby improving the solubility of fezoid anti-inflammatory drugs and platinum drugs. After further research, the inventors also found that the above-mentioned drug molecules can form nanoparticles with certain targeting functions through self-assembly, which is not only convenient for drug administration, but also can utilize GSH in the tumor microenvironment to achieve drug degradation and release, thereby reducing the systemic side effects of the drug.

[0036] Based on the above findings, the first aspect of the present invention provides a method for preparing an amphiphilic drug molecule that simultaneously carries a non-steroidal anti-inflammatory drug and a platinum drug, the method comprising:

[0037] (1) Providing nonsteroidal anti-inflammatory drug prodrugs and platinum drug prodrugs;

[0038] (2) providing a connection framework;

[0039] (3) The nonsteroidal anti-inflammatory drug prodrug and the platinum drug prodrug are bonded to the connecting skeleton through a condensation reaction.

[0040] According to a preferred embodiment of the present invention, the non-steroidal anti-inflammatory drug comprises a structure as shown in formula (A):

[0041]

[0042] The purpose of the present invention is to synthesize platinum drugs and non-steroidal anti-inflammatory drugs into the same drug molecule, thereby improving the convenience and patient compliance when the platinum drugs and non-steroidal anti-inflammatory drugs are co-administered. Any non-steroidal anti-inflammatory drug that can be co-administered with a platinum drug to improve the therapeutic effect of the platinum drug and has the above-mentioned structure can be applied to the present invention.

[0043] According to some preferred embodiments of the present invention, the non-steroidal anti-inflammatory drug is selected from at least one of indomethacin, sulindac and diclofenac.

[0044] In the present invention, the prodrug of a fezoid-anti-inflammatory drug refers to a non-steroidal anti-inflammatory drug molecule connected to a group that can be further connected to a connecting skeleton. Any (modified) fezoid-anti-inflammatory drug molecule having the above characteristics can be applied to the present invention. Preferably, the prodrug of a fezoid-anti-inflammatory drug comprises a fezoid-anti-inflammatory drug and R provided by reagent A. 1 The reagent A is a straight-chain disulfide with hydroxyl groups at both ends, preferably selected from bis(2-hydroxyethyl) disulfide and / or bis(2-hydroxypropyl) disulfide.

[0045] For example, when the nonsteroidal anti-inflammatory drug is indomethacin, the nonsteroidal anti-inflammatory drug prodrug (i.e., indomethacin prodrug, referred to as pre-indo) is selected from the compound having a structure as shown in formula (1):

[0046]

[0047] Where R 1 Provided by reagent A, the reagent A is a straight-chain disulfide with hydroxyl groups at both ends, preferably selected from bis(2-hydroxyethyl) disulfide and / or bis(2-hydroxypropyl) disulfide.

[0048] Those skilled in the art can design prodrug molecules corresponding to other feline anti-inflammatory drugs based on the above content, which will not be described in detail here.

[0049] According to a preferred embodiment of the present invention, the platinum drug is selected from cisplatin, preferably tetravalent cisplatin (CISPt(IV)).

[0050] Preferably, the platinum drug prodrug is selected from a compound having a structure as shown in formula (2):

[0051]

[0052] Where R 2 It is a straight-chain alkyl group with more than 8 C atoms, preferably a straight-chain alkyl group with 10-15 C atoms; R3 is provided by reagent B, and the reagent B is a compound that can provide a carboxyl group and has a C atom number not exceeding 10, preferably selected from succinic anhydride and / or adipic anhydride.

[0053] According to a preferred embodiment of the present invention, the structural units contained in the connecting skeleton are provided by a compound represented by formula (7), a reagent D and a reagent E, wherein the reagent D is a straight-chain disulfide having hydroxyl groups at both ends, preferably selected from bis(2-hydroxyethyl) disulfide and / or bis(2-hydroxypropyl) disulfide; the reagent E is a compound having two acid glycoside groups, preferably selected from 1,2,4,5-cyclohexanetetracarboxylic dianhydride and / or cyclobutanetetracarboxylic dianhydride,

[0054]

[0055] Preferably, the linking skeleton further comprises a capping agent, which is preferably selected from polyethylene glycol, for example, polyethylene glycol 2000, polyethylene glycol 5000, etc.

[0056] According to a preferred embodiment of the present invention, the connecting skeleton comprises a compound having a structure as shown in formula (3):

[0057]

[0058] Here, m is an integer greater than or equal to 80 and less than or equal to 150.

[0059] The linker backbone shown in formula (3) uses polyethylene glycol as a capping agent. Those skilled in the art can reasonably design similar linker backbone molecules when other capping agents are used, which will not be described in detail here.

[0060] In the method provided by the present invention, there is no particular limitation on the specific manner of providing the prodrug and the connecting skeleton in step (1) and step (2). The prodrug and the connecting skeleton can be prepared by the prior art according to the characteristics of the compounds of the aforementioned formula (1) to formula (3), or can be ordered or customized through commercial channels.

[0061] The following will take the case where the fezoid anti-inflammatory drug is indomethacin, the platinum drug is tetravalent cisplatin, the corresponding prodrug molecules are respectively shown in formulas (1) and (2), and the connecting skeleton is shown in formula (3) as an example to describe the preparation method provided by the present invention in detail.

[0062] According to a preferred embodiment of the present invention, step (1) includes the following steps:

[0063] (1-1) Synthesis of a non-steroidal anti-inflammatory drug prodrug: comprising contacting a reagent A with indomethacin in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine and an organic reagent I and performing a first reaction; and / or

[0064] (1-2) Synthetic platinum drug prodrugs, including:

[0065] (1-2-1) The compound represented by the structure of formula (4) is contacted with reagent B in the presence of an organic solvent II and subjected to a second reaction to obtain a compound represented by the structure of formula (5).

[0066]

[0067] (1-2-2) The compound represented by the structure of formula (5) is contacted with reagent C in the presence of an organic solvent III and subjected to a third reaction to obtain a compound represented by the structure of formula (2).

[0068] According to a preferred embodiment of the present invention, in step (1-1), the organic solvent I is selected from N,N-dimethylformamide (DMF) and / or dichloromethane.

[0069] Preferably, the amount of the organic solvent I is 10-20 mL relative to 1 eq of indomethacin.

[0070] Preferably, relative to 1 eq of indomethacin, the amount of reagent A used is 0.8-1.5 eq; the amount of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride used is 1-2 eq; and the amount of 4-dimethylaminopyridine used is 0.05-0.15 eq.

[0071] Preferably, the temperature of the first reaction is 20-30°C.

[0072] More preferably, step (1-1) further comprises a step of first purifying the product of the first reaction (to obtain the compound represented by formula (1), i.e., pre-indo). Preferably, the first purification comprises separating the product obtained by the first reaction by silica gel column chromatography, and more preferably, the first purification is performed using a mixed solution of dichloromethane and methanol (preferably a volume ratio of dichloromethane to methanol of 8-12:1) as a mobile phase.

[0073] In the present invention, there is no particular restriction on the specific source of the compound represented by formula (4) used in step (1-2-1). It can be synthesized according to the existing technology based on the characteristics of the compound, or it can be a finished product purchased directly from a commercial source or through commercial customization.

[0074] According to a preferred embodiment of the present invention, step (1-2-1) further comprises the operation of synthesizing the compound represented by formula (4). Specifically, it may include:

[0075] Cisplatin (structure as shown in formula (11)) is mixed with hydrogen peroxide solution and reacted under the following conditions: temperature of 25-35° C. and reaction time of 5-12 h.

[0076]

[0077] Preferably, the concentration of the hydrogen peroxide solution is 20-40% by weight.

[0078] Preferably, relative to 1 g of cisplatin, the amount of the hydrogen peroxide solution is 10-30 mL.

[0079] More preferably, the operation of synthesizing the compound represented by formula (4) further comprises subjecting the product of the above reaction to a first drying treatment, wherein the temperature of the first drying treatment is preferably 25-50°C.

[0080] According to a preferred embodiment of the present invention, in step (1-2-1), the temperature of the second reaction is 23-40°C.

[0081] Preferably, the organic solvent II is selected from DMF.

[0082] Preferably, the amount of the organic solvent II is 500-700 mL relative to 1 mmol of the compound represented by formula (4).

[0083] Preferably, the amount of reagent B used is 0.8-1.2 mmol relative to 1 mmol of the compound represented by formula (4).

[0084] According to some preferred embodiments of the present invention, step (1-2-1) may further include a second purification operation of the product of the second reaction. Preferably, the second purification method includes: filtering the product of the second reaction, desolventizing the filtrate, dissolving the desolventized product with an alcohol solvent I, adding an ether solvent I, and collecting the precipitate.

[0085] Preferably, the desolventizing treatment comprises distillation under reduced pressure.

[0086] Further preferably, the alcohol solvent I is selected from methanol; and the ether solvent I is selected from diethyl ether.

[0087] According to a preferred embodiment of the present invention, in step (1-2-2), the temperature of the third reaction is 25-50°C.

[0088] Preferably, the organic solvent III is selected from DMF.

[0089] Preferably, the amount of the organic solvent III used is 30-100 mL relative to 1 mmol of the compound represented by formula (5).

[0090] Preferably, the reagent C is selected from the compound having a structure as shown in formula (6), wherein R2 is a straight-chain alkyl group having 8 or more carbon atoms, preferably a straight-chain alkyl group having 10-15 carbon atoms,

[0091] R 2 -N=C=O Formula (6).

[0092] Preferably, the amount of reagent C used is 1-1.2 mmol relative to 1 mmol of the compound represented by formula (5).

[0093] According to some preferred embodiments of the present invention, step (1-2-2) further comprises a step of performing a third purification on the product of the third reaction. Preferably, the third purification comprises: filtering the product of the third reaction, desolventizing the filtrate, dissolving the desolventized product with an alcohol solvent II, adding an ether solvent II, and collecting the precipitate.

[0094] Further preferably, the desolvation treatment comprises rotary evaporation.

[0095] More preferably, the alcohol solvent II is selected from methanol; and the ether solvent II is selected from diethyl ether.

[0096] According to a preferred embodiment of the present invention, step (2) comprises:

[0097] (2-1) contacting a compound having a structure as shown in formula (7), a reagent D and a reagent E in the presence of an organic solvent IV and performing a fourth reaction, and then reacting the fourth reaction product with a capping agent to obtain a polymer as shown in formula (8),

[0098]

[0099] Wherein m is an integer greater than or equal to 80 and less than or equal to 150;

[0100] (2-2) The polymer represented by formula (8) and reagent F are brought into contact in the presence of an organic solvent V and subjected to a fifth reaction to obtain a polymer represented by formula (3).

[0101] In the present invention, there is no particular restriction on the specific source of the compound represented by formula (7), which can be prepared by itself according to the existing technology based on the characteristics of the compound, or directly purchased from a commercial source or through commercial customization.

[0102] According to a preferred embodiment of the present invention, in step (2-1), the conditions of the fourth reaction include: temperature 25-50°C, time 40-60h.

[0103] Preferably, the reagent D is a straight-chain disulfide with hydroxyl groups at both ends, preferably selected from bis(2-hydroxyethyl) disulfide and / or bis(2-hydroxypropyl) disulfide.

[0104] Preferably, the amount of reagent D used is 0.5-1.5 eq relative to 1 eq of the compound represented by formula (7).

[0105] Preferably, the reagent E is a compound having two anhydride groups, preferably selected from 1,2,4,5-cyclohexanetetracarboxylic dianhydride and / or cyclobutanetetracarboxylic dianhydride. Preferably, the amount of reagent E used is 2-3 eq relative to 1 eq of the compound represented by formula (7).

[0106] Preferably, the organic solvent IV is selected from DMF.

[0107] More preferably, the amount of the organic solvent IV used is 15-25 mL relative to 1 eq of the compound represented by formula (7).

[0108] According to a preferred embodiment of the present invention, in step (2-2), the conditions of the fifth reaction include: temperature 25-35°C, time 10-20h.

[0109] Preferably, the reagent F is an acidic compound, preferably selected from trifluoroacetic acid and / or dilute hydrochloric acid (ie, HCl aqueous solution with a mass fraction not exceeding 20%).

[0110] More preferably, the amount of reagent F used is 1-3 mmol relative to 1 mmol of the polymer represented by formula (8).

[0111] Preferably, the organic solvent V is selected from dichloromethane and / or DMF.

[0112] More preferably, the amount of the organic solvent V used is 15-25 mL relative to 1 mmol of the polymer represented by formula (8).

[0113] According to a preferred embodiment of the present invention, step (3) comprises:

[0114] (3-1) contacting the compound represented by formula (2) and the compound represented by formula (3) in the presence of reagent G, reagent H and organic solvent VI and performing a sixth reaction to obtain a compound represented by formula (9), wherein R2 is a straight-chain alkyl group having 8 or more carbon atoms, preferably a straight-chain alkyl group having 10 to 15 carbon atoms; and m is an integer greater than or equal to 80 and less than or equal to 150;

[0115] (3-2) The compound represented by formula (9) is contacted with the compound represented by formula (1) in the presence of reagent J, reagent K and organic solvent VII to carry out the seventh reaction to obtain a compound represented by formula (10), wherein R2 is a straight-chain alkyl group having 8 or more carbon atoms, preferably a straight-chain alkyl group having 10-15 carbon atoms; and m is an integer greater than or equal to 80 and less than or equal to 150.

[0116]

[0117] According to a preferred embodiment of the present invention, in step (3-1), the conditions of the sixth reaction include: reaction temperature 25-35°C, time 10-20h.

[0118] Preferably, the reagent G is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Preferably, the amount of the reagent G used is 1-2 mmol relative to 1 mmol of the compound represented by formula (2).

[0119] Preferably, the reagent H is 4-dimethylaminopyridine. Preferably, the amount of the reagent H used is 0.05-0.15 mmol relative to 1 mmol of the compound represented by formula (2).

[0120] Preferably, the organic solvent VI is selected from N,N-dimethylformamide. Preferably, the amount of the organic solvent IV is 10-20 mL relative to 1 mmol of the compound represented by formula (2).

[0121] More preferably, the molar ratio of the compound represented by formula (2) to the compound represented by formula (3) is 1:1-1.2.

[0122] According to a preferred embodiment of the present invention, in step (3-2), the conditions of the seventh reaction include: reaction temperature 25-35°C, time 10-20h.

[0123] Preferably, the reagent J is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Preferably, the amount of the reagent J used is 1-2 mmol relative to 1 mmol of the compound represented by formula (9).

[0124] Preferably, the reagent K is 4-dimethylaminopyridine.

[0125] More preferably, the amount of reagent J used is 0.05-0.15 mmol relative to 1 mmol of the compound represented by formula (9).

[0126] Preferably, the organic solvent VII is selected from N,N-dimethylformamide.

[0127] More preferably, the amount of the organic solvent IV used is 20-50 mL relative to 1 mmol of the compound represented by formula (9).

[0128] More preferably, the molar ratio of the compound represented by formula (9) to the compound represented by formula (1) is 1:1-1.2.

[0129] Based on the above content, those skilled in the art can reasonably infer the preparation methods and effects when using other non-steroidal anti-inflammatory drugs, platinum drugs and connecting skeletons. For the sake of length, the preparation process of these amphiphilic drug molecules that simultaneously load non-steroidal anti-inflammatory drugs and platinum drugs will not be described in detail here.

[0130] The second aspect of the present invention provides an amphiphilic drug molecule that simultaneously carries a nonsteroidal anti-inflammatory drug and a platinum drug, and the drug molecule is prepared by the method described in the first aspect;

[0131] Alternatively, the structural units constituting the drug molecule include a connecting skeleton and a non-steroidal anti-inflammatory drug prodrug and a platinum drug prodrug bonded to the connecting skeleton through a condensation reaction.

[0132] According to a particularly preferred embodiment of the present invention, the structural unit of the drug molecule is provided by the compound represented by formula (1) and the compound represented by formula (2), and the structural unit provided by the above compounds is bonded to the compound represented by formula (3).

[0133] Among them, in formula (1), R 1 Provided by reagent A, the reagent A is a straight-chain disulfide with hydroxyl groups at both ends (preferably wherein the number of carbon atoms does not exceed 10, preferably 2-5), preferably selected from bis(2-hydroxyethyl) disulfide and / or bis(2-hydroxypropyl) disulfide. In formula (2), R 2 is a straight-chain alkyl group having 8 or more carbon atoms, preferably a straight-chain alkyl group having 10-15 carbon atoms; R 3 Provided by reagent B, the reagent B is a compound capable of providing a carboxyl group and having no more than 10 C atoms, preferably selected from succinic anhydride and / or adipic anhydride, wherein m is an integer greater than or equal to 80 and less than or equal to 150.

[0134] Preferably, the drug molecule is selected from the compound shown in formula (10), wherein R 2 It is a straight-chain alkyl group having 8 or more carbon atoms, preferably a straight-chain alkyl group having 10-15 carbon atoms; m is an integer greater than or equal to 80 and less than or equal to 150.

[0135] The third aspect of the present invention provides an intermediate product obtained by the method according to the first aspect.

[0136] According to a preferred embodiment of the present invention, the intermediate product is selected from the compound shown in formula (9), wherein R 2 It is a straight-chain alkyl group having 8 or more carbon atoms, preferably a straight-chain alkyl group having 10-15 carbon atoms; m is an integer greater than or equal to 80 and less than or equal to 150.

[0137] The fourth aspect of the present invention provides a targeted pharmaceutical composition with anti-tumor function, wherein the active component in the pharmaceutical composition contains the drug molecule described in the second aspect and / or the intermediate product described in the third aspect. It should be understood that the intermediate product used in the above-mentioned pharmaceutical composition is an intermediate product (such as the compound shown in formula (9) etc.) among the intermediate products described in the third aspect that can have corresponding pharmaceutical activity.

[0138] The inventors of the present invention cleverly discovered in their research that the drug molecules (e.g., the compound represented by formula (10)) and some intermediate products (e.g., the compound represented by formula (9)) provided by the present invention are amphiphilic and can form nanoparticles by self-assembly. The nanoparticles have the advantage of being able to utilize the GSH of the tumor microenvironment to achieve degradation, thereby releasing the drug. That is, they can achieve targeted release of the drug, improve the targeting of the drug, and thus reduce the systemic side effects of platinum chemotherapy drugs.

[0139] Based on the above findings, the fifth aspect of the present invention provides a method for preparing a targeted drug composition with anti-tumor function, which comprises preparing nanoparticles containing the drug molecules described in the second aspect and / or the intermediates described in the third aspect.

[0140] According to a preferred embodiment of the present invention, the method for preparing the nanoparticles comprises:

[0141] (A) dissolving the drug molecule in an organic solvent VIII to obtain a drug molecule solution, then first mixing the drug molecule solution with water, and then removing the organic solvent VIII from the product obtained by the first mixing; and / or

[0142] (B) dissolving the intermediate product in an organic solvent IX to obtain an intermediate product solution, then mixing the intermediate product solution with water for a second time, and then removing the organic solvent IX from the product obtained by the second mixing.

[0143] In the above method, mode (A) is the process of preparing the drug molecules provided by the present invention into nanoparticles. The present invention has no particular restrictions on the specific conditions and reagents selected in the process, as long as the desired nanoparticles can be formed (for example, the self-assembly of drug molecules can be achieved to form targeted delivery and release, and the efficacy of the released drug can meet the required requirements).

[0144] According to a preferred embodiment of the present invention, in mode (A), the organic solvent VIII is selected from dimethyl sulfoxide and / or tetrahydrofuran.

[0145] Preferably, the drug molecule content in the drug molecule solution is 10-100 mg / mL.

[0146] Preferably, the first mixing method comprises: adding the drug molecule solution dropwise into water under stirring conditions, and continuing stirring for 5-15 minutes after the addition is completed.

[0147] More preferably, in mode (A), the volume ratio of the drug molecule solution to water is 1:5-20.

[0148] More preferably, in the method (A), the method for removing the organic solvent VIII is selected from dialysis (molecular cut-off is preferably 3000-4000).

[0149] In the above method, mode (B) is the process of preparing nanoparticles from the intermediate product (having corresponding drug activity) provided by the present invention. The present invention has no particular restrictions on the specific conditions and reagents selected in the process, as long as the desired nanoparticles can be formed (for example, the self-assembly of the intermediate product can be achieved to form targeted delivery and release, and the efficacy of the released drug can meet the required requirements).

[0150] According to a preferred embodiment of the present invention, in mode (B), the organic solvent IX is selected from dimethyl sulfoxide and / or tetrahydrofuran.

[0151] Preferably, in the intermediate product solution, the intermediate product content is 10-100 mg / mL.

[0152] Preferably, the second mixing method comprises: adding the intermediate product solution dropwise into water under stirring conditions, and continuing stirring for 5-15 minutes after the addition is completed.

[0153] More preferably, in mode (B), the volume ratio of the intermediate product solution to water is 1:5-20.

[0154] More preferably, in mode (B), the method for removing the organic solvent IX is selected from dialysis (molecular cut-off is preferably 3000-4000).

[0155] The sixth aspect of the present invention provides nanoparticles prepared according to the method described in the fifth aspect.

[0156] According to a preferred embodiment of the present invention, the average particle size of the nanoparticles is 80-120 nm, and the zeta potential is -10 mV to -13 mV.

[0157] Preferably, when the nanoparticles are nanoparticles formed by self-assembly of the aforementioned drug molecules, the average particle size of the nanoparticles is 100-120 nm, and the zeta potential is -11 mV to -13 mV.

[0158] Preferably, when the nanoparticles are nanoparticles formed by self-assembly of the aforementioned intermediate products (having corresponding pharmaceutical activity), the average particle size of the nanoparticles is 80-100 nm, and the zeta potential is -10 mV to -12 mV.

[0159] The seventh aspect of the present invention provides the use of the drug molecule described in the second aspect, the intermediate product described in the third aspect, the pharmaceutical composition described in the fourth aspect, or the nanoparticles described in the sixth aspect in the preparation of anti-tumor targeted drugs.

[0160] In the art, any tumor that can be treated with a combination of a non-steroidal anti-inflammatory drug (such as indomethacin, etc.) and a platinum drug can be treated with an anti-tumor targeted drug made of the drug molecules, intermediates, pharmaceutical compositions, and nanoparticles provided by the present invention. According to some preferred embodiments of the present invention, the tumor is selected from pancreatic cancer and / or breast cancer.

[0161] The present invention will be described in detail below by way of examples. It should be understood that the following examples are only used to further explain and illustrate the content of the present invention by way of example, and are not intended to limit the present invention.

[0162] In the following examples, unless otherwise specified, the reagents and materials used were all commercial products purchased from regular chemical / biological reagent / material suppliers, and the reagents were all analytical grade.

[0163] In the following examples, unless otherwise specified, "room temperature" refers to 25±5°C.

[0164] Example 1

[0165] This example is used to illustrate the synthesis of the drug molecule provided by the present invention.

[0166] The following method is used to prepare the amphiphilic drug molecule that simultaneously loads indomethacin and platinum drugs:

[0167] (1) Synthesis of indomethacin prodrugs and platinum prodrugs

[0168] (1-1) Synthesis of indomethacin prodrug:

[0169]

[0170] Referring to reaction formula (1.1), indomethacin (3 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 4.5 eq), and 4-dimethylaminopyridine (DMAP, 0.3 eq) were dissolved in 30 mL of ultra-dry N,N-dimethylformamide (DMF) and stirred at room temperature for 10 minutes to obtain mixture-A.

[0171] Dissolve bis(2-hydroxyethyl) disulfide (3.5±0.5 eq) in 10 mL of ultra-dry N,N-dimethylformamide, add dropwise to mixture-A, and stir at room temperature overnight (about 12±2 h).

[0172] After the reaction, the mother liquor (i.e., the reaction product) was separated by chromatography on a silica gel column (filler: 200-300 mesh silica gel) (the mobile phase was a mixture of dichloromethane and methanol in a volume ratio of 10:1) to obtain indomethacin prodrug (pre-indo). The product was used 1 H NMR analysis, the results are as follows Figure 1 shown.

[0173] (1-2) Synthesis of platinum prodrugs:

[0174] (1-2-0) Synthesis of tetravalent cisplatin:

[0175]

[0176] Referring to reaction formula (1.2), cisplatin (5 g) and 30 wt % H 2 O 2 The aqueous solution (100 mL) was added to a 150 mL round-bottom flask and stirred at room temperature for 4 h. The supernatant was then removed and the precipitate was dried at 45±5°C to obtain a yellow powder of tetravalent cisplatin HO-CIS(IV)-OH.

[0177] (1-2-1) Synthesis of monocarboxy cisplatin:

[0178]

[0179] Referring to reaction formula (1.3), HO-CIS(IV)-OH (1 mmol) and DMF (10 mL) were added to a dry reaction bottle at room temperature, and then succinic anhydride (0.9±0.1 mmol) was added to the reaction bottle. The mixture was stirred and reacted at 35°C for 24 hours, filtered, and the filtrate was collected, and the solvent was removed from the filtrate by reduced pressure distillation.

[0180] 2 mL of methanol was added to dissolve the remaining solute, and then a large amount of ether was added (the amount of ether added was about 20 times that of methanol) to precipitate the target product.

[0181] The supernatant was discarded by centrifugation, and the solid was collected and dried at 40°C to obtain the product, which was monocarboxy cisplatin CIS(IV)-COOH.

[0182] (1-2-2) Synthesis of C12-monocarboxylic cisplatin

[0183]

[0184] Referring to reaction formula (1.4), CIS(IV)-COOH (1 mmol), dodecyl isocyanate (1.1±0.1 mmol) and 10 ml of ultra-dry DMF were added into a dry reaction bottle, mixed thoroughly, and reacted at room temperature for 24 h.

[0185] After the reaction was completed, the solvent DMF was removed by a rotary evaporator (temperature 55°C). Then 1 mL of anhydrous methanol was added to dissolve the remaining solid, and the resulting mixture was precipitated with 40 mL of anhydrous ether and filtered three times. The product carbon twelve monocarboxy cisplatin C12-CISPt(IV)-COOH was obtained by vacuum drying. The product was used 1 H NMR analysis, the results are shown in Figure 2 .

[0186] (2) Synthetic connection skeleton:

[0187] (2-1) Synthesis of polymer PHDT

[0188]

[0189] Referring to reaction formula (1.6), bis(2-hydroxyethyl) disulfide (5eq) and N-Boc-2,3-dihydroxypropylamine (5eq) were added to a 50 mL round-bottom flask containing 1,2,4,5-cyclohexanetetracarboxylic dianhydride (HPMDA, 11eq), and then 20 mL of ultra-dry DMF was added to the flask. The reaction was stirred continuously for 48 hours. Then polyethylene glycol (mPEG) was added. 5k , 2eq), continue stirring the reaction for 24h to end-cap the polymer. Finally, dialyze (molecular cutoff 8000) and vacuum dry the dialyzed product to obtain the polymer PHDT. 1 H NMR analysis, the results are shown in Figure 3 .

[0190] (2-2) Synthesis of polymer PHDT-OH

[0191] Referring to reaction formula (1.7), trifluoroacetic acid (3 mmol) was added to a DMF solution (about 20 mL) of PHDT (3 mmol) and stirred overnight (about 12±2 h).

[0192] The reaction product was dialyzed (molecular cutoff 8000), and the dialyzed product was vacuum dried to obtain the polymer PHDT-OH. 1 H NMR analysis, the results are shown in Figure 4 .

[0193]

[0194] (3) Bonding the indomethacin prodrug and the platinum prodrug to the connecting skeleton through a condensation reaction:

[0195] (3-1) Synthetic polymer PHDT-PT:

[0196] Referring to reaction formula (1.8), C12-CISPt(IV)-COOH (3 mmol), EDCI (4.5 mmol) and DMAP (0.3 mmol) were dissolved in 30 mL of ultra-dry DMF and stirred for 10 minutes.

[0197] PHDT-OH (3.15±0.15 mmol) was dissolved in 10 mL of ultra-dry DMF and added dropwise to the mixture of C12-CISPt(IV)-COOH, EDCI and DMAP. After the addition was complete, the reaction was stirred at room temperature overnight (about 12±2 h).

[0198] The obtained reaction product was dialyzed (molecular cutoff 8000), and the dialyzed product was vacuum dried to obtain the polymer PHDT-PT. 1 H NMR analysis, the results are shown in Figure 5 .

[0199]

[0200] (3-2) Synthetic polymer INDO-PHDT-PH:

[0201] Referring to reaction formula (1.9), PHDT-PT (3 mmol), EDCI (4.5 mmol), and DMAP (0.3 mmol) were dissolved in 30 mL of ultra-dry DMF and stirred for 10 minutes.

[0202] Pre-indo (3.15±0.15 mmol) was dissolved in 10 mL of ultra-dry DMF and added dropwise to the mixture of PHDT-PT, EDCI and DMAP. The mixture was stirred while being added dropwise. After the addition was completed, the reaction was stirred at room temperature overnight (about 12±2 h).

[0203] The obtained reaction product was dialyzed (molecular cutoff 8000), and the dialyzed product was vacuum dried to obtain the polymer INDO-PHDT-PT. 1 H NMR analysis, the results are shown in Figure 6 .

[0204]

[0205] Example 2

[0206] This example is used to illustrate the preparation of nanoparticles provided by the present invention.

[0207] (1) Preparation of PtNP nanoparticles from the intermediate product (polymer PHDT-PT)

[0208] refer to Figure 7(a) PHDT-PT (30 mg) was dissolved in 1 mL of dimethyl sulfoxide (DMSO) to prepare a DMSO solution of PHDT-PT.

[0209] The DMSO solution of PHDT-PT was dropped into 10 mL of ultrapure water while stirring. After the addition was completed, the reaction was stirred at room temperature for 10 min.

[0210] The reaction product is dialyzed (molecular cutoff 3500) to remove DMSO, and the final product is the intermediate product nanoparticle Pt NP.

[0211] (2) Preparation of Pt-In NPs from drug molecules (polymer INDO-PHDT-PT)

[0212] refer to Figure 7 (b) INDO-PHDT-PT (30 mg) was dissolved in 1 mL DMSO to prepare a DMSO solution of INDO-PHDT-PT.

[0213] The DMSO solution of INDO-PHDT-PT was dropped into 10 mL of ultrapure water while stirring. After the addition was completed, the reaction was stirred at room temperature for 10 min.

[0214] The DMSO in the reaction product is removed by dialysis (molecular cutoff 3500), and the final product is the drug molecule nanoparticle Pt-In NP.

[0215] Test Example 1

[0216] The morphology, particle size and surface potential of the nanoparticles Pt NP and Pt-In NP prepared in Example 2 were characterized by transmission electron microscopy (TEM, HT-7700, Hitachi, Japan) and laser particle size analyzer (DLS, Malvem Zetasizer Nano ZS90, Nano ZS, UK).

[0217] The results are shown in Figure 8 .in, Figure 8 (a) shows the particle size comparison results of PtNP and Pt-InNP obtained by DLS detection. The average particle sizes of PtNP and Pt-InNP are 84.6nm and 113.9nm, respectively. Figure 8 (b) shows the Zeta potential analysis results of PtNP and Pt-InNP. It can be seen from the figure that the surface potential of PtNP is slightly higher than that of Pt-In NP, where the zeta potentials of Pt NP and Pt-In NP are approximately -10.9 mV and -11.8 mV, respectively.

[0218] Test Example 2

[0219] (I) Cytotoxicity assay

[0220] The MTT method was used to detect the killing ability of cisplatin, indomethacin, C12-CISPt(IV)-COOH, Pt NP and Pt-In NP against cancer cells (miapaca-2, pan02).

[0221] The specific method includes: inoculating cells at a density of 5000 cells / well in a 96-well plate, and after the cells are completely attached, respectively adding cisplatin, indomethacin, C12-CISPt(IV)-COOH, Pt NP and Pt-In NP according to the platinum concentration gradient of 0.005μM, 0.05μM, 0.5μM, 5μM, 10μM, 20μM, 40μM for drug treatment, and incubating for 48 hours after drug addition. A control well with only PBS equal in volume to the drug is set on each culture plate.

[0222] After the incubation, MTT was added to the culture wells to a final concentration of 10 wt %. After incubation in a 37° C. incubator for 4 h, 100 μL of 10 wt % SDS was added to each well and cultured in a 37° C. incubator for 12 h.

[0223] The absorbance of each culture well was measured at 570nm (peak absorbance) and 650nm (background absorbance) by an ELISA reader. Cell viability was expressed as the ratio of the absorbance of the test well to the control well. Fig. 9 ,in, Fig. 9 (a) Detection results of miapaca-2, Fig. 9 (b) is the test result of pan02. As can be seen from the figure, the killing effect of indomethacin alone on both cancer cells is poor, cisplatin has a good killing effect on pan02, but the killing effect on miapaca-2 is not good. In contrast, C12-CISPt(IV)-COOH, Pt NP and Pt-In NP have good killing effects on both cancer cells, and are better than cisplatin. Among them, Pt-In NP has the best effect, followed by Pt NP, and then C12-CISPt(IV)-COOH. This shows that the nanoparticles and intermediates provided by the present invention have a good effect of killing cancer cells.

[0224] (II) Verification of tumor suppressor effects in animal models

[0225] Female C57 mice (purchased from Sibeifu (Beijing) Biotechnology Co., Ltd.) of similar age and weight were divided into 4 groups, with 5 mice in each group. Pan02 cells were cultured at 1×10 6The number of cells / mouse was subcutaneously injected into the right side of the mouse trunk to establish a tumor-bearing mouse model. 3 At 3.5mg Ptkg -1 Each group of mice was intravenously injected with PBS, cisplatin, Pt NP and Pt-In NP at a dose of . The tumor volume was recorded every other day. The mice were killed on the 18th day after administration, and the tumors were removed and weighed.

[0226] Fig.10 The figure shows the daily changes in tumor volume of each group of mice. As can be seen from the figure, the tumor volume of mice treated with Pt NP and Pt-In NP grows significantly slower than that of the PBS group and cisplatin group, indicating that Pt NP and Pt-In NP have a good inhibitory effect on tumor growth. According to calculations, compared with PBS, the inhibition rate of tumor growth in mice treated with Pt-In NP reached 81% (tumor growth inhibition rate = (tumor volume of PBS mice-tumor volume of mice in the treatment group) / tumor volume of PBS mice × 100%), the tumor growth inhibition rate of Pt NP on mice was about 59%, and the tumor growth inhibition rate of cisplatin on mice was only 30%.

[0227] Fig.11 The comparison results of tumor volume in mice on day 18 after administration are shown in FIG. Fig.11 (a) is a statistical comparison of tumor weights in mice in different treatment groups; Fig.11 (b) is a comparison of the volume of tumors in mice treated with different groups. The results showed that the tumor weight in the Pt-InNP group was 0.28±0.08g, which was significantly less than 1.00±0.17g in the cisplatin group. It can also be seen from the figure that the tumor volume and weight in the PtNP group were also significantly lower than those in the PBS group, and lower than those in the cisplatin group. It can be seen that the inhibitory effect of the Pt-In NP and Pt NP provided by the present invention on tumors is improved compared to the administration of cisplatin alone, indicating that these nanoparticles have the potential to prepare new and highly efficient targeted anti-tumor drugs.

[0228] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for preparing an amphiphilic drug molecule simultaneously loaded with a non-steroidal anti-inflammatory drug and a platinum drug, characterized in that: The method comprises: (1) Providing nonsteroidal anti-inflammatory drug prodrugs and platinum drug prodrugs; (2) providing a connection framework; (3) The nonsteroidal anti-inflammatory drug prodrug and the platinum drug prodrug are bonded to the connecting skeleton through a condensation reaction.

2. The method according to claim 1, wherein: The non-steroidal anti-inflammatory drug comprises a structure as shown in formula (A): Preferably, the nonsteroidal anti-inflammatory drug is selected from at least one of indomethacin, sulindac and diclofenac; Preferably, the FISA prodrug comprises a FISA and an R1 group provided by a reagent A, wherein the reagent A is a linear disulfide having hydroxyl groups at both ends, preferably selected from bis(2-hydroxyethyl) disulfide and / or bis(2-hydroxypropyl) disulfide; More preferably, the prodrug of the fezoid anti-inflammatory drug comprises a compound having a structure as shown in formula (1): Wherein R1 is provided by reagent A, and the reagent A is a straight-chain disulfide with hydroxyl groups at both ends, preferably selected from bis(2-hydroxyethyl) disulfide and / or bis(2-hydroxypropyl) disulfide; And / or, the platinum drug is selected from cisplatin, preferably tetravalent cisplatin. Preferably, the platinum drug prodrug is selected from a compound having a structure as shown in formula (2): Wherein R2 is a straight-chain alkyl group with 8 or more carbon atoms, preferably a straight-chain alkyl group with 10-15 carbon atoms; R3 is provided by reagent B, and reagent B is a compound capable of providing a carboxyl group and having no more than 10 carbon atoms, preferably selected from succinic anhydride and / or adipic anhydride; And / or, the structural units contained in the connecting skeleton are provided by the compound represented by formula (7), reagent D and reagent E, wherein reagent D is a straight-chain disulfide with hydroxyl groups at both ends, preferably selected from bis(2-hydroxyethyl) disulfide and / or bis(2-hydroxypropyl) disulfide; reagent E is a compound having two acid glycoside groups, preferably selected from 1,2,4,5-cyclohexanetetracarboxylic dianhydride and / or cyclobutanetetracarboxylic dianhydride, Preferably, the linking backbone further comprises a capping agent, and preferably the capping agent is selected from polyethylene glycol; Preferably, the connecting skeleton comprises a compound having a structure as shown in formula (3): Here, m is an integer greater than or equal to 80 and less than or equal to 150.

3. The method according to claim 1 or 2, wherein: Step (1) includes the following steps: (1-1) Synthesis of nonsteroidal anti-inflammatory drug prodrugs: comprising contacting reagent A with indomethacin in the presence of 1-(3.dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine and an organic solvent I and performing a first reaction, wherein the temperature of the first reaction is preferably 20-30° C.; and / or (1-2) Synthetic platinum drug prodrugs, including: (1-2-1) contacting a compound represented by formula (4) with reagent B in the presence of an organic solvent II and performing a second reaction to obtain a compound represented by formula (5), wherein the temperature of the second reaction is preferably 23-40° C., (1-2-2) A compound having a structure as shown in formula (5) is subjected to a third reaction with reagent C in the presence of an organic solvent III to obtain a compound having a structure as shown in formula (2). Preferably, the temperature of the third reaction is 25-50°C.

4. The method according to claim 3, wherein: In step (1-1), the organic solvent I is selected from N,N-dimethylformamide and / or dichloromethane, and preferably, the amount of the organic solvent I is 10-20 mL relative to 1 eq of indomethacin; And / or, in step (1-1), relative to 1 eq of indomethacin, the amount of reagent A used is 0.8-1.5 eq; the amount of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride used is 1-2 eq; the amount of 4-dimethylaminopyridine used is 0.05-0.15 eq; Preferably, step (1-1) further comprises a first purification operation on the product of the first reaction, and preferably the first purification method comprises separating the product obtained from the first reaction by silica gel column chromatography.

5. The method according to claim 3, wherein: In step (1-2-1), the organic solvent II is selected from N,N-dimethylformamide, and more preferably, the amount of the organic solvent II is 500-700 mL relative to 1 mmol of the compound represented by formula (4); And / or, in step (1-2-1), the amount of reagent B used is 0.8-1.2 mmol relative to 1 mmol of the compound represented by formula (4); Preferably, step (1-2-1) further comprises a second purification operation of the product of the second reaction, and preferably the second purification method comprises: filtering the product of the second reaction, desolventizing the filtrate, dissolving the desolventized product with an alcohol solvent I, adding an ether solvent I, and collecting the precipitate; More preferably, the desolventizing treatment comprises distillation under reduced pressure; More preferably, the alcohol solvent I is selected from methanol; the ether solvent I is selected from diethyl ether; And / or, in step (1-2-2), the organic solvent III is selected from N,N-dimethylformamide, and more preferably, the amount of the organic solvent III is 30-100 mL relative to 1 mmol of the compound represented by formula (5); And / or, in step (1-2-2), the reagent C is selected from a compound having a structure as shown in formula (6), wherein R2 is a straight-chain alkyl having 8 or more carbon atoms, preferably a straight-chain alkyl having 10-15 carbon atoms, R2-N=C=O Formula (6); Preferably, in step (1-2-2), the amount of reagent C used is 1-1.2 mmol relative to 1 mmol of the compound represented by formula (5); Preferably, step (1-2-2) further comprises a third purification operation on the product of the third reaction, and the third purification method preferably comprises: filtering the product of the third reaction, desolventizing the filtrate, dissolving the desolventized product with an alcohol solvent II, adding an ether solvent II, and collecting the precipitate; More preferably, the desolvation treatment comprises rotary evaporation; More preferably, the alcohol solvent II is selected from methanol; and the ether solvent II is selected from diethyl ether.

6. The method according to any one of claims 1 to 3, wherein: Step (2) comprises: (2-1) contacting a compound having a structure as shown in formula (7), a reagent D and a reagent E in the presence of an organic solvent IV and performing a fourth reaction, and then reacting the fourth reaction product with a capping agent to obtain a polymer as shown in formula (8), Wherein m is an integer greater than or equal to 80 and less than or equal to 150; (2-2) contacting the polymer represented by formula (8) and reagent F in the presence of an organic solvent V and performing a fifth reaction to obtain a polymer represented by formula (3); Preferably, in step (2-1), reagent D is a linear disulfide having hydroxyl groups at both ends, preferably selected from bis(2-hydroxyethyl) disulfide and / or bis(2-hydroxypropyl) disulfide; preferably, the amount of reagent D is 0.5-1.5 eq relative to 1 eq of the compound represented by formula (7); Preferably, in step (2-1), reagent E is a compound having two glycoside groups, preferably selected from 1,2,4,5-cyclohexanetetracarboxylic dianhydride and / or cyclobutanetetracarboxylic dianhydride; preferably, the amount of reagent E is 2-3 eq relative to 1 eq of the compound represented by formula (7); Preferably, in step (2-1), the organic solvent IV is selected from N,N-dimethylformamide, and more preferably, the amount of the organic solvent IV is 15-25 mL relative to 1 eq of the compound represented by formula (7); More preferably, the conditions of the fourth reaction include: temperature 25-50°C, time 40-60h; Preferably, in step (2-1), the end-capping agent is selected from polyethylene glycol; Preferably, in step (2-2), the reagent F is an acidic compound, preferably selected from trifluoroacetic acid and / or dilute hydrochloric acid; preferably, the amount of the reagent F is 1-3 mmol relative to 1 mmol of the polymer represented by formula (8); Preferably, in step (2-2), the organic solvent V is selected from dichloromethane and / or N,N-dimethylformamide; preferably, the amount of the organic solvent V is 15-25 mL relative to 1 mmol of the polymer represented by formula (8); More preferably, the conditions of the fifth reaction include: temperature 25-35°C, time 10-20h.

7. The method according to any one of claims 1 to 3, wherein: Step (3) includes: (3-1) contacting the compound represented by formula (2) and the compound represented by formula (3) in the presence of reagent G, reagent H and organic solvent VI to carry out a sixth reaction to obtain a compound represented by formula (9), wherein R2 is a straight-chain alkyl group having 8 or more carbon atoms, preferably a straight-chain alkyl group having 10-15 carbon atoms; m is an integer greater than or equal to 80 and less than or equal to 150; (3-2) contacting the compound represented by formula (9) with the compound represented by formula (1) in the presence of reagent J, reagent K and organic solvent VII to carry out the seventh reaction to obtain a compound represented by formula (10), wherein R2 is a straight-chain alkyl group having 8 or more carbon atoms, preferably a straight-chain alkyl group having 10-15 carbon atoms; m is an integer greater than or equal to 80 and less than or equal to 150; Preferably, in step (3-1), the reagent G is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; preferably, the amount of the reagent G is 1-2 mmol relative to 1 mmol of the compound represented by formula (2); Preferably, in step (3-1), the reagent H is selected from 4-dimethylaminopyridine; preferably, the amount of the reagent H is 0.05-0.15 mmol relative to 1 mmol of the compound represented by formula (2); Preferably, in step (3-1), the organic solvent VI is selected from N,N-dimethylformamide; preferably, the amount of the organic solvent IV is 10-20 mL relative to 1 mmol of the compound represented by formula (2); More preferably, in step (3-1), the molar ratio of the compound represented by formula (2) to the compound represented by formula (3) is 1:1-1.2; More preferably, the conditions of the sixth reaction include: reaction temperature 25-35°C, time 10-20h; Preferably, in step (3-2), the reagent J is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; preferably, the amount of the reagent J is 0.05-0.15 mmol relative to 1 mmol of the compound represented by formula (9); Preferably, in step (3-2), the reagent K is 4-dimethylaminopyridine; preferably, the amount of the reagent J is 0.05-0.15 mmol relative to 1 mmol of the compound represented by formula (9); Preferably, in step (3-2), the organic solvent VII is selected from N,N-dimethylformamide; preferably, the amount of the organic solvent IV is 20-50 mL relative to 1 mmol of the compound represented by formula (9); More preferably, in step (3-2), the molar ratio of the compound represented by formula (9) to the compound represented by formula (1) is 1:1-1.2; More preferably, the conditions of the seventh reaction include a reaction temperature of 25-35° C. and a reaction time of 10-20 h, relative to a 20 mL reaction system.

8. An amphiphilic drug molecule simultaneously loaded with a nonsteroidal anti-inflammatory drug and a platinum drug, characterized in that: The drug molecule is prepared by the method described in any one of claims 1 to 7; Alternatively, the structural units constituting the drug molecule include a connecting skeleton and a non-steroidal anti-inflammatory drug prodrug and a platinum drug prodrug bonded to the connecting skeleton through a condensation reaction.

9. The drug molecule according to claim 8, wherein The structural units of the drug molecule are provided by the compound represented by formula (1) and the compound represented by formula (2), and the structural units provided by the above compounds are bonded to the compound represented by formula (3). Wherein R1 is provided by reagent A, and the reagent A is a straight-chain disulfide with hydroxyl groups at both ends, preferably selected from bis(2-hydroxyethyl) disulfide and / or bis(2-hydroxypropyl) disulfide, Wherein R2 is a straight-chain alkyl group with 8 or more carbon atoms, preferably a straight-chain alkyl group with 10-15 carbon atoms; R3 is provided by reagent B, and the reagent B is a compound capable of providing a carboxyl group and having no more than 10 carbon atoms, preferably selected from succinic anhydride and / or adipic anhydride, Wherein m is an integer greater than or equal to 80 and less than or equal to 150; Preferably, the drug molecule is selected from a compound having a structure as shown in formula (10); Wherein R2 is a straight-chain alkyl group having 8 or more carbon atoms, preferably a straight-chain alkyl group having 10-15 carbon atoms; and m is an integer greater than or equal to 80 and less than or equal to 150.

10. The intermediate product obtained by the method according to any one of claims 1 to 7, preferably the intermediate product is selected from the compound shown in formula (9), Wherein R2 is a straight-chain alkyl group having 8 or more carbon atoms, preferably a straight-chain alkyl group having 10-15 carbon atoms; and m is an integer greater than or equal to 80 and less than or equal to 150.

11. A targeted drug composition with anti-tumor function, characterized in that: The active ingredient in the pharmaceutical composition contains the drug molecule according to claim 8 or 9 and / or the intermediate product according to claim 10.

12. A method for preparing a targeted drug composition with anti-tumor function, characterized in that: The method comprises preparing nanoparticles containing the drug molecule according to claim 8 or 9 and / or the intermediate product according to claim 10.

13. The method according to claim 12, wherein: The preparation method of the nanoparticles comprises: (A) dissolving the drug molecule in an organic solvent VIII to obtain a drug molecule solution, then first mixing the drug molecule solution with water, and then removing the organic solvent VIII from the product obtained by the first mixing; and / or (B) dissolving the intermediate product in an organic solvent IX to obtain an intermediate product solution, and then mixing the intermediate product solution with water for a second time, and then removing the organic solvent IX from the product obtained by the second mixing; Preferably, in mode (A), the organic solvent VIII is selected from dimethyl sulfoxide and / or tetrahydrofuran; preferably, the drug molecule content in the drug molecule solution is 10-100 mg / mL; Preferably, in method (A), the first mixing method comprises: adding the drug molecule solution dropwise into water under stirring conditions, and continuing to stir for 5-15 minutes after the addition is completed; More preferably, in mode (A), the volume ratio of the drug molecule solution to water is 1:5-20; More preferably, in method (A), the method for removing the organic solvent VIII is selected from dialysis; Preferably, in mode (B), the organic solvent IX is selected from dimethyl sulfoxide and / or tetrahydrofuran; preferably, the intermediate product content in the intermediate product solution is 10-100 mg / mL; Preferably, in mode (B), the second mixing mode comprises: adding the intermediate product solution dropwise into water under stirring conditions, and continuing stirring for 5-15 minutes after the addition is completed; More preferably, in mode (B), the volume ratio of the intermediate product solution to water is 1:5-20; More preferably, in embodiment (B), the method for removing the organic solvent IX is selected from dialysis.

14. Nanoparticles prepared according to the method of claim 12 or 13.

15. The nanoparticle according to claim 14, wherein The average particle size of the nanoparticles is 80-120 nm, and the zeta potential is -10 mV to -13 mV.

16. Use of the drug molecule according to claim 8 or 9, the intermediate product according to claim 10, the pharmaceutical composition according to claim 11, or the nanoparticles according to claim 14 or 15 in the preparation of anti-tumor targeted drugs, wherein the tumor is preferably selected from pancreatic cancer and / or breast cancer.

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