A tumor microenvironment-responsive nanocomposite hydrogel co-delivery system and a preparation method thereof

Abstract

The application discloses a tumor microenvironment responsive nano-composite hydrogel co-drug delivery system and a preparation method thereof, and belongs to the field of antitumor materials. The nano-composite hydrogel co-drug delivery system is a sodium alginate hydrogel with hyaluronic acid encapsulated drug-loaded nanoparticles embedded in the interior. The drug-loaded nanoparticles encapsulate anthracycline chemotherapy drugs and tyrosine kinase inhibitors; the anthracycline chemotherapy drugs are connected to the hyaluronic acid side chain through a hydrazone bond to form a polymer prodrug, and the tyrosine kinase inhibitors are encapsulated into the hydrophobic core of the nanoparticles through self-assembly of the polymer prodrug molecules to obtain the hyaluronic acid encapsulated drug-loaded nanoparticles. The sodium alginate hydrogel is a dopamine modified sodium alginate hydrogel. The nano-composite hydrogel co-drug delivery system is easy to be injected intratumorally and paratumorally, can be slowly degraded in the body, and can target and synchronously deliver the drugs to tumor cells by using the escaped nanoparticles, so as to inhibit tumor cell proliferation, invasion and migration, and realize a synergistic antitumor effect.

Description

Technical Field

[0001] This invention belongs to the field of antitumor materials, specifically relating to a tumor microenvironment-responsive nanocomposite hydrogel co-loaded drug system and its preparation method. Background Technology

[0002] Cancer is the second leading cause of death after cardiovascular disease. Chemotherapy is currently one of the main methods used in clinical practice to treat malignant tumors. However, conventional chemotherapy drugs have poor selectivity, causing serious damage to normal tissues while treating tumors, thus affecting patients' quality of life. In recent years, intelligent drug delivery systems for tumor treatment have been extensively studied. These drug delivery systems can regulate the in vivo processes of chemotherapy drugs, promote drug distribution and accumulation in tumor tissues, improve cellular uptake and release behavior, and achieve reduced toxicity and enhanced efficacy, demonstrating significant clinical development value.

[0003] Injectable hydrogels have attracted much attention in the field of antitumor drug delivery due to their low toxicity, minimal invasiveness, and adaptability to any irregular cavity. The administration route of hydrogels is usually intratumoral / peritumoral injection. Compared with systemic administration, hydrogel delivery can directly deliver drugs to the tumor site at high concentrations, achieving therapeutic concentrations at smaller doses and effectively reducing the toxic side effects of chemotherapy drugs. Although drug-loaded hydrogels have made some research progress, they still have limitations in tumor treatment: (1) Hydrogels have limited encapsulation efficiency and homogeneity for hydrophobic drugs, which can easily lead to local drug burst release; (2) Drug release is highly dependent on passive diffusion, lacks target selectivity, and most drugs cannot reach deep tumor tissues and have potential toxicity to surrounding healthy tissues; (3) It is difficult to release combination therapy drugs synchronously according to the designed ratio, reducing the synergistic therapeutic effect of drugs. Summary of the Invention

[0004] To address the aforementioned issues, this invention embeds drug-loaded nanoparticles co-loaded with anthracycline chemotherapeutic drugs and tyrosine kinase inhibitors into a hydrogel, constructing a novel nanocomposite hydrogel drug delivery system. This system improves the solubility, stability, and targeting of chemotherapeutic drugs by introducing nanoparticles into the hydrogel; simultaneously, it utilizes the hydrogel's encapsulation to directly deliver the drug-loaded nanoparticles to tumor tissue, effectively enhancing drug accumulation at the tumor site and improving drug bioavailability, thereby achieving safe and efficient tumor treatment.

[0005] To address the shortcomings of existing drug delivery system technologies, the present invention aims to provide a tumor microenvironment-responsive nanocomposite hydrogel co-loading drug system and its preparation method. This nanocomposite hydrogel can improve drug loading rate and bioavailability, enhance tumor treatment efficacy, and reduce toxic side effects. The present invention also provides a preparation method for the aforementioned tumor microenvironment-responsive nanocomposite hydrogel co-loading drug system and its applications.

[0006] To achieve the above-mentioned objectives, the technical solution adopted by the present invention is as follows:

[0007] A tumor microenvironment-responsive nanocomposite hydrogel co-delivery system comprises a sodium alginate hydrogel with drug-loaded nanoparticles encapsulated in hyaluronic acid. The drug-loaded nanoparticles encapsulate anthracycline chemotherapeutic drugs and tyrosine kinase inhibitors. The sodium alginate hydrogel is a dopamine-modified sodium alginate derivative hydrogel. This nanocomposite hydrogel co-delivery system is easily administered intratumorally and adjacently to tumors, degrades slowly in vivo, and utilizes the escaped nanoparticles to deliver drugs to tumor cells simultaneously and in a targeted manner, thereby inhibiting tumor cell proliferation, invasion, and migration, achieving a synergistic anti-tumor effect.

[0008] In the aforementioned tumor microenvironment-responsive nanocomposite hydrogel co-loading drug delivery system, the hyaluronic acid-encapsulated drug-loaded nanoparticles are prepared by a method comprising the following steps: an anthracycline chemotherapeutic drug is linked to the hyaluronic acid side chain via a hydrazone bond to form a polymer prodrug, wherein the anthracycline chemotherapeutic drug may be one or more of doxorubicin, epirubicin, daunorubicin, or aclarubicin. A tyrosine kinase inhibitor is encapsulated into the hydrophobic core of the nanoparticle through the self-assembly of the polymer prodrug molecule, wherein the tyrosine kinase inhibitor may be one or more of lapatinib, sorafenib, gefitinib, or dasatinib.

[0009] In the aforementioned tumor microenvironment-responsive nanocomposite hydrogel co-loading drug delivery system, the particle size range of the drug-loaded nanoparticles is preferably 30–500 nm. More preferably, the particle size of the drug-loaded nanoparticles is 50–200 nm.

[0010] In the above-mentioned tumor microenvironment-responsive nanocomposite hydrogel co-loaded drug system, the preferred mass ratio of anthracycline drugs to tyrosine kinase inhibitors is (2-20) / 1.

[0011] In the aforementioned tumor microenvironment-responsive nanocomposite hydrogel co-loaded drug system, the viscosity of sodium alginate is 200–800 mPa·s, and the molecular weight of hyaluronic acid is 5000–14000 Da.

[0012] In the aforementioned tumor microenvironment-responsive nanocomposite hydrogel co-loaded drug system, the nanocomposite hydrogel is prepared as an injection, wherein the concentration of anthracycline drugs in the injection is at least 0.5 mg / mL, preferably 0.5–1 mg / mL; and the concentration of tyrosine kinase inhibitor drugs is at least 1 mg / mL, preferably 1–6 mg / mL.

[0013] The preparation method of the above-mentioned tumor microenvironment-responsive nanocomposite hydrogel co-loaded drug system includes the following steps: hyaluronic acid-encapsulated drug-loaded nanoparticles and dopamine-modified sodium alginate derivatives are mixed in water, and then the mixed solution is injected into Ca... 2+An aqueous solution was used to obtain a tumor microenvironment-responsive nanocomposite hydrogel co-loaded drug system. The dopamine-modified sodium alginate derivative was prepared by a method comprising the following steps: grafting dopamine onto the side chains of sodium alginate via an amidation reaction to obtain the dopamine-modified sodium alginate derivative ALG-DPA.

[0014] Furthermore, the preparation method of the tumor microenvironment-responsive nanocomposite hydrogel co-loaded drug system includes the following steps: synthesizing hyaluronic acid HA-ADH modified with adipic acid dihydrazide via an amidation reaction, the structural formula of which is shown in formula (I); then grafting anthracycline drugs onto the side chains of HA via hydrazone bonds using a Schiff base reaction to obtain anthracycline polymer prodrugs; subsequently, encapsulating tyrosine kinase inhibitors into nanoparticles through molecular self-assembly of the polymer prodrugs to obtain drug-loaded nanoparticles co-loaded with anthracycline chemotherapeutic drugs and tyrosine kinase inhibitors, i.e., hyaluronic acid-encapsulated drug-loaded nanoparticles; next, mixing the drug-loaded nanoparticles with ALG-DPA in water, and injecting the mixed solution into Ca2+. 2+ Aqueous solution was used to obtain a nanocomposite hydrogel drug delivery system.

[0015]

[0016] In a preferred embodiment, the preparation method includes the following steps:

[0017] (1) Synthesis of HA-ADH: Hyaluronic acid, N-hydroxysuccinimide, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were co-dissolved in water to activate the carboxyl group of hyaluronic acid. Subsequently, an aqueous solution of adipic acid dihydrazide was slowly added dropwise to the system to carry out the reaction. During the reaction, the pH of the reaction system was controlled at 4.8–5.0 using HCl and NaOH solutions. After the reaction was completed, the mixed solution was transferred to a dialysis bag for dialyzing to remove the catalyst and unreacted small molecules. The dialysate was freeze-dried to obtain a white, spongy product, which was adipic acid dihydrazide-modified hyaluronic acid HA-ADH.

[0018] (2) Synthesis of anthracycline polymer prodrug: Anthracycline hydrochloride was dissolved in an organic solvent, and triethylamine was slowly added dropwise to react and remove the hydrochloric acid. Subsequently, HA-ADH was dissolved in an organic solvent and added dropwise to the reaction system to continue the reaction. The resulting mixture was transferred to a dialysis bag for dialyzing to remove unreacted small molecules and organic reagents. The dialysate was freeze-dried to obtain the anthracycline polymer prodrug. The organic solvent is preferably one or a mixture of dimethyl sulfoxide, formamide, and 1,4-dioxane.

[0019] (3) Preparation of drug-loaded nanoparticles: Anthracycline polymer prodrugs and tyrosine kinase inhibitors were co-dissolved in an organic solvent. Under ultrasonic conditions, the mixed solution was slowly added dropwise to a buffer solution. Subsequently, the solution was transferred to a dialysis bag for dialysis. Finally, the resulting dialysate was filtered through a filter membrane to remove unencapsulated drug, yielding drug-loaded nanoparticles. The organic solvent is preferably a mixture of one or more of dimethyl sulfoxide and formamide; the buffer solution is preferably PBS buffer solution.

[0020] (4) Synthesis of ALG-DPA: Sodium alginate, N-hydroxysuccinimide, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were co-dissolved in water to activate the carboxyl groups on the sodium alginate chain. Dopamine hydrochloride aqueous solution was added dropwise to the system to initiate the reaction. During the reaction, the pH of the reaction system was controlled at 4.8–5.0 using HCl and NaOH solutions. After the reaction was complete, the mixed solution was transferred to a dialysis bag for dialyzing to remove the catalyst and unreacted small molecules. ALG-DPA was then obtained by freeze-drying.

[0021] (5) Preparation of nanocomposite hydrogel drug delivery system: ALG-DPA aqueous solution and drug-loaded nanoparticle solution were mixed and shaken thoroughly before the mixture was injected into CaCl2 solution to obtain nanocomposite hydrogel drug delivery system.

[0022] This invention also provides the application of the above-mentioned tumor microenvironment-responsive nanocomposite hydrogel co-loading drug system in the preparation of drugs for treating solid tumors. The solid tumors include cutaneous melanoma, choroidal melanoma, breast cancer, colon cancer, cervical cancer, lung cancer, sarcoma, or glioblastoma. The drug is administered via intratumoral injection or peritumoral injection.

[0023] A tumor treatment drug comprising the aforementioned tumor microenvironment-responsive nanocomposite hydrogel drug delivery system.

[0024] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0025] 1. The tumor microenvironment-responsive nanocomposite hydrogel co-loaded drug system provided by the present invention is easy to inject intratumorally and adjacently, and degrades slowly in vivo, providing long-lasting sustained release of antitumor drugs and achieving continuous tumor treatment.

[0026] 2. This invention utilizes nanoparticles to encapsulate drugs in hydrogels, significantly improving the encapsulation efficiency of hydrophobic drugs. After the nanoparticles escape from the gel, they can target and reach tumor cells, and simultaneously release chemotherapeutic drugs in response to the acidic microenvironment within the tumor cells, thereby exerting a synergistic anti-tumor effect and improving the efficacy of tumor treatment.

[0027] 3. Animal experiments have demonstrated that the nanocomposite hydrogel drug delivery system possesses excellent anti-tumor capabilities. Compared to drug-loaded nanoparticles and hydrogel drug delivery systems encapsulating free drugs, the nanocomposite hydrogel drug delivery system can better inhibit tumor growth and significantly improve the survival rate of mice. Based on this, the present invention provides the application of the tumor microenvironment-responsive nanocomposite hydrogel co-delivery system in the treatment of solid tumors, offering a new approach to tumor therapy. Attached Figure Description

[0028] Figure 1 This is a transmission electron microscope image of the drug-loaded nanoparticles prepared in Example 2.

[0029] Figure 2 This is the particle size distribution of the drug-loaded nanoparticles prepared in Example 2.

[0030] Figure 3 Different Ga in Example 3 2+ Nanocomposite hydrogels prepared at certain concentrations.

[0031] Figure 4 These are scanning electron microscope images of the nanocomposite hydrogel in Example 3 at different magnifications.

[0032] Figure 5 This is the degradation curve of the nanocomposite hydrogel in vivo in Example 4.

[0033] Figure 6 These are the drug release curves for HA-DOX / LAP gel and Free DOX+LAP gel.

[0034] Figure 7 This is the curve showing the change in tumor volume over time in Example 6.

[0035] Figure 8 This is the curve showing the change in mouse body weight over time in Example 6.

[0036] Figure 9 This is the survival curve of the mice in Example 6. Detailed Implementation

[0037] The following further describes the tumor microenvironment-responsive nanocomposite hydrogel co-loading drug delivery system, its preparation method, and its applications provided by this invention. It should be noted that the embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit the invention. Where specific techniques or conditions are not specified in the embodiments, they can be performed according to the techniques or conditions described in the literature in this field, or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0038] Example 1: Synthesis of the polymeric prodrug HA-DOX for doxorubicin

[0039] (1) Synthesis of HA-ADH: 4g of hyaluronic acid with an average molecular weight of approximately 8700 Da was dissolved in 60mL of deionized water. 40mL of a deionized water solution containing 920mg of N-hydroxysuccinimide and 1.54g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride was added, and the mixture was stirred at room temperature for 2h. Subsequently, 17.42g of adipic acid dihydrazide was dissolved in 170mL of deionized water and slowly added dropwise to the reaction system, and the reaction continued for 24h. Throughout the process, the pH of the solution was adjusted to 4.8–5.0 using 0.1M HCl and 0.1M NaOH. The resulting solution was transferred to an MCWO 3500Da dialysis bag and dialyzed continuously in deionized water for 72h. The dialysate was then freeze-dried to obtain a white, spongy product, HA-ADH, which was stored at -20℃ for later use.

[0040] (2) Synthesis of the polymeric prodrug HA-DOX: 20 mg of doxorubicin hydrochloride was dissolved in 5 mL of dimethyl sulfoxide, and 28 μL of triethylamine was slowly added dropwise. The mixture was stirred overnight at room temperature. 80 mg of HA-ADH was dissolved in a mixture of 3 mL of dimethyl sulfoxide and 5 mL of formamide, and slowly added dropwise to the reaction system. After stirring at room temperature for 24 h, the mixture was transferred to an MCWO 3500 Da dialysis bag and dialyzed in deionized water for 72 h to obtain a clear red solution. HA-DOX was obtained by freeze-drying. The absorbance at 480 nm was measured by UV spectrophotometer to determine that the doxorubicin loading in the polymeric prodrug was 12.5%.

[0041] Example 2: Construction and characterization of drug-loaded nanoparticles co-loaded with lapatinib and doxorubicin

[0042] 50 mg of HA-DOX and 37.5 mg of lapatinib were co-dissolved in 1 mL of formamide solution. The mixture was slowly added dropwise to 12 mL of PBS buffer under sonication. The solution was then transferred to a MWCO 3500 Da dialysis bag and dialyzed at room temperature for 72 h, with the dialysate changed every 12 h. Finally, the dialysate was filtered through a 0.45 μm filter to obtain a clear, purplish-red solution. The absorbance at 480 nm and 365 nm was measured using a UV spectrophotometer, determining that the doxorubicin loading in the drug-loaded nanoparticles was 5.8% and the lapatinib loading was 35.7%.

[0043] The shape and size distribution of the obtained drug-loaded nanoparticles were determined by transmission electron microscopy and dynamic light scattering, and the results are as follows: Figure 1 and Figure 2 As shown. From Figure 1 It can be seen that the drug-loaded nanoparticles have a spherical structure. From Figure 2 It is known that the average particle size of the drug-loaded nanoparticles is 74.4 nm.

[0044] Example 3: Preparation and structural characterization of nanocomposite hydrogels

[0045] 4 g of sodium alginate (ALG, 200–500 mPa·s) was dissolved in 350 mL of deionized water. Then, 30 mL of a deionized water solution containing 2.3 g of N-hydroxysuccinimide and 3.8 g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride was added, and the mixture was stirred at room temperature for 2 h. Subsequently, 3.8 g of dopamine hydrochloride was dissolved in 20 mL of deionized water and slowly added dropwise to the reaction system. The reaction was continued at room temperature with stirring for 24 h. Throughout the reaction, the pH of the solution was adjusted to 4.8–5.0 using 0.1 M HCl and 0.1 M NaOH. After the reaction was complete, the mixture was transferred to a 14000 Da dialysis bag and dialyzed with deionized water for 72 h. Finally, the dialysate was freeze-dried to obtain a gray, spongy ALG-DPA.

[0046] ALG-DPA solution and drug-loaded nanoparticle solution were mixed at a volume ratio of 2 / 3, wherein the concentration of ALG-DPA was 50 mg / mL, the concentration of doxorubicin in the nanoparticle solution was 1 mg / mL, and the concentration of lapatinib was 6 mg / mL. 1 mL of the mixed solution was injected into 3 mL of 1 wt% CaCl2 solution to obtain the nanocomposite hydrogel HA-DOX / LAP gel.

[0047] Figure 3 The gelation effect of nanocomposite hydrogels in CaCl2 solutions of different concentrations is shown. Figure 4 The images are scanning electron microscope images of the nanocomposite hydrogel at different magnifications. As can be seen, the nanocomposite hydrogel exhibits a loose and porous morphology, with drug-loaded nanoparticles attached to the pore walls of the gel.

[0048] Example 4: In vivo degradation of nanocomposite hydrogels

[0049] 150 μL of nanocomposite hydrogel was placed subcutaneously in female Balb / c nude mice. The gel was removed at 7, 14 and 21 days and weighed.

[0050] Figure 5 The curve shows the weight change of the gel. 21 days after subcutaneous implantation, 24.3% of the gel remained, indicating that the gel can slowly degrade and release the drug in vivo.

[0051] Example 5: Simultaneous sustained release of chemotherapy drugs by nanocomposite hydrogel

[0052] To verify the simultaneous drug release properties of the nanocomposite hydrogel, a free drug-encapsulated hydrogel (Free DOX+LAP gel) was prepared as a control. The Free DOX+LAP gel was prepared as follows: An ALG-DPA solution was mixed with a drug solution containing free doxorubicin and lapatinib at a volume ratio of 2 / 3 under ultrasonic conditions. The concentration of ALG-DPA was 50 mg / mL, and the concentrations of doxorubicin and lapatinib in the drug solution were 1 mg / mL and 6 mg / mL, respectively. 1 mL of the mixture was injected into 3 mL of 1 wt% CaCl2 solution to obtain the Free DOX+LAP gel.

[0053] Take 1 mL of HA-DOX / LAP gel and Free DOX+LAP gel respectively and place them in 4 mL of pH 6.5 buffer solution. Shake in a constant temperature shaker at 37℃ (120 r / min). Sample at pre-set time points, taking 2 mL of supernatant each time, and simultaneously adding an equal volume of fresh pH 6.5 buffer solution. After sampling, determine the drug concentration using a UV spectrophotometer, and then calculate the release amount of DOX and LAP at each time point using the corresponding standard curve, plotting the drug release curve. Figure 6 As shown, the cumulative release of DOX and LAP from HA-DOX / LAP gel within 14 days was 30.8% and 29.8%, respectively, achieving proportional drug release. The drug ratio of Free DOX+LAP gel changed after the third day of release, with a cumulative release of 33% DOX and 26.1% LAP within 14 days.

[0054] Example 6: Establishment and Treatment of MUM-2B Cell Subcutaneous Tumor Model

[0055] Establishment of MUM-2B cell subcutaneous tumor model in nude mice: 100 μL containing 2 × 10 6 A suspension of MUM-2B cells was injected subcutaneously into the right ventral dorsal region of healthy female Balb / c nude mice aged 5–6 weeks. Tumors were allowed to develop until they reached a size of 100 mm². 3Nude mice were randomly divided into the following 7 groups: intratumoral injection with buffered solution (PBS), intratumoral injection with blank gel (ALG-DPA gel), intratumoral injection with free drug (Free DOX+LAP), intratumoral injection with drug-loaded nanoparticles (HA-DOX / LAP), intratumoral injection with hydrogel encapsulating free drug (Free DOX+LAP gel), single-drug nanocomposite hydrogel (HA-DOX gel), and dual-drug nanocomposite hydrogel (HA-DOX / LAP gel), with 5 mice in each group. Each group received 150 μL of the drug, with DOX at a dose of 5 mg / kg and LAP at a dose of 30 mg / kg. The day of administration was recorded as day 0. Mice were weighed every two days, and the length (L, mm) and width (W, mm) of the tumor were measured, and the tumor volume (V, mm²) was calculated. 3 The formula is as follows: V = L × W 2 / 2, the maximum tumor volume is 1000 mm. 3 .

[0056] Figure 7 The figures show the tumor growth curves in mice over time. Compared to free drugs and nanoparticles, drug encapsulation by hydrogels can improve the therapeutic effect on tumors. HA-DOX / LAP gel showed significantly higher inhibitory effects on tumor growth than Free DOX+LAP gel and HA-DOX gel, indicating that the combined use of dual drugs and drug delivery via nanocomposite hydrogels can enhance the anti-tumor effect.

[0057] Figure 8 The curves showing the weight change of mice in each group are shown. No significant weight fluctuations were observed in any of the treatment groups, indicating that the intratumoral injection method and dosage have good safety.

[0058] Figure 9 Survival curves for each group of mice were shown. After 6 weeks of feeding, all mice in the PBS group and ALG-DPA gel group died, one mouse survived in both the Free DOX+LAP group and the HA-DOX / LAP group, four mice survived in the Free DOX+LAP gel group, two mice survived in the HA-DOX gel group, and no mice died in the HA-DOX / LAP gel group. This indicates that the prepared HA-DOX / LAP gel can effectively prolong the survival time of mice.

Claims

1. A tumor microenvironment-responsive nanocomposite hydrogel drug delivery system, characterized in that: The drug delivery system is a sodium alginate hydrogel with drug-loaded nanoparticles encapsulated in hyaluronic acid; the drug-loaded nanoparticles encapsulate anthracycline chemotherapy drugs and tyrosine kinase inhibitors; the sodium alginate hydrogel is a dopamine-modified sodium alginate hydrogel. The hyaluronic acid-encapsulated drug-loaded nanoparticles are prepared by a method comprising the following steps: an anthracycline chemotherapy drug is linked to the hyaluronic acid side chain via a hydrazone bond to form a polymer prodrug, and a tyrosine kinase inhibitor is encapsulated into the hydrophobic core of the nanoparticles through self-assembly of the polymer prodrug molecule, thereby obtaining hyaluronic acid-encapsulated drug-loaded nanoparticles. The anthracycline chemotherapy drug is doxorubicin, and the tyrosine kinase inhibitor is lapatinib.

2. The tumor microenvironment-responsive nanocomposite hydrogel drug delivery system according to claim 1, characterized in that: The particle size range of the drug-loaded nanoparticles encapsulated in hyaluronic acid is 30–500 nm.

3. The preparation method of the tumor microenvironment-responsive nanocomposite hydrogel drug delivery system according to claim 1 or 2, characterized in that, Includes the following steps: Hyaluronic acid-encapsulated drug-loaded nanoparticles and dopamine-modified sodium alginate were blended in water, and then the blended solution was injected into Ca2+. 2+ A tumor microenvironment-responsive nanocomposite hydrogel drug delivery system was obtained by using an aqueous solution.

4. The preparation method of the tumor microenvironment-responsive nanocomposite hydrogel drug delivery system according to claim 3, characterized in that, Includes the following steps: Hyaluronic acid modified with adipic acid dihydrazide was synthesized via amidation. Anthracycline chemotherapeutic drugs were grafted onto the side chains of hyaluronic acid via hydrazone bonds using a Schiff base reaction to obtain anthracycline polymer prodrugs. Tyrosine kinase inhibitors were encapsulated into nanoparticles via the self-assembly of the anthracycline polymer prodrugs to obtain hyaluronic acid-encapsulated drug-loaded nanoparticles. Next, dopamine was grafted onto the side chains of sodium alginate via amidation to obtain dopamine-modified sodium alginate ALG-DPA. The drug-loaded nanoparticles and ALG-DPA were blended in water, and the blend solution was injected into a Ca2+ solution. 2+ A tumor microenvironment-responsive nanocomposite hydrogel drug delivery system was obtained by using an aqueous solution.

5. The preparation method of the tumor microenvironment-responsive nanocomposite hydrogel drug delivery system according to claim 3, characterized in that, Includes the following steps: (1) Synthesis of hyaluronic acid modified with adipic dihydrazide: Hyaluronic acid, N-hydroxysuccinimide, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were co-dissolved in water to activate the carboxyl group of hyaluronic acid. Then, an aqueous solution of adipic dihydrazide was added to the reaction to obtain hyaluronic acid modified with adipic dihydrazide. (2) Synthesis of anthracycline polymer prodrug: Anthracycline chemotherapeutic drug hydrochloride was dissolved in an organic solvent, and triethylamine was added to react and dehydrochloride was removed; hyaluronic acid modified with adipic dihydrazide was dissolved in an organic solvent and added to the reaction system to continue the reaction and obtain anthracycline polymer prodrug; (3) Preparation of drug-loaded nanoparticles: anthracycline polymer prodrugs and tyrosine kinase inhibitors were co-dissolved in an organic solvent, and the mixed solution was added to a buffer solution under ultrasonic conditions to obtain drug-loaded nanoparticles; (4) Synthesis of dopamine-modified sodium alginate: Sodium alginate, N-hydroxysuccinimide, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were co-dissolved in water to activate the carboxyl group of sodium alginate. A solution of dopamine hydrochloride was added to the system to react and obtain dopamine-modified sodium alginate. (5) Preparation of nanocomposite hydrogel drug delivery system: Dopamine-modified sodium alginate solution was mixed with drug-loaded nanoparticle solution, and after thorough shaking, the mixed solution was injected into CaCl2 solution to obtain nanocomposite hydrogel drug delivery system.

6. The application of the tumor microenvironment-responsive nanocomposite hydrogel drug delivery system according to claim 1 or 2 in the preparation of tumor therapeutic drugs, characterized in that: The tumor treatment drug mentioned is a drug for treating choroidal melanoma.

7. A tumor treatment drug, characterized in that: The tumor microenvironment-responsive nanocomposite hydrogel drug delivery system as described in claim 1 or 2.

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