CN-116531317-B - Antitumor hydrogel based on hunger therapy and preparation and application thereof

Abstract

The invention discloses an anti-tumor hydrogel based on hunger therapy, and preparation and application thereof. After the DHA solution, the AI solution, the Ink solution and the ALG solution are simply mixed, DHA/AI/ink@ALG is formed, in-situ hydrogel is formed in tumor tissues by injection through a simple method, under 1064nm laser irradiation, AI decomposition is started by utilizing a low-temperature photothermal effect to generate alkyl free radicals, and damage of DHA-induced mitochondrial oxidative stress is aggravated by the alkyl free radicals and inhibition of GLUT1 by the DHA is intensified to reduce glucose intake, so that DHA-induced cell starvation therapy is enhanced, the effect of anti-tumor therapy is obviously improved, and a novel mode is provided for high-efficiency and low-toxicity cancer therapy.

Inventors

• SHEN SHUN
• SU XIAOMIN

Assignees

• 上海市浦东医院（复旦大学附属浦东医院）

Dates

Publication Date

20260512

Application Date

20230523

Claims (6)

1. 1. The injectable hydrogel is characterized in that the injectable hydrogel is dihydroartemisinin DHA/2,2 '-azobis [2- (2-imidazolin-2-yl) propane ] dihydrochloride AI/ink@sodium alginate ALG, and is obtained by ultrasonic homogenization after mixing sodium alginate ALG solution with 2,2' -azobis [2- (2-imidazolin-2-yl) propane ] dihydrochloride AI solution, dihydroartemisinin DHA solution and Ink solution; The sodium alginate ALG solution is prepared by dissolving sodium alginate ALG powder in ultrapure water, the 2,2 '-azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride AI solution is prepared by dissolving 2,2' -azobis [2- (2-imidazoline-2-yl) propane ] dihydrochloride AI powder in ultrapure water, the dihydroartemisinin DHA solution is prepared by dissolving dihydroartemisinin DHA powder in dimethyl sulfoxide, diluting the dihydroartemisinin DHA mother solution to a target concentration by using ultrapure water, the Ink solution is prepared by diluting the Ink mother solution by using ultrapure water, and the Ink mother solution is prepared by adding the Ink powder into an aqueous solution of polyvinylpyrrolidone with a concentration of 8-10 mg/mL under ultrasound, transferring the aqueous solution into a hydrothermal reaction kettle after the dispersion is completed, heating the aqueous solution for 5-7 h at 140-170 ℃, and cooling to room temperature.
2. 2. The injectable hydrogel according to claim 1, wherein in the mixed solution of dihydroartemisinin DHA/2,2 '-azobis [2- (2-imidazolin-2-yl) propane ] dihydrochloride AI/Ink @ sodium alginate ALG, the concentration of sodium alginate ALG is 5-8 mg/mL, the concentration of 2,2' -azobis [2- (2-imidazolin-2-yl) propane ] dihydrochloride AI is 1-2 mg/mL, the concentration of dihydroartemisinin DHA is 1-2 mmol/L, and the concentration of Ink is 150-400 mg/mL.
3. 3. Use of an injectable hydrogel according to claim 1 or 2 in the preparation of a medicament for optically controlled assisted tumor therapy, wherein the tumor therapy is starvation therapy of a tumor, which is liver cancer.
4. 4. The use according to claim 3, wherein the medicament is an injection agent for in situ injection in tumour tissue.
5. 5. The use of claim 3, wherein the light control means near infrared light irradiation in a wavelength range between 1000-1700 nm.
6. 6. The use of claim 3, wherein the light control is 1064 nm laser shots.

Description

Antitumor hydrogel based on hunger therapy and preparation and application thereof Technical Field The invention belongs to the field of biological medicine, and in particular relates to antitumor hydrogel based on hunger therapy, and preparation and application thereof. Background Abnormal cellular metabolism and excessive nutrient consumption are one of the main physiological characteristics of tumors. Thus, starvation treatment of tumors by blocking blood supply and consuming critical nutrients has been widely studied as an attractive cancer treatment. The wobbe found that the uptake of glucose by tumor cells was highly demanding, and that tumor growth and proliferation was promoted by anaerobic glycolysis. Tumor cells rely strongly on glycolysis to gain energy rather than oxygen. Based on this metabolic characteristic of tumor cells, researchers have developed two starvation therapies, glucose starvation therapy and vascular embolism therapy, for treating tumors. Vascular embolization therapy is a strategy for inducing starvation treatment by blocking blood, which rapid blood flow may affect plaque formation or lead to ineffective embolization, and glucose starvation therapy is a therapy in which glucose oxidase (GOx) is used as a starvation-inducing drug and glucose in tumor cells is effectively consumed, and is receiving increasing attention. GOX mediates various anticancer therapies and has excellent performance in cancer treatment, however, GOX has some unavoidable limitations in treating tumors, namely, GOX is a protein in nature and is easy to degrade, so that the bioavailability is low, GOX can inhibit catalytic reaction of glutathione reductase in vitro in cancer cells and non-cancer cells, nonspecific administration possibly has systemic toxicity, targeting-free capability and larger toxicity and instability of GOX limit the antitumor effect, and excessive H 2O2 generated by glucose oxidation can accelerate metastasis and invasion of tumors and can generate irreversible oxidative damage to surrounding normal tissues. Based on this, researchers focused on a reasonably designed drug delivery system with targeting function to deliver GOX to cancer cell tissue sites, reducing degradation and loss during transport. For example, chinese patent application number 202111526167.8 discloses a Mn-based degradable MOF nanoreactor, and a preparation method and application thereof, wherein the nanoreactor comprises inner core Mn-based MOF nanoparticles, the surface of which is functionalized and grafted with pH-responsive shell copolymer PEG-CDM-PEI, and the Mn-based MOF nanoparticles are loaded with bio-enzyme GOx and IDO immunosuppressant, and the combined therapy of tumor starvation/oxidation/IDO immunization is regulated and controlled by pH/ROS dual-responsive drug controlled release. For another example, chinese patent application No. 202110395713.2 discloses a porphyrin-based metal-organic framework nano-carrier, which is obtained by co-loading glucose oxidase and a metal nano-enzyme with catalase-like activity into a cell membrane-coated porphyrin-based metal-organic framework nano-particle. The cell membrane modification enhances accumulation of tumor parts, porphyrin molecules with acoustic power effect form a metal organic framework structure through coordination, acoustic power effect is improved, hydrogen peroxide of tumor tissues is decomposed by metal nano enzyme to generate oxygen, glucose of the tumor tissues can be consumed by glucose oxidase, energy supply of tumor cells is cut off, and finally the aim of enhancing and killing tumors by combining acoustic power and starvation treatment is achieved. For another example, the chinese patent application number 201911083865.8 discloses a degradable antitumor nano-drug based on hunger therapy, and a preparation method and application thereof. Dissolving dopamine hydrochloride in Tris-HCl buffer solution, adding glucose oxidase, rapidly stirring, centrifuging liquid after secondary filtration and an equal volume of prepared silver cube solution, precipitating and mixing, carrying out ultrasonic treatment on the mixed solution, standing, centrifuging to obtain precipitate, and re-suspending the precipitate in the PBS buffer solution to obtain the glucose oxidase-loaded silver cubes. The particle glucose oxidase has a loading amount of 10% -25%, an average particle size of 100-150 nm, and can be degraded in an acidic and hydrogen peroxide environment at a tumor part. The nano-drug combines starvation therapy of glucose oxidase consuming glucose at tumor site with photothermal therapy of nano-silver cubes to achieve tumor treatment effect. The above-mentioned nanoreactors are all directly loaded with glucose oxidase (GOx), the system is relatively complex, and the application defects of GOX are still not completely avoided. Disclosure of Invention In view of the problems existing in the prior art, unlike the conventional thought of carrying glucose