A reduction-responsive photopolymerizable supramolecular monomer and its preparation method and application

Abstract

The present invention belongs to the technical field of preparation of tumor-targeted drug carriers, and specifically discloses a reduction-responsive photopolymerizable supramolecular monomer, a preparation method thereof, and an application thereof. The reduction-responsive photopolymerizable supramolecular monomer disclosed by the present invention uses the disulfide bond of cystamine dihydrochloride as the center of the molecular skeleton, replaces one end of the disulfide bond with a hydrophilic elementary dendritic alkoxy ether, and introduces a hydrophobic elementary triphenylamine or tetraphenylethylene with aggregation-induced emission (AIE) effect at the other end. The supramolecular monomer prepared by the present invention can self-assemble in a solution to form a supramolecular polymer, and the disulfide bond can be broken under the action of a reducing compound, thereby realizing the targeted release of the loaded drug under the tumor microenvironment. Under ultraviolet light irradiation, partial cross-linking can be achieved to improve the stability of the polymer.

Description

Technical Field

[0001] The present invention relates to the technical field of preparation of tumor-targeted drug carriers, and in particular to a reduction-responsive photopolymerizable supramolecular monomer and a preparation method and application thereof. Background Art

[0002] Self-assembling peptides based on tumor microenvironment response can overcome the limitations of large-sized assemblies such as poor tissue permeability and targeting. However, the supramolecular nanostructures formed by some self-assembling peptides are currently bound by non-covalent interactions. This binding force is weaker than that of covalent bonds, making the peptide self-assemblies lack stability in the in vivo environment. Therefore, the design of more stable and high-performance supramolecular assemblies has attracted attention.

[0003] If the supramolecular assembly is further connected by new covalent bonds by covalent bonding, the structural fixation of the supramolecular assembly can be achieved, which is expected to solve the above-mentioned problems. In order to better simulate the supramolecular multi-level self-assembly behavior of biomacromolecules from the molecular level to the macroscopic scale, effectively prepare a more stable supramolecular self-assembly system that responds to multiple factors such as tumor microenvironment-temperature, improve tumor targeting specificity and give it corresponding biological properties, it will have very important academic value and is of great significance to the development of new intelligent biomaterials.

[0004] Therefore, how to provide a reduction-responsive photopolymerizable supramolecular monomer and its preparation method and application, improve the stability of the supramolecular self-assembly system, and improve the tumor targeting specificity is a difficult problem to be solved urgently in this field. Summary of the invention

[0005] In view of this, the present invention provides a reduction-responsive photopolymerizable supramolecular monomer and a preparation method and application thereof, so as to solve the problems of poor stability of the existing system and poor targeted release effect after drug encapsulation.

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

[0007] A reduction-responsive photopolymerizable supramolecular monomer, wherein the structure of the reduction-responsive photopolymerizable supramolecular monomer is as follows:

[0008]

[0009] in,

[0010] X is CH3 or CH2CH3.

[0011] Another object of the present invention is to provide a method for preparing a reduction-responsive photopolymerizable supramolecular monomer, comprising the following steps:

[0012] 1) reacting 4-bromotriphenylamine with 4-carboxyphenylboronic acid to obtain compound 1-a or reacting TEP-OH with tert-butyl bromoacetate, and then reacting the reaction product with trifluoroacetic acid to obtain compound 1-a;

[0013] 2) reacting di-tert-butyl dicarbonate with cystamine dihydrochloride to obtain compound 2-a;

[0014] 3) subjecting compound G1-OH to oxidation reaction to obtain compound 3-a; compound 3-a reacts with malonic acid to obtain compound 3-b;

[0015] 4) Compound 2-a, compound 3-b, 1-hydroxybenzotriazole, N,N-diisopropylethylamine and an organic solvent are mixed to carry out a first reaction; after the reaction is complete, the mixture is mixed with 1-ethyl-(3-dimethylaminopropyl)carbodiimide to carry out a second reaction to obtain compound 3-c;

[0016] 5) reacting compound 3-c with trifluoroacetic acid to obtain compound 3-d;

[0017] 6) Compound 3-d, compound 1-a, 1-hydroxybenzotriazole, N,N-diisopropylethylamine and an organic solvent are mixed to carry out a first reaction; after the reaction is complete, the mixture is mixed with 1-ethyl-(3-dimethylaminopropyl)carbodiimide to carry out a second reaction to obtain a reduction-responsive photopolymerizable supramolecular monomer;

[0018] There is no order restriction for steps 1) to 3);

[0019] The structural formula of compound 1-a is The structural formula of compound 2-a is The structural formula of compound G1-OH is The structural formula of compound 3-a is The structural formula of compound 3-b is The structural formula of compound 3-c is The structural formula of compound 3-d is

[0020] Among them, X in compound G1-OH, compound 3-a, compound 3-b and compound 3-c is CH3 or CH2CH3.

[0021] Preferably, the reaction in step 1) is as follows:

[0022] 4-bromotriphenylamine, 4-carboxyphenylboric acid, tetrabutylammonium bromide, an organic solvent, a K2CO3 solution and Pd(PPH3)4 are mixed and reacted under anaerobic conditions to obtain compound 1-a;

[0023] The usage ratio of 4-bromotriphenylamine, 4-carboxyphenylboric acid, tetrabutylammonium bromide, organic solvent, K2CO3 solution and Pd(PPH3)4 is 0.01356-0.11627mol: 0.01088-0.01305mol: 1.356-1.627mmol: 45-60mL: 30-45mL: 0.0519-0.0736mmol;

[0024] The concentration of the K2CO3 solution is 0.8-1.2 mol / L;

[0025] The reaction temperature is 75-80°C and the reaction time is 20-25h;

[0026] Or TPE-OH, tert-butyl bromoacetate, potassium carbonate and a first organic solvent are mixed to perform a first reaction, and then the reaction product is mixed with trifluoroacetic acid and a second organic solvent to perform a second reaction to obtain compound 1-a;

[0027] The usage ratio of TPE-OH, tert-butyl bromoacetate, potassium carbonate, the first organic solvent, trifluoroacetic acid and the second organic solvent is 1.7-2 mmol: 1.8-2.2 mmol: 2.47-3 mmol: 15-25 mL: 1-1.5 mL: 6-8 mL;

[0028] The temperature of the first reaction is 80-90°C, and the time of the first reaction is 10-15h;

[0029] The second reaction time is 1.5 to 2.5 hours.

[0030] Preferably, the reaction in step 2) is as follows:

[0031] Di-tert-butyl dicarbonate, triethylamine, cystamine dihydrochloride and an organic solvent are mixed and reacted to obtain compound 2-a;

[0032] The molar volume ratio of di-tert-butyl dicarbonate, triethylamine, cystamine dihydrochloride and organic solvent is 0.02-0.03 mol: 8.4-10.0 mL: 0.02-0.03 mol: 30-35 mL;

[0033] The reaction time is 20 to 30 minutes.

[0034] Preferably, the oxidation reaction in step 3) is as follows:

[0035] Compound G1-OH, pyridinium chlorochromate and an organic solvent are mixed and subjected to oxidation reaction to obtain compound 3-a;

[0036] The molar volume ratio of the compound G1-OH, pyridinium chlorochromate and the organic solvent is 3.1408-3.777 mmol: 4.712-5.654 mmol: 20-25 mL;

[0037] The mixing temperature is -5 to 5°C, and the mixing time is 25 to 35 minutes;

[0038] The oxidation reaction time is 10 to 15 hours.

[0039] Preferably, the reaction of compound 3-a described in step 3) with malonic acid is as follows:

[0040] Compound 3-a, malonic acid, piperidine and an organic solvent are mixed and reacted to obtain compound 3-b;

[0041] The molar volume ratio of the compound 3-a, malonic acid, piperidine and organic solvent is 1.024-1.229 mmol: 2.048-2.458 mmol: 0.1-0.12 mL: 15-25 mL;

[0042] The reaction temperature is 50-80° C., and the reaction time is 10-15 hours.

[0043] Preferably, in step 4), the molar volume ratio of compound 2-a, compound 3-b, 1-hydroxybenzotriazole, organic solvent and 1-ethyl-(3-dimethylaminopropyl)carbodiimide is 0.4582-0.5498 mmol: 0.5040-0.6048 mmol: 0.5498-0.6598 mmol: 20-30 mL: 0.6872-0.8246 mmol;

[0044] The amount of N,N-diisopropylethylamine added is such that the pH value of the reaction system of the first reaction is 9 to 10;

[0045] In step 4), the temperature of the first reaction is -5 to 5°C, and the time of the first reaction is 15 to 20 minutes;

[0046] In step 4), the second reaction is firstly carried out at -5 to 5°C for 15 to 20 minutes, and then at room temperature for 10 to 15 hours.

[0047] Preferably, the reaction in step 5) is as follows:

[0048] Compound 3-c, trifluoroacetic acid and an organic solvent are mixed to perform a first reaction, and then mixed with methanol to perform a second reaction to obtain compound 3-d;

[0049] The molar volume ratio of the compound 3-c, trifluoroacetic acid, organic solvent and methanol is 0.3337-0.4004 mmol: 0.9913-1.2887 mL: 7-8 mL: 30-40 mL;

[0050] The mixing temperature is -5 to 5°C, and the mixing time is 12 to 18 minutes;

[0051] The time of the first reaction is 0.8 to 1.2 hours; the time of the second reaction is 25 to 35 minutes.

[0052] Preferably, in step 6), the molar volume ratio of the compound 3-d, the compound 1-a, 1-hydroxybenzotriazole, the organic solvent and 1-ethyl-(3-dimethylaminopropyl)carbodiimide is 0.3337-0.4004 mmol: 0.3337-0.4004 mmol: 0.4004-0.4805 mmol: 20-26 mL: 0.5005-0.8010 mmol;

[0053] The amount of N,N-diisopropylethylamine added is such that the pH value of the reaction system of the first reaction is 9 to 10;

[0054] In step 6), the temperature of the first reaction is -5 to 5°C, and the time of the first reaction is 18 to 22 minutes;

[0055] In step 6), the second reaction is firstly carried out at -5 to 5°C for 12 to 18 minutes, and then at room temperature for 10 to 15 hours.

[0056] Another object of the present invention is to provide an application of a reduction-responsive photopolymerizable supramolecular monomer prepared by the preparation method in the preparation of a novel tumor targeting drug.

[0057] The invention uses the disulfide bond of cystamine dihydrochloride as the center of the molecular skeleton, replaces one end of the disulfide bond with a hydrophilic elementary dendritic alkoxy ether, and introduces a hydrophobic elementary triphenylamine at the other end to prepare a supramolecular monomer having temperature sensitivity and reduction response, aggregation-induced luminescence effect, and photopolymerization. The supramolecular polymer drug carrier with reduction response is formed by self-assembly (the supramolecular polymer can break the disulfide bond under the action of a reducing compound, thereby realizing the targeted release of the loaded drug under a tumor microenvironment, and providing the possibility for the application of the supramolecular assembly in drug coating). The controlled release of the drug in the tumor site is realized through the reducing microenvironment of the tumor site where GSH is overexpressed; the cinnamic acid double bond elementary introduced in the supramolecular monomer realizes the photopolymerization effect of the supramolecular assembly through [2+2] cycloaddition under ultraviolet light, thereby improving the stability of the supramolecular assembly; and the triphenylamine or tetraphenylethylene elementary introduced in the molecule has an aggregation-induced luminescence effect, and its application in supramolecular fluorescent materials can be further developed.

[0058] It can be seen from the above technical solutions that, compared with the prior art, the present invention has the following beneficial effects:

[0059] The reduction-responsive supramolecular polymer based on the reduction-responsive performance of disulfide bonds can achieve targeted release of loaded anticancer drugs in the tumor microenvironment, improve the bioavailability of anticancer drugs, and provide possibilities for the application of supramolecular assemblies in drug coating. At the same time, the supramolecular polymer can be partially cross-linked under ultraviolet light irradiation to improve the stability of the polymer. The present invention provides a new method for the preparation of supramolecular polymers that can be photopolymerized and respond to multiple environmental stimuli, and provides an important experimental basis for expanding its use as a new tumor-targeted drug carrier. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0061] Figure 1 TPA-Ph-COOH prepared in Example 1 in d6-DMSO 1 H NMR spectrum;

[0062] Figure 2 The Boc-SS-NH2 prepared in Example 1 in d6-DMSO 1 H NMR spectrum;

[0063] Figure 3G1=COOH prepared in Example 1 in d6-DMSO 1 H NMR spectrum;

[0064] Figure 4 G1 = SS-Boc prepared in Example 1 in d6-DMSO 1 H NMR spectrum;

[0065] Figure 5 G1 = SS-TPA prepared in Example 1 in d6-DMSO 1 HNMR spectrum;

[0066] Figure 6 The mass spectrum of G1=SS-TPA prepared in Example 1 of the present invention;

[0067] Figure 7 The fluorescence spectra of G1=SS-TPA prepared in Example 1 in solvents with different H2O / THF ratios;

[0068] Figure 8 The fluorescence spectrum of G1=SS-TPA prepared in Example 1 after DTT reduction changes with time;

[0069] Fig. 9 The fluorescence spectrum of G1=SS-TPA coated with naproxen prepared in Example 1 after being reduced with DTT;

[0070] Fig.10 Comparison of fluorescence spectra of naproxen coated with G1=SS-TPA at different concentrations prepared in Example 1;

[0071] Fig.11 The TPE-COOH prepared in Example 2 in d6-CDCl3 1 H NMR spectrum;

[0072] Fig.12 G1-SS-TPE prepared in Example 2 in d6-DMSO 1 H NMR spectrum;

[0073] Fig.13 The release of naproxen from G1-SS-TPE prepared in Example 2 under DTT reduction. DETAILED DESCRIPTION

[0074] The present invention provides a reduction-responsive photopolymerizable supramolecular monomer, the structure of which is as follows:

[0075]

[0076] in, X is CH3 or CH2CH3.

[0077] The present invention also provides a method for preparing a reduction-responsive photopolymerizable supramolecular monomer, comprising the following steps:

[0078] 1) reacting 4-bromotriphenylamine with 4-carboxyphenylboronic acid to obtain compound 1-a or reacting TEP-OH with tert-butyl bromoacetate, and then reacting the reaction product with trifluoroacetic acid to obtain compound 1-a;

[0079] 2) reacting di-tert-butyl dicarbonate with cystamine dihydrochloride to obtain compound 2-a;

[0080] 3) subjecting compound G1-OH to oxidation reaction to obtain compound 3-a; compound 3-a reacts with malonic acid to obtain compound 3-b;

[0081] 4) Compound 2-a, compound 3-b, 1-hydroxybenzotriazole, N,N-diisopropylethylamine and an organic solvent are mixed to carry out a first reaction; after the reaction is complete, the mixture is mixed with 1-ethyl-(3-dimethylaminopropyl)carbodiimide to carry out a second reaction to obtain compound 3-c;

[0082] 5) reacting compound 3-c with trifluoroacetic acid to obtain compound 3-d;

[0083] 6) Compound 3-d, compound 1-a, 1-hydroxybenzotriazole, N,N-diisopropylethylamine and an organic solvent are mixed to carry out a first reaction; after the reaction is complete, the mixture is mixed with 1-ethyl-(3-dimethylaminopropyl)carbodiimide to carry out a second reaction to obtain a reduction-responsive photopolymerizable supramolecular monomer;

[0084] There is no specific order for steps 1) to 3).

[0085] In the present invention, the reaction described in step 1) is as follows:

[0086] 4-Bromotriphenylamine, 4-carboxyphenylboric acid, tetrabutylammonium bromide, an organic solvent, a K2CO3 solution and Pd(PPH3)4 are mixed and reacted under anaerobic conditions to obtain compound 1-a.

[0087] In the present invention, the dosage ratio of 4-bromotriphenylamine, 4-carboxyphenylboric acid, tetrabutylammonium bromide, organic solvent, K2CO3 solution and Pd(PPH3)4 is 0.01356-0.11627 mol: 0.01088-0.01305 mol: 1.356-1.627 mmol: 45-60 mL: 30-45 mL: 0.0519-0.0736 mmol; preferably 0.05-0.1 mol: 0.011-0.013 mol: 1.4-1.6 mmol: 50-55 mL: 35-40 mL: 0.06-0.07 mmol; further preferably 0.08 mol: 0.012 mol: 1.5 mmol: 52 mL: 38 mL: 0.0519-0.065 mmol.

[0088] In the present invention, the concentration of the K2CO3 solution is 0.8-1.2 mol / L, specifically 0.9 mol / L, 1 mol / L, 1.1 mol / L;

[0089] In the present invention, the reaction temperature is 75-80°C, specifically 76°C, 77°C, 78°C, 79°C; the reaction time is 20-25h, specifically 21h, 22h, 23h, 24h.

[0090] In the present invention, the organic solvent in step 1) is preferably tetrahydrofuran.

[0091] In the present invention, TPE-OH, tert-butyl bromoacetate, potassium carbonate and a first organic solvent are mixed for a first reaction, and then the reaction product is mixed with trifluoroacetic acid and a second organic solvent for a second reaction to obtain compound 1-a.

[0092] In the present invention, the usage ratio of TPE-OH, tert-butyl bromoacetate, potassium carbonate, the first organic solvent, trifluoroacetic acid and the second organic solvent is 1.7-2 mmol: 1.8-2.2 mmol: 2.47-3 mmol: 15-25 mL: 1-1.5 mL: 6-8 mL; preferably 1.8-1.9 mmol: 1.9-2.1 mmol: 2.6-2.9 mmol: 18-22 mL: 1.1-1.4 mL: 6.5-7.5 mL; further preferably 1.85 mmol: 2 mmol: 2.8 mmol: 20 mL: 1.2 mL: 7 mL.

[0093] In the present invention, the temperature of the first reaction is 80-90°C, specifically 82°C, 84°C, 85°C, 86°C, 88°C; the time of the first reaction is 10-15h, specifically 11h, 12h, 13h, 14h.

[0094] In the present invention, the time of the second reaction is 1.5 to 2.5 h, specifically 1.6 h, 1.8 h, 2 h, 2.2 h, or 2.4 h.

[0095] In the present invention, the reaction described in step 2) is as follows:

[0096] Di-tert-butyl dicarbonate, triethylamine, cystamine dihydrochloride and an organic solvent are mixed and reacted to obtain compound 2-a.

[0097] In the present invention, the molar volume ratio of di-tert-butyl dicarbonate, triethylamine, cystamine dihydrochloride and organic solvent is 0.02-0.03 mol: 8.4-10.0 mL: 0.02-0.03 mol: 30-35 mL; preferably 0.022-0.026 mol: 8.5-9.5 mL: 0.024-0.026 mol: 32-34 mL; further preferably 0.025 mol: 9 mL: 0.025 mol: 33 mL.

[0098] In the present invention, the reaction time is 20 to 30 minutes, specifically 22 minutes, 24 minutes, 25 minutes, 26 minutes, or 28 minutes.

[0099] In the present invention, the mixing in step 2) is preferably performed by first mixing di-tert-butyl dicarbonate, triethylamine and part of the organic solvent to obtain a first mixed solution, and then mixing cystamine dihydrochloride with the remaining organic solvent to obtain a second mixed solution; and then dropping the first mixed solution into the second mixed solution.

[0100] In the present invention, the volume ratio of part of the organic solvent to the remaining organic solvent is preferably 15 to 20:15, more preferably 16 to 19:15, and further preferably 18:15.

[0101] In the present invention, the dropping rate is preferably 15-20 mL / 20 min, specifically 16 mL / 20 min, 17 mL / 20 min, 18 mL / 20 min, 19 mL / 20 min.

[0102] In the present invention, the organic solvent in step 2) is preferably methanol.

[0103] In the present invention, the oxidation reaction described in step 3) is as follows:

[0104] Compound G1-OH, pyridinium chlorochromate and an organic solvent are mixed and subjected to oxidation reaction to obtain compound 3-a.

[0105] In the present invention, the molar volume ratio of the compound G1-OH, pyridinium chlorochromate and the organic solvent is 3.1408-3.777 mmol: 4.712-5.654 mmol: 20-25 mL; preferably 3.2-3.6 mmol: 4.8-5.5 mmol: 22-24 mL; further preferably 3.5 mmol: 5 mmol: 23 mL.

[0106] In the present invention, the organic solvent is preferably dichloromethane.

[0107] In the present invention, the mixing temperature is -5 to 5°C, specifically -4°C, -2°C, 0°C, 2°C, 4°C; the mixing time is 25 to 35 min, specifically 26 min, 28 min, 30 min, 32 min, 34 min.

[0108] In the present invention, the oxidation reaction time is 10 to 15 hours, specifically 11 hours, 12 hours, 13 hours, or 14 hours.

[0109] In the present invention, the reaction of compound 3-a described in step 3) with malonic acid is as follows:

[0110] Compound 3-a, malonic acid, piperidine and an organic solvent are mixed and reacted to obtain compound 3-b.

[0111] In the present invention, the molar volume ratio of the compound 3-a, malonic acid, piperidine and organic solvent is 1.024-1.229 mmol: 2.048-2.458 mmol: 0.1-0.12 mL: 15-25 mL; preferably 1.1-1.2 mmol: 2.1-2.4 mmol: 0.11 mL: 18-22 mL; further preferably 1.15 mmol: 2.2 mmol: 0.11 mL: 20 mL; the organic solvent is preferably pyridine.

[0112] In the present invention, the reaction temperature is 50-80°C, specifically 55°C, 60°C, 65°C, 70°C, 75°C; the reaction time is 10-15h, specifically 11h, 12h, 13h, 14h.

[0113] In the present invention, the molar volume ratio of compound 2-a, compound 3-b, 1-hydroxybenzotriazole, organic solvent and 1-ethyl-(3-dimethylaminopropyl)carbodiimide in step 4) is 0.4582-0.5498 mmol: 0.5040-0.6048 mmol: 0.5498-0.6598 mmol: 20-30 mL: 0.6872-0.8246 mmol; preferably 0.48-0.52 mmol: 0.52-0.56 mmol: 0.55-0.65 mmol: 24-26 mL: 0.7-0.8 mmol; further preferably 0.5 mmol: 0.55 mmol: 0.6 mmol: 25 mL: 0.75 mmol.

[0114] In the present invention, the amount of N,N-diisopropylethylamine added is such that the pH value of the reaction system of the first reaction is 9 to 10, specifically 9.2, 9.4, 9.5, 9.6, or 9.8.

[0115] In the present invention, the organic solvent in step 4) is preferably dichloromethane.

[0116] In the present invention, the temperature of the first reaction in step 4) is -5 to 5°C, specifically -4°C, -2°C, 0°C, 2°C, 4°C; the time of the first reaction is 15 to 20 min, specifically 16 min, 17 min, 18 min, 19 min.

[0117] In the present invention, the second reaction in step 4) is first reacted at -5 to 5°C, specifically -4°C, -2°C, 0°C, 2°C, 4°C for 15 to 20 minutes, specifically 16 minutes, 17 minutes, 18 minutes, 19 minutes; and then reacted at room temperature for 10 to 15 hours, specifically 11 hours, 12 hours, 13 hours, 14 hours.

[0118] In the present invention, the reaction described in step 5) is as follows:

[0119] Compound 3-c, trifluoroacetic acid and an organic solvent are mixed to perform a first reaction, and then mixed with methanol to perform a second reaction to obtain compound 3-d.

[0120] In the present invention, the molar volume ratio of the compound 3-c, trifluoroacetic acid, organic solvent and methanol is 0.3337-0.4004 mmol: 0.9913-1.2887 mL: 7-8 mL: 30-40 mL; preferably 0.35-0.4 mmol: 1-1.2 mL: 7.2-7.8 mL: 32-38 mL; further preferably 0.38 mmol: 1.1 mL: 7.5 mL: 35 mL;.

[0121] In the present invention, the organic solvent in step 5) is preferably dichloromethane.

[0122] In the present invention, the mixing temperature is -5 to 5°C, specifically -4°C, -2°C, 0°C, 2°C, 4°C; the mixing time is 12 to 18 minutes, specifically 14 minutes, 15 minutes, 16 minutes, 17 minutes.

[0123] In the present invention, the time of the first reaction is 0.8 to 1.2 h, specifically 0.9 h, 1 h, or 1.1 h; the time of the second reaction is 25 to 35 min, specifically 26 min, 28 min, 30 min, 32 min, or 34 min.

[0124] In the present invention, the molar volume ratio of the compound 3-d, compound 1-a, 1-hydroxybenzotriazole, organic solvent and 1-ethyl-(3-dimethylaminopropyl)carbodiimide in step 6) is 0.3337~0.4004mmol:0.3337~0.4004mmol:0.4004~0.4805mmol:20~26mL:0.5005~0.8010mmol; preferably 0.35~0.4mmol:0.35~0.4mmol:0.42~0.46mmol:21~24mL:0.68~0.75mmol; further preferably 0.38mmol:0.38mmol:0.45mmol:22mL:0.7mmol.

[0125] In the present invention, the amount of N,N-diisopropylethylamine added is such that the pH value of the reaction system of the first reaction is 9 to 10, specifically 9.2, 9.4, 9.5, 9.6, or 9.8.

[0126] In the present invention, the organic solvent in step 6) is preferably dichloromethane.

[0127] In the present invention, the temperature of the first reaction in step 6) is -5 to 5°C, specifically -4°C, -2°C, 0°C, 2°C, 4°C; the time of the first reaction is 18 to 22 min, specifically 19 min, 20 min, 21 min.

[0128] In the present invention, the second reaction in step 6) is first reacted at -5 to 5°C, specifically -4°C, -2°C, 0°C, 2°C, 4°C for 15 minutes, and then reacted at room temperature for 10 to 15 hours, specifically 11 hours, 12 hours, 13 hours, 14 hours.

[0129] In the present invention, the reactions in step 1), step 3), step 4) and step 6) are preferably carried out under anaerobic conditions, and the anaerobic conditions are preferably in the nitrogen range.

[0130] The present invention also provides an application of a reduction-responsive photopolymerizable supramolecular monomer prepared by the preparation method in the preparation of a novel tumor-targeting drug.

[0131] The following are some embodiments of the present invention, but not all. All other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0132] Example 1

[0133]

[0134] Synthesis of compound 1-a: Weigh 4-bromotriphenylamine (4.3960 g, 0.01356 mol), 4-carboxyphenylboronic acid (1.5 g, 0.01088 mol), and tetrabutylammonium bromide (0.4371 g, 1.356 μmol) and add them to a 250 mL round-bottom flask containing 60 mL of tetrahydrofuran, add 45 mL of K2CO3 solution (1 mol / L) to the above system, replace N2, and stir magnetically. After 30 minutes, quickly add 0.0736 mmol of Pd(PPH3)4 to the round-bottom flask, replace N2 with an oil pump again to ensure anaerobic conditions, heat to reflux in an oil bath at 78°C, react for 24 hours, and detect with TLC (DCM / MeOH=10 / 1, v / v). Stop the reaction after the reaction is judged to be complete. First, tetrahydrofuran was rotary evaporated, and then extracted and washed with a mixed solution of ethyl acetate / hydrochloric acid (2M) = 1:2 (v / v). The organic phase was dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness. 7.5g of silica gel powder was weighed for loading, and column chromatography (DCM / MeOH = 30 / 1, v / v) was performed to obtain 1.4011g of bright yellow powder solid (referred to as TPA-Ph-COOH), with a yield of 45.21%. The corresponding hydrogen spectrum is shown in Figure 1 As shown: 1 H NMR (400MHz, d6-DMSO) δ: 7.02-7.13 (m, 9H, Ar-H), 7.33-7.36 (m, 5H, Ar-H), 7.66 (d, 2H, J = 8. 7Hz,Ar-H),7.72(d,2H,J=8.4Hz,Ar-H),7.99(d,2H,J=8.1Hz,Ar-H),12.917(s,1H,COOH-H)

[0135] Synthesis of compound 2-a: Di-tert-butyl dicarbonate (4.36 g, 0.0200 mol) was dissolved in 20 mL of methanol, and triethylamine (8.4 mL, 6.07 g, 0.0600 mol) was added as a catalyst. Cystamine dihydrochloride (4.5 g, 0.0200 mol) was weighed and added to a 100 mL round-bottom flask. After 15 mL of methanol solution was added to completely dissolve it, the first system was added dropwise (20 min) to the above round-bottom flask using a constant pressure dropping funnel. A magnetic bar was added, and the reaction was stirred for 20 min. The reaction was stopped after TLC detection (DCM / MeOH=15 / 1, v / v) was completed. Methanol was evaporated, and 40 mL 1M NaH2PO4 (pH = 4.2) was added to completely dissolve the large amount of white solid produced. After complete extraction with ether, the lower aqueous phase was collected, and the pH was adjusted to 9 with 1M NaOH. Ethyl acetate was used to continue washing the extracted aqueous phase. The upper organic phase was dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness to obtain 1.9127 g of a yellow-green oily liquid (referred to as Boc-SS-NH2), with a yield of 37.89%. The corresponding hydrogen spectrum is shown in Figure 2 As shown: 1 H NMR(400MHz,d6-DMSO)δ:1.38(s,9H,CH3),2.71-2.79(m,8H,CH2,NH2),3.17-3.20(m,2H,CH2),6.99(s,1H,NH)

[0136] Synthesis of compound 3-a: Weigh G1-OH (2g, 3.1408mmol) and add it to a 100mL round-bottom flask, and add 25mL of dry dichloromethane solution to the flask, then add pyridinium chlorochromate (1.0155g, 4.7122mmol) to the above system, replace N2, stir magnetically for 30min under ice bath conditions, then remove the ice bath and turn to room temperature, and react for 12h under N2 protection. The next day, TLC detection (DCM / MeOH=30 / 1, v / v) stopped the reaction after the reaction was complete. Weigh 2.9g of silica gel powder for sample loading, and purify by column chromatography (DCM / MeOH=40 / 1, v / v) to obtain 1.9059g of light brown oil (recorded as G1-CHO), with a yield of 95.60%.

[0137] Synthesis of compound 3-b: Weigh compound G1-CHO (0.650 g, 1.0240 mmol) and malonic acid (0.2131 g, 2.0480 mmol), dissolve in 15 mL of pyridine, add 0.1 mL of piperidine to the above system, replace N2, add magnetic stirring, and keep the temperature at 60 ° C for 12 hours. The next day, first cool the reaction system to room temperature, add 20 mL of DCM to the reaction mixture to dilute it, rinse with 20 mL of distilled water, and then adjust the pH to 1 with 30% HCl. The organic phase was extracted until TLC detected that there was no target compound. The organic phase was dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain a crude product. 1.8 g of silica gel powder was added to load the sample. After column chromatography (first use DCM / MeOH = 40 / 1, v / v to load the column and completely elute the impurities, and then continue to elute the target compound with DCM / MeOH = 10 / 1, v / v mobile phase), 0.3199 g of yellow oily liquid (denoted as G1 = COOH) was obtained, with a yield of 47.29%. The corresponding hydrogen spectrum is shown in Figure 3 As shown: 1 H NMR(400MHz,d6-DMSO)δ:1.07-1.10(m,9H,CH3),3.41-4.15(m,42H,CH2),6.48(d,1H,J =15.90Hz,C=CH),6.96(s,1H,Ar-H),7.38(d,1H,J=15.80Hz,C=CH),12.22(s,1H,COOH)

[0138] Synthesis of compound 3-c: Weigh the above-synthesized Boc-SS-NH2 (0.1156 g, 0.4582 mmol) and G1=COOH (0.3199 g, 0.5040 mmol) and dissolve them in 20 mL of dry dichloromethane, add 1-hydroxybenzotriazole (0.07429 g, 0.5498 mmol), and use N,N-diisopropylethylamine to adjust the pH to 10; replace N2, first react under ice-salt bath conditions for 15 minutes, and then quickly add 1-ethyl-(3-dimethylaminopropyl)carbodiimide (0.1317 g, 0.6872 mmol) to the round-bottom flask, replace nitrogen again to ensure an oxygen-free environment, stir the reaction in an ice bath for 15 minutes, then remove the ice bath, and react at room temperature for 12 hours. The next day, after TLC detection (DCM / MeOH=20 / 1, v / v) determined that the reaction was complete, the reaction solution was extracted with 10% potassium bisulfate, the organic phase was dried with anhydrous sodium sulfate, filtered, and the solvent was spin-dried to obtain a crude product. 1g of silica gel powder was weighed for sample loading and column chromatography (DCM / MeOH=30 / 1, v / v) was performed to obtain 0.2972g of a yellow oily liquid (denoted as G1=SS-Boc), with a yield of 74.64%. The corresponding hydrogen spectrum is shown in Figure 4 As shown: 1H NMR(400MHz,d6-DMSO)δ:1.06-1.11(m,9H,CH3),1.37(s,9H,CH3),2.75-2.85(m,4H,CH2),3.16-4.15(m,42H,C H2),6.55(s,1H,C=CH),6.89(s,2H,Ar-H),6.99(m,1H,NH),7.33(d,1H,J=15.5Hz,C=CH),8.18-8.20(m,1H,NH)

[0139] Synthesis of compound 3-d: G1 = SS-Boc (0.2900 g, 0.3337 mmol) was weighed and placed in a round-bottom flask, 7 mL of dichloromethane was added thereto, the above system was placed in an ice bath, and 0.9913 mL of trifluoroacetic acid was added dropwise, and the reaction was stirred for 15 min under magnetic stirring, and then the reaction was continued at room temperature for 1 h, and TLC detection (DCM / MeOH = 20 / 1, v / v) was performed. After the reaction was observed to be complete, 30 mL of MeOH was added to the round-bottom flask and the reaction was continued for another 30 min, and the methanol was dried by rotary evaporation. Then 4 mL of dichloromethane was added to the round-bottom flask and evaporated to dryness, and the operation was repeated three times to ensure that the trifluoroacetic acid was completely removed to obtain G1 = SS-NH2.

[0140] Synthesis of compound 3-e: Weigh the above-obtained G1=SS-NH2 (0.2570 g, 0.3337 mmol), TPA-Ph-COOH (0.1218 g, 0.3337 mmol) and catalyst 1-hydroxybenzotriazole (0.05411 g, 0.4004 mmol) and add them to a round-bottom flask in sequence, then add 20 mL of dry dichloromethane to dissolve it, and adjust the pH to an alkaline environment of about 9 with N,N-diisopropylethylamine; replace nitrogen, react under ice bath conditions for 20 min, then quickly add 1-ethyl-(3-dimethylaminopropyl)carbodiimide (0.1280 g, 0.6675 mmol), replace nitrogen again to ensure an oxygen-free environment, stir the reaction under ice bath for 15 min, remove the ice bath device, and react at room temperature for 12 h. The next day, TLC detection (DCM / MeOH=20 / 1, v / v) stopped the reaction after the reaction was complete. After the reaction solution was washed and extracted completely with 10% potassium bisulfate solution, the organic phase was dried over anhydrous sodium sulfate and filtered, the solvent was evaporated to dryness to obtain a crude product, 1g of silica gel powder was added to load the sample, and column chromatography (DCM / MeOH=40 / 1, v / v) was performed to obtain the final product of a light blue oily liquid: 0.2345g of a reduction-responsive photopolymerizable supramolecular monomer (denoted as G1=SS-TPA), with a yield of 62.90%. The corresponding mass spectrum is shown in Figure 6 As shown, the hydrogen spectrum is Figure 5 As shown: 1H NMR(400MHz,d6-DMSO)δ:1.07-1.10(m,9H,CH3),2.85-2.89(m,2H,CH2),2.93-2.96(m,2H,CH2),3.37-4.13(m,44H,CH2),6.59 (d,1H,J=15.5Hz,C=CH),6.89(s,2H,Ar-H),7.03-7.92(m,18H,Ar-H),8.23-8.26(m,1H,C=CH),8.71-8.74(m,1H,NH); + )calcd for C 62 H 83 N3O 14 S2[M+H] + 1158.4730, found 1158.5454.

[0141] The triphenylamine group has an AIE effect. Since it is a hydrophobic group, as the proportion of aqueous solution in the mixed solvent gradually increases, the triphenylamine derivatives will aggregate in the mixed solvent and the fluorescence intensity will gradually increase, which can confirm that the assembly has an AIE effect. In order to verify the AIE effect of the molecular monomer, 0.01 mg mL -1 G1=SS-TPA solution with different water ratios. It can be observed that the luminescence becomes more obvious under the irradiation of 365nm ultraviolet light. Using a fluorescence spectrophotometer, set the excitation wavelength to 303nm, the excitation and emission slits to 2.5nm and 5nm respectively, scan the fluorescence spectrum at 310-600nm, and observe the change of fluorescence intensity, such as Figure 7 As shown, the greater the proportion of aqueous solution, the higher the fluorescence intensity of the molecular aggregates at 453 nm.

[0142] The reduction response of G1 = SS-TPA molecules was investigated using a fluorescence spectrophotometer to observe the change in fluorescence intensity over time. 0.02 mg mL -1 G1=SS-TPA solution and 10mmoL·L -1 DTT solution, take 750 μL of G1=SS-TPA and dilute to 4 mL to make 3.75 μg·mL -1 The product solution was used as a control, and 750 μL of the above high concentration solutions were diluted to 4 mL, and the changes in fluorescence intensity were detected at intervals of 2 hours. Figure 8As shown, it can be observed that the fluorescence intensity only slightly decreases after the reducing agent DTT is just added. This may be because the disulfide bonds have not been reduced and broken just after DTT is added. As time goes on, the fluorescence intensity gradually decreases to varying degrees. Since the disulfide bridge is broken by DTT, the molecules are disassembled, the hydrophobic luminescent groups fall off, and the aggregates become smaller. After the 24th hour, the fluorescence intensity still decreases significantly. The fluorescence intensity at this time is significantly lower than that before the addition of the reducing compound. It can be judged that most of the disulfide bonds have been broken 24 hours after the addition of DTT. The compound has a relatively sensitive response to the reducing agent, and it is judged that the G1=SS-TPA supramolecular monomer has a reduction response.

[0143] Naproxen (Nap) was used as the loaded drug, and the loading and release of the drug by the supramolecular assembly was studied by fluorescence spectrophotometry. The disulfide bridge will break in the reducing environment after adding DTT, so DTT was added to the molecular monomer solution with Nap added to study the effect of the reduction response on the loading and release of the supramolecular monomer.

[0144] In a mixed solvent of Tris-HCl (pH = 7.4) and THF (v / v = 9:1), 0.05 mg mL -1 G1 = SS-TPA solution, add 0.02 mg mL -1 0.05 mg·mL of Nap solution -1 G1 = SS-TPA solution and solution with 1.875mmol DTT added after drug coating. The product concentration is doubled while other conditions remain unchanged. Three solutions are prepared in the same way. The excitation wavelength is set to 303nm, and the emission and excitation slits are selected to be 2.5nm and 2.5nm respectively. Under this condition, the changes in the fluorescence spectrum are observed. Fig. 9 As shown in the figure, the fluorescence intensity of Nap dropped significantly after adding G1=SS-TPA solution, which indicates that the supramolecular monomers self-assembled to form nanosphere particles that encapsulated Nap in the middle. After adding DTT, the fluorescence intensity of the solution gradually increased over time. This is because the disulfide bonds broke in a reducing environment, the molecular assembly was disassembled, the encapsulated Nap was released, the Nap in the solution gradually increased, and the fluorescence became stronger. Fig.10 As shown in the figure, the coating of Nap by two concentrations of G1 = SS-TPA is compared. The fluorescence intensity of Nap in 0.1 mg·mL-1 G1 = SS-TPA solution is higher than that in 0.05 mg·mL -1 The G1-SS-TPA solution was lower, indicating that the drug loading capacity of the G1=SS-TPA assembly would gradually increase with the increase of concentration.

[0145] Example 2

[0146]

[0147] Synthesis of compound 1-a: Weigh compound TPE-OH (0.600 g, 1.7 mmol), tert-butyl bromoacetate (0.3420 g, 1.8 mmol), and 2.47 mmol K2CO3 and dissolve them in 15 mL acetonitrile, add magnetic stirring, and keep the temperature at 85°C for 12 hours. The next day, filter out the insoluble K2CO3, and remove the acetonitrile in the reaction system by rotary evaporation under heating to 40°C. Add 6mL DCM and 1mL TFA to the flask, stir vigorously to react for 2h, then extract with an equal volume of distilled water 3 times, take the lower organic phase and evaporate it, add a small amount of DCM and continue to evaporate it, repeat the above operation 3 to 4 times, weigh 1g silica gel sample, column chromatography purification (use DCM / MeOH=40 / 1, v / v column loading and elution to the impurity point, change to PE / EA=5 / 1, v / v mobile phase to continue elution), and obtain 1-a as a yellow-green oily liquid (recorded as TPE-COOH) 0.4570g, with a yield of 70.50%. The corresponding hydrogen spectrum is shown in Fig.11 As shown: 1 H NMR (43MHz, d6-DMSO): δ = 4.05 (s, 2H, CH2), 6.25-7.55 (d, 19H, Ar-H)

[0148] Synthesis of compound 3-f: G1 = SS-NH2 (0.2570 g, 0.2804 mmol), TPE-COOH (0.1140 g, 0.2804 mmol) and catalyst 1-hydroxybenzotriazole (0.05411 g, 0.3361 mmol) obtained above (Example 1) were weighed and added to a round-bottom flask in sequence, and then 20 mL of dry dichloromethane was added to dissolve it, and the pH was adjusted to an alkaline environment of 9 with N, N-diisopropylethylamine; nitrogen was replaced, and the reaction was carried out under ice bath conditions for 20 min, and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide (0.0825 g, 0.4206 mmol) was quickly added, and nitrogen was replaced again to ensure an oxygen-free environment. After stirring the reaction in an ice bath for 15 min, the ice bath device was removed and the reaction was carried out at room temperature for 12 h. The next day, the reaction was stopped after TLC detection (DCM / MeOH=20 / 1, v / v) was complete. After the reaction solution was washed and extracted completely with 10% potassium bisulfate solution, the organic phase was dried over anhydrous sodium sulfate and filtered, the solvent was evaporated to dryness to obtain a crude product, 1g of silica gel powder was added to load the sample, and column chromatography (DCM / MeOH=40 / 1, v / v) was performed to obtain the final product of a light blue oily liquid: 0.1971g of a reduction-responsive photopolymerizable supramolecular monomer 3-f (denoted as G1-SS-TPE), with a yield of 58.60%. The corresponding hydrogen spectrum is shown in Fig.12 As shown: 1 H NMR(400MHz,d6-DMSO)δ:1.05-1.10(m,9H,CH3),2.81-2.84(m,2H,CH2),2.89-2.92(m,2H,CH2),3.33-4.47( m,48H,CH2),6.71(m,1H,C=CH),6.74(m,1H,C=CH)6.85-7.32(m,21H,Ar-H),8.23(m,1H,NH),8.58(m,1H,NH)

[0149] Fluorescence spectroscopy was used to investigate the encapsulation of the drug naproxen (Nap) by G1-SS-TPE. One end of the Nap molecule is a carboxyl group, so it was dissolved in an alkaline aqueous solution; the drug molecule itself can emit fluorescence, so a fluorescence spectrophotometer can be used to observe the encapsulation of naproxen. Fig.13 As shown in the figure, the fluorescence intensity of the pure naproxen solution is stronger than that of the mixed solution of Nap naproxen and G1-SS-TPE, which indicates that part of Nap is coated by G1-SS-TPE and the fluorescence is quenched; when G1-SS-TPE is reduced, the hydrophobic groups of the molecules fall off, the supramolecular assembly disassembles, the fluorescence intensity increases greatly, and the coated drug molecules have been released.

[0150] The various embodiments in this specification are described in a progressive manner, and each embodiment focuses on the differences from other embodiments. The same or similar parts between the various embodiments can be referenced to each other.

[0151] The above description of the disclosed embodiments enables one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A reduction-responsive photopolymerizable supramolecular monomer, characterized in that: The structure of the reduction-responsive photopolymerizable supramolecular monomer is as follows: in, X is CH3 or CH2CH3.

2. The method for preparing a reduction-responsive photopolymerizable supramolecular monomer according to claim 1, characterized in that: The steps include: 1) reacting 4-bromotriphenylamine with 4-carboxyphenylboronic acid to obtain compound 1-a or reacting TEP-OH with tert-butyl bromoacetate, and then reacting the reaction product with trifluoroacetic acid to obtain compound 1-a; 2) reacting di-tert-butyl dicarbonate with cystamine dihydrochloride to obtain compound 2-a; 3) subjecting compound G1-OH to oxidation reaction to obtain compound 3-a; compound 3-a reacts with malonic acid to obtain compound 3-b; 4) Compound 2-a, compound 3-b, 1-hydroxybenzotriazole, N,N-diisopropylethylamine and an organic solvent are mixed to carry out a first reaction; after the reaction is complete, the mixture is mixed with 1-ethyl-(3-dimethylaminopropyl)carbodiimide to carry out a second reaction to obtain compound 3-c; 5) reacting compound 3-c with trifluoroacetic acid, and after the reaction is complete, reacting with methanol to obtain compound 3-d; 6) Compound 3-d, compound 1-a, 1-hydroxybenzotriazole, N,N-diisopropylethylamine and an organic solvent are mixed to carry out a first reaction; after the reaction is complete, the mixture is mixed with 1-ethyl-(3-dimethylaminopropyl)carbodiimide to carry out a second reaction to obtain a reduction-responsive photopolymerizable supramolecular monomer; There is no order restriction for steps 1) to 3); The structural formula of compound 1-a is The structural formula of compound 2-a is The structural formula of compound G1-OH is The structural formula of compound 3-a is The structural formula of compound 3-b is The structural formula of compound 3-c is The structural formula of compound 3-d is Among them, X in compound G1-OH, compound 3-a, compound 3-b and compound 3-c is CH3 or CH2CH3.

3. The method for preparing a reduction-responsive photopolymerizable supramolecular monomer according to claim 2, characterized in that: The reaction of step 1) is as follows: 4-bromotriphenylamine, 4-carboxyphenylboric acid, tetrabutylammonium bromide, an organic solvent, a K2CO3 solution and Pd(PPH3)4 are mixed and reacted under anaerobic conditions to obtain compound 1-a; The usage ratio of 4-bromotriphenylamine, 4-carboxyphenylboric acid, tetrabutylammonium bromide, organic solvent, K2CO3 solution and Pd(PPH3)4 is 0.01356-0.11627mol: 0.01088-0.01305mol: 1.356-1.627mmol: 45-60mL: 30-45mL: 0.0519-0.0736mmol; The concentration of the K2CO3 solution is 0.8-1.2 mol / L; The reaction temperature is 75-80°C and the reaction time is 20-25h; Or TPE-OH, tert-butyl bromoacetate, potassium carbonate and a first organic solvent are mixed to perform a first reaction, and then the reaction product is mixed with trifluoroacetic acid and a second organic solvent to perform a second reaction to obtain compound 1-a; The usage ratio of TPE-OH, tert-butyl bromoacetate, potassium carbonate, the first organic solvent, trifluoroacetic acid and the second organic solvent is 1.7-2 mmol: 1.8-2.2 mmol: 2.47-3 mmol: 15-25 mL: 1-1.5 mL: 6-8 mL; The temperature of the first reaction is 80-90°C, and the time of the first reaction is 10-15h; The second reaction time is 1.5 to 2.5 hours.

4. The method for preparing a reduction-responsive photopolymerizable supramolecular monomer according to claim 3, characterized in that: The reaction of step 2) is as follows: Di-tert-butyl dicarbonate, triethylamine, cystamine dihydrochloride and an organic solvent are mixed and reacted to obtain compound 2-a; The molar volume ratio of di-tert-butyl dicarbonate, triethylamine, cystamine dihydrochloride and organic solvent is 0.02-0.03 mol: 8.4-10 mL: 0.02-0.03 mol: 30-35 mL; The reaction time is 20 to 30 minutes.

5. The method for preparing a reduction-responsive photopolymerizable supramolecular monomer according to claim 4, characterized in that: The oxidation reaction in step 3) is as follows: Compound G1-OH, pyridinium chlorochromate and an organic solvent are mixed and subjected to oxidation reaction to obtain compound 3-a; The molar volume ratio of the compound G1-OH, pyridinium chlorochromate and the organic solvent is 3.1408-3.777 mmol: 4.712-5.654 mmol: 20-25 mL; The mixing temperature is -5 to 5°C, and the mixing time is 25 to 35 minutes; The oxidation reaction time is 10 to 15 hours.

6. The method for preparing a reduction-responsive photopolymerizable supramolecular monomer according to claim 5, characterized in that: The reaction of the compound 3-a described in step 3) with malonic acid is as follows: Compound 3-a, malonic acid, piperidine and an organic solvent are mixed and reacted to obtain compound 3-b; The molar volume ratio of the compound 3-a, malonic acid, piperidine and organic solvent is 1.024-1.229 mmol: 2.048-2.458 mmol: 0.1-0.12 mL: 15-25 mL; The reaction temperature is 50-80° C., and the reaction time is 10-15 hours.

7. The method for preparing a reduction-responsive photopolymerizable supramolecular monomer according to claim 6, characterized in that: In step 4), the molar volume ratio of compound 2-a, compound 3-b, 1-hydroxybenzotriazole, organic solvent and 1-ethyl-(3-dimethylaminopropyl)carbodiimide is 0.4582-0.5498 mmol: 0.5040-0.6048 mmol: 0.5498-0.6598 mmol: 20-30 mL: 0.6872-0.8246 mmol; The amount of N,N-diisopropylethylamine added is such that the pH value of the reaction system of the first reaction is 9 to 10; In step 4), the temperature of the first reaction is -5 to 5°C, and the time of the first reaction is 15 to 20 minutes; In step 4), the second reaction is firstly carried out at -5 to 5°C for 15 to 20 minutes, and then at room temperature for 10 to 15 hours.

8. The method for preparing a reduction-responsive photopolymerizable supramolecular monomer according to claim 7, characterized in that: The reaction of step 5) is as follows: Compound 3-c, trifluoroacetic acid and an organic solvent are mixed to perform a first reaction, and then mixed with methanol to perform a second reaction to obtain compound 3-d; The molar volume ratio of the compound 3-c, trifluoroacetic acid, organic solvent and methanol is 0.3337-0.4004 mmol: 0.9913-1.2887 mL: 7-8 mL: 30-40 mL; The mixing temperature is -5 to 5°C, and the mixing time is 12 to 18 minutes; The time of the first reaction is 0.8 to 1.2 hours; the time of the second reaction is 25 to 35 minutes.

9. The method for preparing a reduction-responsive photopolymerizable supramolecular monomer according to claim 8, characterized in that: In step 6), the molar volume ratio of the compound 3-d, the compound 1-a, 1-hydroxybenzotriazole, the organic solvent and 1-ethyl-(3-dimethylaminopropyl)carbodiimide is 0.3337-0.4004 mmol: 0.3337-0.4004 mmol: 0.4004-0.4805 mmol: 20-26 mL: 0.5005-0.8010 mmol; The amount of N,N-diisopropylethylamine added is such that the pH value of the reaction system of the first reaction is 9 to 10; In step 6), the temperature of the first reaction is -5 to 5°C, and the time of the first reaction is 18 to 22 minutes; In step 6), the second reaction is firstly carried out at -5 to 5°C for 12 to 18 minutes, and then at room temperature for 10 to 15 hours.

10. Use of the reduction-responsive photopolymerizable supramolecular monomer prepared by the preparation method according to any one of claims 2 to 9 in the preparation of tumor targeting drugs.

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