CN-116672303-B - Tumor microenvironment response type nano composite hydrogel drug co-carrying system and preparation method thereof

CN116672303BCN 116672303 BCN116672303 BCN 116672303BCN-116672303-B

Abstract

The invention discloses a tumor microenvironment response type nano composite hydrogel drug co-carrying system and a preparation method thereof, belonging to the field of anti-tumor materials. The nano composite hydrogel drug-loading system is sodium alginate hydrogel with hyaluronic acid encapsulated drug-loading nano particles embedded inside. The drug-loaded nanoparticle encapsulates an anthracycline chemotherapeutic drug and a tyrosine kinase inhibitor, wherein the anthracycline chemotherapeutic drug is connected to a hyaluronic acid side chain through a hydrazone bond to form a polymer prodrug, and the tyrosine kinase inhibitor is self-assembled and encapsulated into a nanoparticle hydrophobic core through a polymer prodrug molecule to obtain the hyaluronic acid encapsulated drug-loaded nanoparticle. The sodium alginate hydrogel is dopamine-modified sodium alginate hydrogel. The nano composite hydrogel drug co-loading system is easy to inject in and beside tumor, can be slowly degraded in vivo, and utilizes the escaped nano particles to synchronously deliver the drug to tumor cells in a targeted manner, thereby inhibiting proliferation, invasion and migration of the tumor cells and realizing the synergistic anti-tumor effect.

Inventors

GUO ZHIHAO
ZHU RUOHUA
LI YUMEI
LI JILIANG

Assignees

温州医科大学

Dates

Publication Date: 20260508
Application Date: 20230522

Claims (7)

1. A tumor microenvironment response type nano composite hydrogel drug-loading system is characterized in that the drug-loading system is sodium alginate hydrogel with hyaluronic acid encapsulated drug-loading nano particles embedded inside, wherein the drug-loading nano particles encapsulate anthracycline chemotherapeutics and tyrosine kinase inhibitors; The hyaluronic acid encapsulated drug-loaded nanoparticle is prepared by a method comprising the following steps that an anthracycline chemotherapeutic drug is connected to a hyaluronic acid side chain through a hydrazone bond to form a polymer prodrug, and a tyrosine kinase inhibitor is self-assembled and encapsulated into a nanoparticle hydrophobic core through a polymer prodrug molecule to obtain the hyaluronic acid encapsulated drug-loaded nanoparticle; The anthracycline chemotherapeutic drug is doxorubicin, and the tyrosine kinase inhibitor is lapatinib.
2. The tumor microenvironment responsive nanocomposite hydrogel drug delivery system of claim 1, wherein the particle size range of the hyaluronic acid encapsulated drug delivery nanoparticles is 30-500 nm.
3. The preparation method of the tumor microenvironment response type nano-composite hydrogel drug-loading system according to claim 1 or 2 is characterized by comprising the following steps of blending hyaluronic acid encapsulated drug-loading nano-particles and dopamine modified sodium alginate into water, and then injecting the blended solution into Ca 2+ aqueous solution to obtain the tumor microenvironment response type nano-composite hydrogel drug-loading system.
4. The preparation method of the tumor microenvironment response type nano composite hydrogel drug-loading system is characterized by comprising the following steps of synthesizing adipic acid dihydrazide modified hyaluronic acid through amidation reaction, grafting an anthracycline chemotherapeutic drug to a side chain of the hyaluronic acid through hydrazone bond through Schiff base reaction to obtain an anthracycline polymer prodrug, encapsulating a tyrosine kinase inhibitor into nanoparticles through molecular self-assembly of the anthracycline polymer prodrug to obtain hyaluronic acid encapsulated drug-loading nanoparticles, grafting dopamine to a sodium alginate side chain through amidation reaction to obtain dopamine modified sodium alginate ALG-DPA, blending the drug-loading nanoparticles and ALG-DPA in water, and injecting a blend solution into Ca 2+ aqueous solution to obtain the tumor microenvironment response type nano composite hydrogel drug-loading system.
5. The method for preparing the tumor microenvironment-responsive nanocomposite hydrogel drug delivery system according to claim 3, comprising the steps of: (1) The synthesis of adipic acid dihydrazide modified hyaluronic acid comprises the steps of co-dissolving hyaluronic acid, N-hydroxysuccinimide and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride in water to perform reaction so as to activate carboxyl of the hyaluronic acid, and then adding adipic acid dihydrazide aqueous solution to perform reaction to obtain adipic acid dihydrazide modified hyaluronic acid; (2) The synthesis of anthracycline polymer prodrug includes dissolving anthracycline chemotherapeutic medicine hydrochloride in organic solvent, adding triethylamine to react to eliminate hydrochloric acid; dissolving adipic acid dihydrazide modified hyaluronic acid in an organic solvent, adding the organic solvent into a reaction system, and continuing to react to obtain an anthracycline polymer prodrug; (3) The preparation of drug-loaded nano-particles comprises the steps of co-dissolving an anthracycline polymer prodrug and a tyrosine kinase inhibitor in an organic solvent, and adding the mixed solution into a buffer solution under the ultrasonic condition to obtain the drug-loaded nano-particles; (4) The synthesis of dopamine-modified sodium alginate comprises the steps of co-dissolving sodium alginate, N-hydroxysuccinimide and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride in water to activate carboxyl of sodium alginate, and adding dopamine hydrochloride aqueous solution into a system to react to obtain dopamine-modified sodium alginate; (5) The preparation of the nano composite hydrogel drug-loading system comprises the steps of blending a dopamine modified sodium alginate solution and a drug-loading nanoparticle solution, sufficiently oscillating, and then injecting the mixed solution into a CaCl 2 solution to obtain the nano composite hydrogel drug-loading system.
6. The application of the tumor microenvironment responsive nano-composite hydrogel drug-loading system in preparing a tumor therapeutic drug, as claimed in claim 1 or 2, is characterized in that the tumor therapeutic drug is a choroidal melanoma therapeutic drug.
7. A tumor therapeutic drug, which is characterized by comprising the tumor microenvironment responsive nanocomposite hydrogel drug delivery system according to claim 1 or 2.

Description

Tumor microenvironment response type nano composite hydrogel drug co-carrying system and preparation method thereof Technical Field The invention belongs to the field of anti-tumor materials, and particularly relates to a tumor microenvironment response type nano composite hydrogel drug co-carrying system and a preparation method thereof. Background Cancer is the second most fatal disease next to cardiovascular disease. Chemotherapy is one of the main means for treating malignant tumor clinically at the present stage, but the conventional chemotherapy has poor selectivity, and can cause serious damage to normal tissues while treating tumor, thereby affecting the life quality of patients. In recent years, intelligent drug delivery systems for tumor treatment are widely studied, and the drug delivery systems can regulate the in-vivo process of chemotherapeutic drugs, promote the distribution and accumulation of the drugs in tumor tissues, improve the cell uptake and release behaviors of the drugs, realize attenuation and synergy and have good clinical development value. The injectable hydrogel has the characteristics of low toxicity, minimally invasive property, suitability for any irregular cavity and the like, and is highly concerned in the field of anti-tumor drug delivery. The hydrogel is usually injected in tumor or around tumor, and compared with systemic administration, the hydrogel can directly deliver the drug to tumor site in high concentration, and reach therapeutic window concentration at smaller dosage, thereby effectively reducing the toxic and side effects of chemotherapy drugs. Although the drug-loaded hydrogel has been developed to a certain extent, the drug-loaded hydrogel still has limitations in tumor treatment, such as (1) the hydrogel has limited encapsulation efficiency and homogeneity for hydrophobic drugs, which can easily cause local drug burst release, (2) the release of drugs is highly dependent on passive diffusion, lacks targeting selectivity, most drugs cannot reach deep tumor tissues and have potential toxicity to surrounding healthy tissues, and (3) the drug-loaded hydrogel is difficult to release synchronously according to the design proportion for combined treatment, so that the synergistic treatment effect of the drugs is reduced. Disclosure of Invention In order to solve the problems, the invention embeds drug-carrying nano particles carrying anthracycline chemotherapeutics and tyrosine kinase inhibitors into the hydrogel, thereby constructing a novel nano composite hydrogel drug-carrying system. The system improves the solubility of the chemotherapeutic drugs, enhances the stability of the drugs and improves the targeting property of the drugs by introducing nano particles into the hydrogel, and simultaneously, directly delivers the drug-loaded nano particles to tumor tissues by utilizing the entrapment of the hydrogel, thereby effectively enhancing the enrichment of the drugs at the tumor, improving the bioavailability of the drugs and further realizing the safe and efficient treatment of the tumors. Aiming at the defects of the existing drug delivery system technology, the invention aims to provide a tumor microenvironment response type nano-composite hydrogel drug co-carrying system and a preparation method thereof. The nano composite hydrogel can improve the loading rate and bioavailability of the medicine, enhance the tumor treatment effect and reduce the toxic and side effects. The invention also provides a preparation method and application of the tumor microenvironment response type nano-composite hydrogel drug co-carrying system. In order to achieve the above purpose, the invention adopts the following technical scheme: A drug-loaded system of tumor microenvironment responsive nano composite hydrogel is sodium alginate hydrogel internally embedded with hyaluronic acid encapsulated drug-loaded nanoparticles, wherein the drug-loaded nanoparticles encapsulate anthracycline chemotherapeutics and tyrosine kinase inhibitors, and the sodium alginate hydrogel is dopamine modified sodium alginate derivative hydrogel. The nano composite hydrogel drug co-carrying system is easy to inject in and beside tumor, can be slowly degraded in vivo, and utilizes the escaped nano particles to synchronously deliver the drug to tumor cells in a targeted manner, thereby inhibiting proliferation, invasion and migration of the tumor cells and realizing the synergistic anti-tumor effect. In the tumor microenvironment responsive type nano composite hydrogel drug co-carrying system, the hyaluronic acid encapsulated drug-carrying nano particles are prepared by a method comprising the step that an anthracycline chemotherapeutic drug is connected to a hyaluronic acid side chain through a hydrazone bond to form a polymer prodrug, and the anthracycline chemotherapeutic drug can be one or more of doxorubicin, epirubicin, daunorubicin or aclacin. The tyrosine kinase inhibitor, which may be one or mo