An antitumor drug and a preparation method and application thereof

Abstract

The application provides an antitumor drug, a preparation method and application thereof, and belongs to the technical field of medicines. 4 The Fe3O NPs are deposited with polydopamine on the surface, then a COF layer is formed on the surface through a one-pot method, and an antitumor compound is loaded; further, doxorubicin is loaded on the surface, and then the antitumor drug is prepared by reacting with F127 coupled with folate and oligomeric hyaluronic acid. The antitumor drug prepared by the application has high anticancer activity and drug resistance reversal, high drug loading rate, is not prone to aggregation, has good biocompatibility, good targeting and slow release, and has good application in chemotherapy, photodynamic therapy, photothermal therapy and nuclear magnetic imaging, so that the antitumor drug becomes a new generation of diagnosis and treatment integrated reagent.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to an anti-tumor drug, its preparation method, and its application. Background Technology

[0002] Malignant tumors have become one of the major diseases threatening human health. Traditional tumor treatments such as chemotherapy and radiotherapy, while widely used clinically, face multiple challenges, including low solubility of antitumor drugs, strong systemic toxicity, poor targeting efficacy, tumor drug resistance, and the unique tumor microenvironment. Nanotechnology intervention in tumor therapy improves drug targeting, enhancing efficacy and reducing adverse reactions.

[0003] Nanoscale carriers (1-1000 nm) have sizes similar to those of biomembranes and extracellular matrix pores, enabling them to passively accumulate in tumor tissues through enhanced permeability and retention. Nanocarriers modified with antibodies, nucleic acid aptamers, or small molecule ligands can actively target specific antigens on the surface of tumor cells, significantly increasing drug concentrations at the tumor site. The unique physicochemical properties of nanomaterials can significantly improve drug solubility and stability, reducing adverse drug reactions. Nanodelivery systems can respond to specific stimuli from the tumor microenvironment, achieving controlled drug release and precisely regulating drug metabolism kinetics. Currently marketed mature nano-anti-tumor drugs include doxorubicin liposomes, paclitaxel albumin nanoparticles, and paclitaxel polymer micelles.

[0004] Indole-3-carbinol (1,2,3-Triazole, I3C) is an active ingredient isolated from cruciferous vegetables, exhibiting strong inhibitory activity against cancer cells. In an acidic environment, indole-3-carbinol undergoes polymerization to form dimers, trimers, and cyclic polymers; these polymers are the actual molecules responsible for its antitumor effects in vivo. Currently, it is believed that the inhibitory effect of indole-3-carbinol on tumor cells stems from its metabolic detoxification of carcinogens in vivo and its influence on various detoxification enzymes such as AFB1-8,9-cyclooxygenase, benzo[a]pyrene hydroxylase (BPOH), and cyclooxygenase (EH). Clearly, indole-3-carbinol can serve as an important anticancer core compound; by using it as a structural framework to introduce anticancer pharmacophores, it is possible to obtain candidate compounds with even better anticancer activity. 1,2,3-Triazole (Tz) is a very important nitrogen-containing heterocyclic compound. It is a five-membered heterocycle composed of three nitrogen atoms and two carbon atoms. It has a special planar rigid structure, which gives it a strong ability to intercalate into DNA. At the same time, it has a large dipole moment, which enables it to form a variety of non-covalent interactions with different biological targets, such as hydrophobicity, hydrogen bonding, van der Waals forces and dipole-dipole bonds. Therefore, it has excellent anti-tumor activity.

[0005] However, there is currently no research on compounds obtained by combining the indole-3-methanol skeleton and the 1,2,3-triazole structure, nor on their antitumor effects. Furthermore, improving targeted drug delivery and drug loading, and preparing suitable nano-formulations are also directions of this invention. Summary of the Invention

[0006] The purpose of this invention is to propose an anti-tumor drug, its preparation method, and its application. This drug has high anti-cancer activity and can reverse drug resistance. It has a high drug loading rate, is not prone to aggregation, has good biocompatibility, and has good targeting and sustained-release properties. It has good applications in chemotherapy, photodynamic therapy, photothermal therapy, and magnetic resonance imaging, making it a new generation of integrated diagnostic and therapeutic reagent.

[0007] The technical solution of this invention is implemented as follows:

[0008] This invention provides an antitumor compound, the structural formula of which is shown in Formula I: Formula I;

[0009] Where R= , , or .

[0010] This invention is the first to combine the indole-3-methanol skeleton with the 1,2,3-triazole structure to obtain a new compound (I3CTz), which increases the anticancer activity of indole-3-methanol. At the same time, the preparation method is simple, the synthesis conditions are mild, the yield is relatively high, and it can overcome the common problem of drug resistance to antitumor drugs (such as doxorubicin) and also has good inhibitory activity against drug-resistant cells.

[0011] This invention further protects a method for preparing the above-mentioned antitumor compound, comprising the following steps:

[0012] S1. 6-Bromoindole-3-methanol, m-aminophenylacetylene, catalyst, 4,5-bis(diphenylphosphino-9,9-dimethyloxanthracene), and potassium tert-butoxide were mixed and heated to react. The mixture was filtered, the residue was washed, the solvent was removed under reduced pressure, and the intermediate was purified by column chromatography to obtain intermediate 1, with the following structure: ;

[0013] S2. Intermediate 1, substituted benzyl azide, tert-butanol, water, copper sulfate and sodium ascorbate were mixed and heated to react, filtered, the residue was washed, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography to obtain the antitumor compound.

[0014] As a further improvement of the present invention, the molar ratio of 6-bromoindole-3-methanol, m-aminophenylacetylene, catalyst, 4,5-bisdiphenylphosphino-9,9-dimethyloxanthracene and potassium tert-butoxide in step S1 is 1:1-1.2:0.02-0.025:0.03-0.04:1.5-2, the heating reaction temperature is 75-85℃, and the catalyst is Pd2(dba)3.

[0015] As a further improvement of the present invention, the molar ratio of intermediate 1, substituted benzyl azide, copper sulfate and sodium ascorbate in step S2 is 1:1-1.2:0.2-0.4:0.3-0.6, and the heating reaction temperature is 65-75°C; the substituted benzyl azide is selected from at least one of 2,4-dibromobenzyl azide, 3-chloro-4-fluorobenzyl azide, 2-fluoro-4-bromobenzyl azide, and 2-fluoro-6-chlorobenzyl azide.

[0016] The present invention further protects an antitumor drug comprising 0.1-99.9% by weight of the above-mentioned antitumor compound and 0.1-99.9% by weight of pharmaceutically acceptable excipients.

[0017] As a further improvement of the present invention, polydopamine is deposited on the surface of Fe3O4NPs, and then a COF layer is formed on the surface by a one-pot method, and an antitumor compound is loaded. Doxorubicin is further loaded onto the surface, and then reacted with F127 coupled with folic acid and oligomeric hyaluronic acid to obtain an antitumor drug.

[0018] This invention further protects a method for preparing the above-mentioned antitumor drug, comprising the following steps:

[0019] (1) Dissolve ferric chloride and ferrous chloride in water, heat and stir under an inert atmosphere, add ammonia dropwise, react in a water bath, separate with a magnet, wash, and dry to obtain Fe3O4NPs;

[0020] (2) Fe3O4NPs were added to Tris-HCl solution, dopamine hydrochloride was added, the mixture was heated and stirred, centrifuged, washed and dried to obtain Fe3O4@PDA NPs;

[0021] Magnetic iron oxide nanoparticles exhibit good magnetic response, while polydopamine demonstrates good photoresponsiveness. Therefore, the resulting antitumor drugs can be effectively used in chemotherapy, photodynamic therapy, photothermal therapy, and magnetic resonance imaging, making them a next-generation integrated diagnostic and therapeutic reagent. Furthermore, surface-modified magnetic iron oxide nanoparticles are less susceptible to encapsulation by plasma proteins, thus preventing phagocytosis, reducing their clearance rate, and prolonging their circulation time in the bloodstream.

[0022] (3) Dissolve 2,4,6-tricarboxymethyl phloroglucinol and 1,3,5-tris(4-aminophenyl)benzene in ethanol respectively, and add them dropwise alternately to a water-ethanol solution containing Fe3O4@PDA NPs. Stir the reaction at room temperature, centrifuge, wash, and dry to obtain Fe3O4@PDA@COF;

[0023] Fe3O4@PDA@COF was prepared by a one-pot method. The COF structure has unique advantages for drug delivery systems, including: (1) The high nitrogen content provides free lone pairs of electrons. The high density of electrons in the pore walls can interact with drug molecules through hydrogen bonds and π-π interactions, giving COF a strong drug loading capacity. It can also respond to the stimulation of the biological environment, which is conducive to targeted release and makes drug release more precise and efficient; (2) The high specific surface area and suitable pore geometry of COF provide high drug loading efficiency; (3) Since there are no heavy metals and metal oxides in COF, the cytotoxicity produced during in vivo degradation is small, or even non-existent, and the biocompatibility is good.

[0024] (4) Fe3O4@PDA@COF, antitumor compounds and doxorubicin were added to water, heated and stirred to react, centrifuged, washed and dried to obtain Fe3O4@PDA@COF@I3CTz / Dox;

[0025] This invention reveals that the prepared antitumor compound exhibits a good synergistic effect with doxorubicin. Furthermore, the antitumor compound can reverse the doxorubicin resistance phenotype in tumor cells, acting as a chemosensitizer. This invention utilizes a COF (coated oxygen carrier) as a drug carrier, significantly increasing the loading capacity of both doxorubicin (Dox) and the antitumor compound (I3CTz), while also providing a sustained-release effect.

[0026] (5) Folic acid and oligomeric hyaluronic acid were dissolved in DMSO, N,N'-carbonyl diimidazole was added, and the mixture was stirred at room temperature in the dark. F127 was added, and the reaction was continued by stirring. The mixture was dialyzed and dried to obtain FA / HA-F127.

[0027] (6) Add FA / HA-F127 and Fe3O4@PDA@COF@I3CTz / Dox to water, heat and stir to react, centrifuge, wash and dry to obtain antitumor drugs.

[0028] To improve drug targeting, folic acid and oligomeric hyaluronic acid were conjugated with F127. By leveraging the specific recognition of receptors on the surface of cancer cells by oligomeric hyaluronic acid and folic acid, a "dual-targeting" delivery system was achieved. This significantly improved the precise accumulation of drugs at the tumor site, reduced the amount of chemotherapy drugs absorbed, decreased chemotherapy side effects, and improved patient compliance. The prepared FA / HA-F127 can act as an amphiphilic material, self-assembling into micelles in aqueous solution to encapsulate hydrophobic COF drugs, forming a nanoscale drug carrier. This allows for more effective exudation from tumor blood vessels and retention within tumor tissue, achieving passive targeting. Simultaneously, the good hydrophilicity of folic acid and oligomeric hyaluronic acid significantly improved the water dispersibility of the prepared antitumor drug, preventing aggregation and enhancing biocompatibility and degradability.

[0029] As a further improvement of the present invention, in step (1), the mass ratio of ferric chloride to ferrous chloride is 3.24:1.26, the heating and stirring temperature is 45-55℃, the water bath stirring time is 20-40 min, and the ammonia water is added to the solution pH value of 10-11; in step (2), the pH value of the Tris-HCl solution is 8.5-9.5, the mass ratio of Fe3O4NPs to dopamine hydrochloride is 10:3-5, the heating and stirring reaction temperature is 40-50℃, and the time is 4-8 h; in step (3), the mass ratio of 2,4,6-tricarboxymethyl phloroglucinol, 1,3,5-tris(4-aminophenyl)benzene and Fe3O4@PDA NPs is 4-8.5:10-18:3-5, and the room temperature stirring reaction time is 8-10 h.

[0030] As a further improvement of the present invention, in step (4), the mass ratio of Fe3O4@PDA@COF, antitumor compound and doxorubicin is 1:0.1-0.3:0.5-0.7, the temperature of the heating and stirring reaction is 30-35℃, and the time is 6-10h; in step (5), the mass ratio of folic acid, oligomeric hyaluronic acid, N,N'-carbonyl diimidazole and F127 is 0.7-1:0.3-0.5:0.4-0.7:6-6.5, the stirring time at room temperature in the dark is 20-28h, and the stirring reaction time is 20-28h; in step (6), the mass ratio of FA / HA-F127 and Fe3O4@PDA@COF@I3CTz / Dox is 1:4-7, the temperature of the heating and stirring reaction is 30-35℃, and the time is 6-10h.

[0031] This invention further protects the use of the above-mentioned antitumor compound and the above-mentioned antitumor drug in the preparation of antitumor drugs.

[0032] The present invention has the following beneficial effects:

[0033] 1. This invention prepares a novel anti-tumor compound with high anti-cancer activity, which is simple to prepare, has mild synthesis conditions, and a relatively high yield. It can also overcome the common problem of drug resistance to anti-tumor drugs (such as doxorubicin) and has good inhibitory activity against drug-resistant cells.

[0034] 2. This invention co-loads an antitumor compound with doxorubicin to synergistically fight cancer. At the same time, the antitumor compound can reverse the drug resistance phenotype of tumor cells to doxorubicin, thus acting as a chemotherapy sensitizer.

[0035] 3. The antitumor drug prepared by this invention uses magnetic iron oxide nanoparticles coated with polydopamine as the core, which enables the prepared antitumor drug to have good applications in chemotherapy, photodynamic therapy, photothermal therapy and MRI, making it a new generation of integrated diagnostic and therapeutic reagent.

[0036] 4. This invention forms a COF layer on the surface of the core using a one-pot method, and then loads antitumor compounds and doxorubicin, which greatly improves the drug loading rate and has a sustained-release effect, prolonging the efficacy. At the same time, the carrier has low toxicity and good biocompatibility.

[0037] 5. This invention further utilizes the prepared amphiphilic conjugate FA / HA-F127 to achieve a "dual-targeting" delivery system, significantly improving the precise enrichment of drugs at the tumor site, reducing the intake of chemical drugs, reducing chemotherapy side effects, and improving patient compliance. By encapsulating the hydrophobic COF drug inside, a nanoscale drug carrier is formed, which can more effectively seep out from the tumor blood vessels and remain in the tumor tissue to achieve passive targeting. At the same time, it improves the water dispersibility, biocompatibility, and degradability of the prepared antitumor drug. Attached Figure Description

[0038] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0039] Figure 1 The magnetic hysteresis curve of the antitumor drug prepared in Example 5;

[0040] Figure 2 The infrared spectrum of the antitumor drug prepared in Example 5;

[0041] Figure 3 This is a SEM image of the antitumor drug prepared in Example 5. Detailed Implementation

[0042] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0043] DMSO, dimethyl sulfoxide; F127, poloxamer 407; oligomeric hyaluronic acid, molecular weight 5 kDa; folic acid, >97%.

[0044] Drug loading (%) = (m 投药量 -m 上清液中药物的质量 ) / m 复合材料的总质量 ×100%

[0045] Examples 1-4

[0046] This embodiment provides a method for preparing the above-mentioned antitumor compound, and the synthetic route is as follows:

[0047] ;

[0048] Includes the following steps:

[0049] S1. 100 mmol of 6-bromoindole-3-methanol, 110 mmol of m-aminophenylacetylene, 2.2 mmol of catalyst Pd2(dba)3, 3.5 mmol of 4,5-bis(diphenylphosphino-9,9-dimethyloxanthracene), and 180 mmol of potassium tert-butoxide were added to 500 mL of N,N-dimethylformamide. The mixture was heated to 80 °C and the reaction was monitored by TLC. After the TLC results indicated complete conversion of the starting material, the reaction solution was cooled, filtered, and the residue was washed several times with ethyl acetate. The solvent was removed by rotary evaporation under reduced pressure. The residue was separated by column chromatography, eluted, and purified to obtain the target product, intermediate 1. ESI-MS calculated value: C 17 H 15 N₂O(M+H) + 263.11, measured value: 263.1, yield: 78%. NMR results: 1 H NMR (300MHz, CDCl3) δ10.1 (br, 1H), 6.93-6.98 (m, 2H), 6.76-6.8 (m, 2H), 6.65 ( s, 1H), 6.37-6.42 (m, 3H), 4.67 (s, 2H), 4.0 (br, 1H), 3.12 (s, 1H), 2.1 (br, 1H);

[0050] S2. Mix 50 mmol of intermediate 1, 57 mmol of substituted benzyl azide, 100 mL of tert-butanol, 100 mL of water, 15 mmol of copper sulfate, and 20 mmol of sodium ascorbate, heat to 70 °C, and react. Monitor the reaction process by TLC. After the TLC results show that the starting material has been completely converted, add 200 mL of dichloromethane, filter the reaction solution, extract the aqueous phase twice with dichloromethane, combine the organic phases, dry them with anhydrous magnesium sulfate, concentrate them, and recrystallize them with methanol to obtain the antitumor compound.

[0051] Raw materials and products are shown in Table 1:

[0052]

[0053] Antitumor compound A: ESI-MS calculated value: C 24 H 20 Br2N5O(M+H) + 554.25, measured value: 554.3, yield: 52%. NMR results: 1 H NMR (300MHz, CDCl3) δ10.2 (br, 1H), 7.7 (s, 1H), 7.42 (s, 1H), 7.12 (s, 2H), 7.05 (m, 1H), 6.8-6 .9 (m, 3H), 6.69 (s, 1H), 6.4-6.45 (m, 3H), 4.92 (s, 2H), 4.65 (s, 2H), 4.0 (br, 1H), 2.0 (br, 1H).

[0054] Antitumor compound B: ESI-MS calculated value: C 24 H 20 ClFN5O(M+H) + 448.89, measured value: 448.9, yield: 54%. NMR results: 1 H NMR (300MHz, CDCl3) δ10.0 (br, 1H), 7.6 (s, 1H), 7.05-7.1 (m, 2H), 6.8-6.9 (m, 5H), 6.62 (s, 1H), 6.4-6.45 (m, 3H), 4.98 (s, 2H), 4.69 (s, 2H), 4.1 (br, 1H), 2.0 (br, 1H).

[0055] Antitumor compound C: ESI-MS calculated value: C 24 H 20 BrFN5O(M+H) + 493.34, measured value: 493.3, yield: 55%. NMR results: 1H NMR (300MHz, CDCl3) δ10.5 (br, 1H), 7.8 (s, 1H), 6.8-7.1 (m, 7H), 6.64 (s, 1H), 6.35-6.4 (m, 3H), 4.92 (s, 2H), 4.61 (s, 2H), 4.0 (br, 1H), 2.1 (br, 1H).

[0056] Antitumor compound D: ESI-MS calculated value: C 24 H 20 ClFN5O(M+H) + 448.89, measured value: 448.9, yield: 49%. NMR results: 1 H NMR (300MHz, CDCl3) δ10.3 (br, 1H), 7.65 (s, 1H), 6.7-6.9 (m, 8H), 6.38-6.42 (m, 3H), 4.9 (s, 2H), 4.58 (s, 2H), 4.2 (br, 1H), 2.2 (br, 1H).

[0057] Test Example 1

[0058] Five tumor cell lines were selected: human gastric cancer cell line SGC7901, human lung cancer cell line A549, human ovarian cancer cell line OVCA433, human breast cancer cell line MCF-7, and human liver cancer cell line HePG2. The CKK-8 assay was used: 1×10⁻⁶ cells were used... 4 100 μL of cells were seeded into 96-well plates and cultured at 37°C for 24 h. Then, 20 μL of different concentrations of the antitumor compounds prepared in Examples 1-4 were added, and the plates were cultured for another 48 h. Next, 10 μL of CCK-8 solution was added to each well, and the plates were incubated at 37°C for 4 h. The absorbance at 450 nm was measured using a microplate reader, and the IC50 was calculated. 50 The drug concentrations were 200, 100, 10, 1, 0.1, and 0.01 μg / mL; the positive control drug cisplatin concentrations were 200, 20, 2, 0.2, and 0.02 μg / mL. The results are shown in Table 2.

[0059] Table 2

[0060] ;

[0061] As can be seen from the table above, the antitumor compounds obtained in Examples 1-4 of this invention have good antitumor activity.

[0062] Test Example 2

[0063] The drug-resistant cell line was established from human non-small cell lung cancer cells, PC-9 cells. 10 5Cells were seeded at 1 mL per well in 12-well plates and cultured overnight before treatment. High-dose chemotherapy drug doxorubicin (100×IC) was used. 50 Cells were subjected to a 24-hour shock treatment at a specific concentration to induce doxorubicin resistance in cancer cells. The culture medium was then changed twice weekly, and the drug concentration was gradually increased as cell growth improved. Once cells adhered to the culture medium, a drug-resistant cell line was obtained. The IC50 of doxorubicin against the drug-resistant cell line was then tested. 50 Add 1 μmol / L of the antitumor compound prepared in Examples 1-4 and different concentrations of doxorubicin to each well. Incubate at 37°C in a constant temperature incubator containing 5% CO2 for 72 h. Add MTT and measure the optical density. Calculate the fold reversal of doxorubicin-induced killing of drug-resistant PC-9 cells.

[0064] ;

[0065] The results are shown in Table 3.

[0066] Table 3

[0067] ;

[0068] As shown in the table above, the antitumor compounds prepared in Examples 1-4 of this invention have a good effect on reversing drug resistance in drug-resistant cells.

[0069] Example 5

[0070] This embodiment provides a method for preparing an antitumor drug, including the following steps:

[0071] (1) Dissolve 3.24 g of ferric chloride and 1.26 g of ferrous chloride in 300 mL of water, heat to 45 °C under nitrogen atmosphere, stir, add ammonia dropwise until the pH of the solution is 10-11, react in water bath for 40 min, separate with a magnet, wash, dry, and obtain Fe3O4NPs;

[0072] (2) Add 1g of Fe3O4NPs to a Tris-HCl solution with a pH of 8.5-9.5, add 0.3g of dopamine hydrochloride, heat to 40℃, stir for 8h, centrifuge, wash, and dry to obtain Fe3O4@PDA NPs;

[0073] (3) Dissolve 0.4g of 2,4,6-tricarboxymethyl phloroglucinol and 1g of 1,3,5-tris(4-aminophenyl)benzene in 10mL of ethanol, and add them dropwise to 100mL of water-ethanol solution (volume ratio 1:2) containing 0.3g of Fe3O4@PDA NPs. Stir the reaction at room temperature for 8h, centrifuge, wash, and dry to obtain Fe3O4@PDA@COF;

[0074] (4) 1g Fe3O4@PDA@COF, 0.1g antitumor compound A and 0.5g doxorubicin were added to 300mL of water, heated to 30℃, stirred for 10h, centrifuged, washed and dried to obtain Fe3O4@PDA@COF@I3CTzA / DOX; the drug loading of antitumor compound I (I3CTzA) was 5.14%; the drug loading of doxorubicin (DOX) was 27.67%;

[0075] (5) Dissolve 0.7g folic acid and 0.3g oligo hyaluronic acid in 100mL DMSO, add 0.4g N,N'-carbonyl diimidazole, stir at room temperature in the dark for 24h, add 6g F127, continue stirring for 20h, dialyze with a dialysis bag with a molecular weight cutoff of 8kDa for 3d, dry, and obtain FA / HA-F127;

[0076] (6) Add 1g FA / HA-F127 and 4g Fe3O4@PDA@COF@I3CTzA / DOX to 700mL of water, heat to 30℃, stir and react for 10h, centrifuge, wash, dry and obtain antitumor drug. Figure 1 The magnetic hysteresis curve of the prepared antitumor drug shows that its saturation magnetization is 39 emu / g. Figure 2 The infrared spectrum of the complex shows that it was successfully synthesized. Figure 3 The SEM image shows that the particle size of this anti-tumor drug is between 150-250 nm.

[0077] Example 6

[0078] This embodiment provides a method for preparing an antitumor drug, including the following steps:

[0079] (1) Dissolve 3.24 g of ferric chloride and 1.26 g of ferrous chloride in 300 mL of water, heat to 55 °C under nitrogen atmosphere, stir, add ammonia dropwise until the pH of the solution is 10-11, react in water bath for 20 min, separate with a magnet, wash, dry, and obtain Fe3O4NPs;

[0080] (2) Add 1g of Fe3O4NPs to a Tris-HCl solution with a pH of 8.5-9.5, add 0.5g of dopamine hydrochloride, heat to 50℃, stir for 4h, centrifuge, wash, and dry to obtain Fe3O4@PDA NPs;

[0081] (3) Dissolve 0.85g of 2,4,6-tricarboxymethyl phloroglucinol and 1.8g of 1,3,5-tris(4-aminophenyl)benzene in 10mL of ethanol, and add them dropwise to 100mL of a water-ethanol solution (volume ratio 1:2) containing 0.5g of Fe3O4@PDA NPs. Stir the reaction at room temperature for 10h, centrifuge, wash, and dry to obtain Fe3O4@PDA@COF;

[0082] (4) 1g Fe3O4@PDA@COF, 0.3g antitumor compound I A and 0.7g doxorubicin were added to 300mL of water, heated to 35℃, stirred for 6h, centrifuged, washed and dried to obtain Fe3O4@PDA@COF@I3CTzA / DOX; the drug loading of I3CTzA was 6.89%; the drug loading of DOX was 29.67%;

[0083] (5) Dissolve 0.7-1g folic acid and 0.5g oligo hyaluronic acid in 100mL DMSO, add 0.7g N,N'-carbonyl diimidazole, stir at room temperature in the dark for 24h, add 6.5g F127, continue stirring for 28h, dialyze with a dialysis bag with a molecular weight cutoff of 8kDa for 3d, dry, and obtain FA / HA-F127;

[0084] (6) Add 1g FA / HA-F127 and 7g Fe3O4@PDA@COF@I3CTzA / DOX to 700mL of water, heat to 35℃, stir and react for 6h, centrifuge, wash, dry and obtain antitumor drug.

[0085] Example 7

[0086] This embodiment provides a method for preparing an antitumor drug, including the following steps:

[0087] (1) Dissolve 3.24 g of ferric chloride and 1.26 g of ferrous chloride in 300 mL of water, heat to 50 °C under nitrogen atmosphere, stir, add ammonia dropwise until the pH of the solution is 10-11, react in water bath for 30 min, separate with a magnet, wash, dry, and obtain Fe3O4NPs;

[0088] (2) 1g of Fe3O4NPs was added to a Tris-HCl solution with a pH of 8.5-9.5, 0.4g of dopamine hydrochloride was added, the mixture was heated to 45℃, stirred for 6h, centrifuged, washed and dried to obtain Fe3O4@PDA NPs;

[0089] (3) Dissolve 0.65g of 2,4,6-tricarboxymethyl phloroglucinol and 1.4g of 1,3,5-tris(4-aminophenyl)benzene in 10mL of ethanol, and add them dropwise to 100mL of a water-ethanol solution (volume ratio 1:2) containing 0.4g of Fe3O4@PDA NPs. Stir the reaction at room temperature for 9h, centrifuge, wash, and dry to obtain Fe3O4@PDA@COF;

[0090] (4) 1g Fe3O4@PDA@COF, 0.2g antitumor compound I A and 0.6g doxorubicin were added to 300mL of water, heated to 32℃, stirred for 8h, centrifuged, washed and dried to obtain Fe3O4@PDA@COF@I3CTzA / DOX; the drug loading of I3CTzA was 6.82%; the drug loading of DOX was 28.86%;

[0091] (5) Dissolve 0.85g folic acid and 0.4g oligo hyaluronic acid in 100mL DMSO, add 0.55g N,N'-carbonyl diimidazole, stir at room temperature in the dark for 24h, add 6.2g F127, continue stirring for 24h, dialyze with a dialysis bag with a molecular weight cutoff of 8kDa for 3d, dry, and obtain FA / HA-F127;

[0092] (6) Add 1g FA / HA-F127 and 5.5g Fe3O4@PDA@COF@I3CTzA / DOX to 700mL of water, heat to 32℃, stir and react for 8h, centrifuge, wash, dry and obtain antitumor drug.

[0093] Example 8

[0094] Compared to Example 7, the only difference is that antitumor compound A was replaced by an equal mass of antitumor compound B. The drug loading of I3CTzB was 5.94%.

[0095] Example 9

[0096] Compared to Example 7, the only difference is that antitumor compound A is replaced by an equal mass of antitumor compound C. The drug loading of I3CTzC is 6.20%.

[0097] Example 10

[0098] Compared to Example 7, the only difference is that antitumor compound A is replaced by an equal mass of antitumor compound D. The drug loading of I3CTzD is 6.49%.

[0099] Comparative Example 1

[0100] The only difference from Example 7 is that doxorubicin was not added.

[0101] Includes the following steps:

[0102] (1) Dissolve 3.24 g of ferric chloride and 1.26 g of ferrous chloride in 300 mL of water, heat to 50 °C under nitrogen atmosphere, stir, add ammonia dropwise until the pH of the solution is 10-11, react in water bath for 30 min, separate with a magnet, wash, dry, and obtain Fe3O4NPs;

[0103] (2) 1g of Fe3O4NPs was added to a Tris-HCl solution with a pH of 8.5-9.5, 0.4g of dopamine hydrochloride was added, the mixture was heated to 45℃, stirred for 6h, centrifuged, washed and dried to obtain Fe3O4@PDA NPs;

[0104] (3) Dissolve 0.65g of 2,4,6-tricarboxymethyl phloroglucinol and 1.4g of 1,3,5-tris(4-aminophenyl)benzene in 10mL of ethanol, and add them dropwise to 100mL of a water-ethanol solution (volume ratio 1:2) containing 0.4g of Fe3O4@PDA NPs. Stir the reaction at room temperature for 9h, centrifuge, wash, and dry to obtain Fe3O4@PDA@COF;

[0105] (4) 1g Fe3O4@PDA@COF and 0.8g antitumor compound I A were added to 300mL of water, heated to 32℃, stirred for 8h, centrifuged, washed, and dried to obtain Fe3O4@PDA@COF@I3CTzA; the drug loading of I3CTzA was 18.67%;

[0106] (5) Dissolve 0.85g folic acid and 0.4g oligo hyaluronic acid in 100mL DMSO, add 0.55g N,N'-carbonyl diimidazole, stir at room temperature in the dark for 24h, add 6.2g F127, continue stirring for 24h, dialyze with a dialysis bag with a molecular weight cutoff of 8kDa for 3d, dry, and obtain FA / HA-F127;

[0107] (6) Add 1g FA / HA-F127 and 5.5g Fe3O4@PDA@COF@I3CTzA to 700mL of water, heat to 32℃, stir and react for 8h, centrifuge, wash, dry and obtain antitumor drug.

[0108] Comparative Example 2

[0109] The only difference from Example 7 is that the antitumor compound A was not added.

[0110] Includes the following steps:

[0111] (1) Dissolve 3.24 g of ferric chloride and 1.26 g of ferrous chloride in 300 mL of water, heat to 50 °C under nitrogen atmosphere, stir, add ammonia dropwise until the pH of the solution is 10-11, react in water bath for 30 min, separate with a magnet, wash, dry, and obtain Fe3O4NPs;

[0112] (2) 1g of Fe3O4NPs was added to a Tris-HCl solution with a pH of 8.5-9.5, 0.4g of dopamine hydrochloride was added, the mixture was heated to 45℃, stirred for 6h, centrifuged, washed and dried to obtain Fe3O4@PDA NPs;

[0113] (3) Dissolve 0.65g of 2,4,6-tricarboxymethyl phloroglucinol and 1.4g of 1,3,5-tris(4-aminophenyl)benzene in 10mL of ethanol, and add them dropwise to 100mL of a water-ethanol solution (volume ratio 1:2) containing 0.4g of Fe3O4@PDA NPs. Stir the reaction at room temperature for 9h, centrifuge, wash, and dry to obtain Fe3O4@PDA@COF;

[0114] (4) Add 1g Fe3O4@PDA@COF and 0.8g doxorubicin to 300mL of water, heat to 32℃, stir and react for 8h, centrifuge, wash, and dry to obtain Fe3O4@PDA@COF@DOX; the drug loading of DOX is 30.91%;

[0115] (5) Dissolve 0.85g folic acid and 0.4g oligo hyaluronic acid in 100mL DMSO, add 0.55g N,N'-carbonyl diimidazole, stir at room temperature in the dark for 24h, add 6.2g F127, continue stirring for 24h, dialyze with a dialysis bag with a molecular weight cutoff of 8kDa for 3d, dry, and obtain FA / HA-F127;

[0116] (6) Add 1g FA / HA-F127 and 5.5g Fe3O4@PDA@COF@DOX to 700mL of water, heat to 32℃, stir and react for 8h, centrifuge, wash, dry and obtain antitumor drug.

[0117] Comparative Example 3

[0118] The only difference from Example 7 is that folic acid was not added.

[0119] Includes the following steps:

[0120] (1) Dissolve 3.24 g of ferric chloride and 1.26 g of ferrous chloride in 300 mL of water, heat to 50 °C under nitrogen atmosphere, stir, add ammonia dropwise until the pH of the solution is 10-11, react in water bath for 30 min, separate with a magnet, wash, dry, and obtain Fe3O4NPs;

[0121] (2) 1g of Fe3O4NPs was added to a Tris-HCl solution with a pH of 8.5-9.5, 0.4g of dopamine hydrochloride was added, the mixture was heated to 45℃, stirred for 6h, centrifuged, washed and dried to obtain Fe3O4@PDA NPs;

[0122] (3) Dissolve 0.65g of 2,4,6-tricarboxymethyl phloroglucinol and 1.4g of 1,3,5-tris(4-aminophenyl)benzene in 10mL of ethanol, and add them dropwise to 100mL of a water-ethanol solution (volume ratio 1:2) containing 0.4g of Fe3O4@PDA NPs. Stir the reaction at room temperature for 9h, centrifuge, wash, and dry to obtain Fe3O4@PDA@COF;

[0123] (4) Add 1g Fe3O4@PDA@COF, 0.2g antitumor compound I A and 0.6g doxorubicin to 300mL of water, heat to 32℃, stir and react for 8h, centrifuge, wash and dry to obtain Fe3O4@PDA@COF@I3CTzA / DOX;

[0124] (5) Dissolve 1.25g oligomeric hyaluronic acid in 100mL DMSO, add 0.55g N,N'-carbonyldiimidazole, stir at room temperature in the dark for 24h, add 6.2g F127, continue stirring for 24h, dialyze with a dialysis bag with a molecular weight cutoff of 8kDa for 3d, dry, and obtain HA-F127;

[0125] (6) Add 1g HA-F127 and 5.5g Fe3O4@PDA@COF@I3CTzA / DOX to 700mL of water, heat to 32℃, stir and react for 8h, centrifuge, wash, dry, and obtain the antitumor drug.

[0126] Comparative Example 4

[0127] The only difference from Example 7 is that oligomeric hyaluronic acid was not added.

[0128] Includes the following steps:

[0129] (1) Dissolve 3.24 g of ferric chloride and 1.26 g of ferrous chloride in 300 mL of water, heat to 50 °C under nitrogen atmosphere, stir, add ammonia dropwise until the pH of the solution is 10-11, react in water bath for 30 min, separate with a magnet, wash, dry, and obtain Fe3O4NPs;

[0130] (2) 1g of Fe3O4NPs was added to a Tris-HCl solution with a pH of 8.5-9.5, 0.4g of dopamine hydrochloride was added, the mixture was heated to 45℃, stirred for 6h, centrifuged, washed and dried to obtain Fe3O4@PDA NPs;

[0131] (3) Dissolve 0.65g of 2,4,6-tricarboxymethyl phloroglucinol and 1.4g of 1,3,5-tris(4-aminophenyl)benzene in 10mL of ethanol, and add them dropwise to 100mL of a water-ethanol solution (volume ratio 1:2) containing 0.4g of Fe3O4@PDA NPs. Stir the reaction at room temperature for 9h, centrifuge, wash, and dry to obtain Fe3O4@PDA@COF;

[0132] (4) Add 1g Fe3O4@PDA@COF, 0.2g antitumor compound I A and 0.6g doxorubicin to 300mL of water, heat to 32℃, stir and react for 8h, centrifuge, wash and dry to obtain Fe3O4@PDA@COF@I3CTzA / DOX;

[0133] (5) Dissolve 1.25g folic acid in 100mL DMSO, add 0.55g N,N'-carbonyldiimidazole, stir at room temperature in the dark for 24h, add 6.2g F127, continue stirring for 24h, dialyze with a dialysis bag with a molecular weight cutoff of 8kDa for 3d, dry, and obtain FA-F127;

[0134] (6) Add 1g FA-F127 and 5.5g Fe3O4@PDA@COF@I3CTzA / DOX to 700mL of water, heat to 32℃, stir and react for 8h, centrifuge, wash, dry and obtain antitumor drug.

[0135] Comparative Example 5

[0136] Compared with Example 7, the only difference is that steps (5) and (6) were not performed.

[0137] Includes the following steps:

[0138] (1) Dissolve 3.24 g of ferric chloride and 1.26 g of ferrous chloride in 300 mL of water, heat to 50 °C under nitrogen atmosphere, stir, add ammonia dropwise until the pH of the solution is 10-11, react in water bath for 30 min, separate with a magnet, wash, dry, and obtain Fe3O4NPs;

[0139] (2) 1g of Fe3O4NPs was added to a Tris-HCl solution with a pH of 8.5-9.5, 0.4g of dopamine hydrochloride was added, the mixture was heated to 45℃, stirred for 6h, centrifuged, washed and dried to obtain Fe3O4@PDA NPs;

[0140] (3) Dissolve 0.65g of 2,4,6-tricarboxymethyl phloroglucinol and 1.4g of 1,3,5-tris(4-aminophenyl)benzene in 10mL of ethanol, and add them dropwise to 100mL of a water-ethanol solution (volume ratio 1:2) containing 0.4g of Fe3O4@PDA NPs. Stir the reaction at room temperature for 9h, centrifuge, wash, and dry to obtain Fe3O4@PDA@COF;

[0141] (4) Add 1g Fe3O4@PDA@COF, 0.2g antitumor compound I A and 0.6g doxorubicin to 300mL of water, heat to 32℃, stir for 8h, centrifuge, wash and dry to obtain Fe3O4@PDA@COF@I3CTzA / DOX, which is an antitumor drug.

[0142] Comparative Example 6

[0143] The only difference from Example 7 is that no COF layer was prepared.

[0144] Includes the following steps:

[0145] (1) Dissolve 3.24 g of ferric chloride and 1.26 g of ferrous chloride in 300 mL of water, heat to 50 °C under nitrogen atmosphere, stir, add ammonia dropwise until the pH of the solution is 10-11, react in water bath for 30 min, separate with a magnet, wash, dry, and obtain Fe3O4NPs;

[0146] (2) 1g of Fe3O4NPs was added to a Tris-HCl solution with a pH of 8.5-9.5, 0.4g of dopamine hydrochloride was added, the mixture was heated to 45℃, stirred for 6h, centrifuged, washed and dried to obtain Fe3O4@PDA NPs;

[0147] (3) 1g Fe3O4@PDA NPs, 0.2g antitumor compound I A and 0.6g doxorubicin were added to 300mL of water, heated to 32℃, stirred for 8h, centrifuged, washed and dried to obtain Fe3O4@PDA@I3CTzA / DOX; the drug loading of I3CTzA was 0.89% and the drug loading of DOX was 2.85%;

[0148] (4) Dissolve 0.85g folic acid and 0.4g oligo hyaluronic acid in 100mL DMSO, add 0.55g N,N'-carbonyldiimidazole, stir at room temperature in the dark for 24h, add 6.2g F127, continue stirring for 24h, dialyze with a dialysis bag with a molecular weight cutoff of 8kDa for 3d, dry, and obtain FA / HA-F127;

[0149] (5) Add 1g FA / HA-F127 and 5.5g Fe3O4@PDA@I3CTzA / DOX to 700mL of water, heat to 32℃, stir and react for 8h, centrifuge, wash, dry and obtain antitumor drug.

[0150] Comparative Example 7

[0151] The only difference from Example 7 is that no PDA layer was prepared.

[0152] Includes the following steps:

[0153] (1) Dissolve 3.24 g of ferric chloride and 1.26 g of ferrous chloride in 300 mL of water, heat to 50 °C under nitrogen atmosphere, stir, add ammonia dropwise until the pH of the solution is 10-11, react in water bath for 30 min, separate with a magnet, wash, dry, and obtain Fe3O4NPs;

[0154] (2) Dissolve 0.65g of 2,4,6-tricarboxymethyl phloroglucinol and 1.4g of 1,3,5-tris(4-aminophenyl)benzene in 10mL of ethanol, and add them dropwise to 100mL of a water-ethanol solution (volume ratio 1:2) containing 0.4g of Fe3O4 NPs. Stir the reaction at room temperature for 9h, centrifuge, wash, and dry to obtain Fe3O4@COF;

[0155] (3) 1g Fe3O4@COF, 0.2g antitumor compound I A and 0.6g doxorubicin were added to 300mL of water, heated to 32℃, stirred for 8h, centrifuged, washed and dried to obtain Fe3O4@COF@I3CTzA / DOX; the drug loading of I3CTzA was 4.10%; the drug loading of DOX was 18.72%;

[0156] (4) Dissolve 0.85g folic acid and 0.4g oligo hyaluronic acid in 100mL DMSO, add 0.55g N,N'-carbonyldiimidazole, stir at room temperature in the dark for 24h, add 6.2g F127, continue stirring for 24h, dialyze with a dialysis bag with a molecular weight cutoff of 8kDa for 3d, dry, and obtain FA / HA-F127;

[0157] (5) Add 1g FA / HA-F127 and 5.5g Fe3O4@COF@I3CTzA / DOX to 700mL of water, heat to 32℃, stir and react for 8h, centrifuge, wash, dry and obtain antitumor drug.

[0158] Test Example 3

[0159] Fourth-generation mouse ascites tumor cells S180 were taken and diluted with PBS to a concentration of 5 × 10⁻⁶. 7Cell suspension at a concentration of 0.2 mL / mL was subcutaneously injected into the right upper limb axilla of ICR mice. The entire procedure was completed within 30 minutes. On the second day after injection, the mice were weighed and randomly divided into four groups: model group, positive control group, Examples 5-10, and Comparative Examples 1-7, with eight mice in each group. Administration was by injection. The experimental groups received 5 mg / kg cisplatin at a volume of 0.2 mL / 20 g. The positive control group received cisplatin 2 mg / kg via gavage at a volume of 0.2 mL / 20 g, administered every other day for a total of three times. The model group received an equal volume of physiological saline. After each administration, the tumor was irradiated with near-infrared light (808 nm) for 10 minutes, followed by a low-frequency magnetic field (50 Hz) applied to the tumor site for another 10 minutes. At the end of the experiment, the tumor volume was measured three times using calipers, and the average value was taken, including both the long and short diameters of the tumor.

[0160] The formula for calculating tumor volume is: Volume = 0.5 × Major axis × Minor axis 2 .

[0161] Tumor growth inhibition rate (%) = [1 - T (tumor volume in the experimental group) / C (tumor volume in the model group)] × 100%.

[0162] The results are shown in Table 4.

[0163] Table 4

[0164] ;

[0165] As can be seen from the table above, the antitumor drugs prepared in Examples 5-10 of the present invention have good antitumor effects.

[0166] In Comparative Examples 1 and 2, the effects of using only a single antitumor compound A or doxorubicin were reduced, indicating that the prepared antitumor compound and doxorubicin have a good synergistic effect.

[0167] In Comparative Examples 3 and 4, the antitumor drugs had only hyaluronic acid or folic acid on their surfaces, respectively. In Comparative Example 5, neither hyaluronic acid nor folic acid was present on the surface, resulting in a significant decrease in antitumor efficacy. This demonstrates that simultaneously conjugating folic acid and hyaluronic acid with F127, through the specific recognition of receptors on the surface of cancer cells by hyaluronic acid and folic acid, achieves a "dual-targeting" delivery system. This significantly improves the precise accumulation of drugs at the tumor site, reduces the amount of chemotherapy drugs absorbed, decreases chemotherapy side effects, and improves patient compliance. The prepared FA / HA-F127 can act as an amphiphilic material, self-assembling into micelles in aqueous solution to encapsulate hydrophobic COF drugs, forming a nanoscale drug carrier. This allows for more effective exudation from tumor blood vessels and retention within tumor tissue, achieving passive targeting.

[0168] In Comparative Example 6, the lack of a COF layer structure resulted in a significant decrease in drug loading. COF carriers possess strong drug loading capacity and can respond to biological environmental stimuli, which is beneficial for targeted release, making drug release more precise and efficient, and exhibiting high drug loading efficiency.

[0169] In Comparative Example 7, which lacked a PDA layer, polydopamine exhibited good photoresponsiveness and a synergistic anti-tumor effect. Simultaneously, it enhanced the binding force with the COF layer and increased the drug loading capacity, thereby strengthening the anti-tumor effect.

[0170] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An antitumor compound, characterized in that, The structural formula of the antitumor compound is shown in Formula I: ； Formula I Where R= , , or .

2. A method for preparing the antitumor compound as described in claim 1, characterized in that, Includes the following steps: S1. 6-Bromoindole-3-methanol, m-aminophenylacetylene, catalyst, 4,5-bis(diphenylphosphino-9,9-dimethyloxanthracene), and potassium tert-butoxide were mixed and heated to react. The mixture was filtered, the residue was washed, the solvent was removed under reduced pressure, and the intermediate was purified by column chromatography to obtain intermediate 1, with the following structure: ; S2. Intermediate 1, substituted benzyl azide, tert-butanol, water, copper sulfate and sodium ascorbate were mixed and heated to react, filtered, the residue was washed, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography to obtain the antitumor compound.

3. The preparation method according to claim 2, characterized in that, In step S1, the molar ratio of 6-bromoindole-3-methanol, m-aminophenylacetylene, catalyst, 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthracene, and potassium tert-butoxide is 1:1-1.2:0.02-0.025:0.03-0.04:1.5-2, the heating reaction temperature is 75-85℃, and the catalyst is Pd2(dba)3.

4. The preparation method according to claim 2, characterized in that, In step S2, the molar ratio of intermediate 1, substituted benzyl azide, copper sulfate, and sodium ascorbate is 1:1-1.2:0.2-0.4:0.3-0.6, and the heating reaction temperature is 65-75℃; the substituted benzyl azide is selected from at least one of 2,4-dibromobenzyl azide, 3-chloro-4-fluorobenzyl azide, 2-fluoro-4-bromobenzyl azide, and 2-fluoro-6-chlorobenzyl azide.

5. An antitumor drug, characterized in that, It consists of 0.1-99.9% by weight of the antitumor compound of claim 1 and 0.1-99.9% by weight of pharmaceutically acceptable excipients.

6. The antitumor drug according to claim 5, characterized in that, Polydopamine was deposited on the surface of Fe3O4NPs, and then a COF layer was formed on the surface by a one-pot method. Antitumor compounds were loaded onto the surface, and doxorubicin was further loaded onto the surface. Then, it was reacted with F127 coupled with folic acid and oligomeric hyaluronic acid to prepare an antitumor drug.

7. A method for preparing an antitumor drug as described in claim 6, characterized in that, Includes the following steps: (1) Dissolve ferric chloride and ferrous chloride in water, heat and stir under an inert atmosphere, add ammonia dropwise, react in a water bath, separate with a magnet, wash, and dry to obtain Fe3O4NPs; (2) Fe3O4NPs were added to Tris-HCl solution, dopamine hydrochloride was added, the mixture was heated and stirred, centrifuged, washed and dried to obtain Fe3O4@PDA NPs; (3) Dissolve 2,4,6-tricarboxymethyl phloroglucinol and 1,3,5-tris(4-aminophenyl)benzene in ethanol respectively, and add them dropwise alternately to a water-ethanol solution containing Fe3O4@PDA NPs. Stir the reaction at room temperature, centrifuge, wash, and dry to obtain Fe3O4@PDA@COF; (4) Fe3O4@PDA@COF, antitumor compounds and doxorubicin were added to water, heated and stirred to react, centrifuged, washed and dried to obtain Fe3O4@PDA@COF@I3CTz / Dox; (5) Folic acid and oligomeric hyaluronic acid were dissolved in DMSO, N,N'-carbonyldiimidazole was added, and the mixture was stirred at room temperature in the dark. F127 was added, and the reaction was continued by stirring. The mixture was dialyzed and dried to obtain FA / HA-F127. (6) Add FA / HA-F127 and Fe3O4@PDA@COF@I3CTz / Dox to water, heat and stir to react, centrifuge, wash and dry to obtain antitumor drugs.

8. The preparation method according to claim 7, characterized in that, In step (1), the mass ratio of ferric chloride to ferrous chloride is 3.24:1.26, the heating and stirring temperature is 45-55℃, the water bath stirring time is 20-40 min, and ammonia is added to the solution to a pH of 10-11; in step (2), the pH of the Tris-HCl solution is 8.5-9.5, the mass ratio of Fe3O4NPs to dopamine hydrochloride is 10:3-5, the heating and stirring reaction temperature is 40-50℃, and the time is 4-8 h; in step (3), the mass ratio of 2,4,6-tricarboxymethyl phloroglucinol, 1,3,5-tris(4-aminophenyl)benzene, and Fe3O4@PDA NPs is 4-8.5:10-18:3-5, and the room temperature stirring reaction time is 8-10 h.

9. The preparation method according to claim 7, characterized in that, In step (4), the mass ratio of Fe3O4@PDA@COF, the antitumor compound, and doxorubicin is 1:0.1-0.3:0.5-0.7, and the heating and stirring reaction temperature is 30-35℃ for 6-10h. In step (5), the mass ratio of folic acid, oligomeric hyaluronic acid, N,N'-carbonyl diimidazole, and F127 is 0.7-1:0.3-0.5:0.4-0.7:6-6.5, and the stirring time at room temperature in the dark is 20-28h, and the stirring reaction time is 20-28h. In step (6), the mass ratio of FA / HA-F127 and Fe3O4@PDA@COF@I3CTz / Dox is 1:4-7, and the heating and stirring reaction temperature is 30-35℃ for 6-10h.

10. The use of an antitumor compound as described in claim 1, or an antitumor drug as described in claim 5 or 6, in the preparation of an antitumor drug.

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