A photothermal responsive hydrogel and a preparation method thereof

Abstract

The present application relates to a kind of injectable hydrogel for photothermal therapy and its preparation method, belong to photothermal hydrogel field.The present application is with new organic small molecule photosensitizer and chitosan as raw material, by introducing glutaraldehyde, constructs a kind of injectable hydrogel with photothermal effect.The injectable photothermal hydrogel of the present application overcomes the shortcoming that traditional hydrogel cannot be regulated temperature, can be regulated by adjusting the content of photosensitizer to regulate the temperature of hydrogel under near-infrared laser irradiation, has potential photothermal antitumor activity, and has wide application prospect in the preparation of hydrogel biomaterial and drug for photothermal therapy.

Description

Technical Field

[0001] This invention belongs to the field of photothermal gels, specifically relating to an injectable photothermal gel and its preparation method. Background Technology

[0002] Cancer, with its low cure rate and high recurrence rate, has always threatened people's lives. Intratumoral injection, as a non-intravenous drug delivery method in tumor treatment, directly delivers anti-tumor drugs to the lesion, significantly increasing the drug concentration at the tumor site while significantly reducing the distribution of drugs in normal tissues / organs. It has advantages such as enhanced efficacy, reduced toxicity, and minimal invasiveness, and is widely used in clinical tumor treatment.

[0003] Photothermal therapy is an emerging treatment for superficial tumors. It utilizes materials with high photothermal conversion efficiency, injected near the tumor tissue, and then converted into heat energy under external light to kill cancer cells. Photothermal therapy has attracted considerable attention in cancer treatment due to its advantages such as non-invasive tumor ablation and deep tissue penetration.

[0004] Hydrogels exhibit excellent stability and good biocompatibility, showing no significant acute toxicity in animals. Introducing photosensitizers into the hydrogels allows for precise temperature regulation, further expanding the effectiveness of this treatment strategy. Therefore, injectable photothermal hydrogels hold promise for medical applications. Summary of the Invention

[0005] The purpose of this invention is to provide an injectable photothermal hydrogel and its preparation method. The hydrogel has good injectability and its temperature can be increased under near-infrared laser irradiation.

[0006] This invention first provides a method for preparing an injectable photothermal gel, the steps of which are as follows:

[0007] Step 1: Add 2,5-bis(diphenylamino)terephthalaldehyde and rhodanine-3-acetic acid to 1,4-dioxane and stir. Then slowly add triethylamine and reflux at 110°C for 7 hours. After the reaction system cools, remove the solvent under reduced pressure and recrystallize to obtain the photosensitizer.

[0008] Step 2: Add NHS and EDC to the photosensitizer ethanol solution, heat and stir at 60°C for 1 hour, and cool to obtain the first solution;

[0009] Step 3: Add chitosan to water, slowly add nitric acid, heat and stir at 80°C for 1.5 hours, and cool to obtain the second solution;

[0010] Step 4: Slowly add the first solution to the second solution, heat and stir at 80°C under argon for 7 hours, cool and freeze dry to obtain chitosan-grafted photosensitizer solid;

[0011] Step 5: Dissolve the chitosan-grafted photosensitizer solid in water, add a crosslinking agent, and obtain an injectable photothermal hydrogel.

[0012] Preferably, the photosensitizer is the novel small-molecule organic photosensitizer mentioned in step one.

[0013] Preferably, the chitosan is 95% chitosan, 85% chitosan, low-viscosity chitosan, or carboxymethyl chitosan.

[0014] Preferably, in step two, the molar ratio of photosensitizer to NHS and EDC is 1:10:3.2.

[0015] Preferably, the volume ratio of water to nitric acid in step three is 80:1.

[0016] Preferably, the molar ratio of photosensitizer to chitosan in step four is 1:0.06 to 1.2.

[0017] Preferably, the crosslinking agent in step five is glutaraldehyde, adipaldehyde, heptaaldehyde, or octanaldehyde.

[0018] Preferably, hydrogels containing different concentrations of photosensitizer exhibit different temperatures under near-infrared laser irradiation. Attached Figure Description

[0019] Figure 1 Photograph of injectable photothermal gel.

[0020] Figure 2 Chitosan is a photosensitizer grafted onto chitosan. Chitosan is a photosensitizer that can be injected with photothermal hydrogel infrared spectrum.

[0021] Figure 3 Fluorescence spectra of injectable photothermal gel and photosensitizer.

[0022] Figure 4 The image shows the ultraviolet absorption spectrum of the injectable photothermal hydrogel, chitosan grafted with photosensitizer, chitosan, photosensitizer, and glutaraldehyde.

[0023] Figure 5 Temperature curves of injectable photothermal hydrogels containing 7.5%, 5%, 2.5%, and 1% photosensitizers and water under near-infrared laser irradiation. Detailed Implementation

[0024] This invention first provides a method for preparing an injectable photothermal gel, the steps of which are as follows:

[0025] The present invention will be further described below with reference to the embodiments, but it is not intended to limit the present invention. All raw materials involved in the embodiments are commercially available.

[0026] Example

[0027] Take a 25 mL single-necked flask, add 234 mg of 2,5-bis(diphenylamino)terephthalaldehyde, 191 mg of rhodanine-3-acetic acid, and 6 mL of 1,4-dioxane, and stir for 2 minutes. Then slowly add 650 μL of triethylamine to the single-necked flask, and stir under reflux at 110 °C for 7 hours. After the reaction system cools, remove the solvent under reduced pressure, and recrystallize the crude product from dichloromethane / anhydrous ethanol to obtain the photosensitizer.

[0028] The molecular formula of the photosensitizer is shown below:

[0029] Take a 10mL single-necked bottle, add 20mg of photosensitizer, 45.84mg of EDC, 8.96mg of NHS and 4mL of ethanol, stir and reflux at 60℃ for 1 hour to activate the carboxyl groups.

[0030] Take a 100mL two-necked bottle, attach a condenser and a constant pressure dropping funnel, add 39.36mg chitosan, 32mL ultrapure water, and 160uL nitric acid, and stir and reflux at 80℃ for 1.5 hours.

[0031] The photosensitizer ethanol solution, cooled to room temperature, was placed in a constant pressure dropping funnel and slowly added to a two-necked flask. The mixture was stirred and refluxed at 80°C for 7 hours under argon atmosphere. After cooling to room temperature, it was freeze-dried to obtain the chitosan-grafted photosensitizer.

[0032] Dissolve 20 mg of chitosan-grafted photosensitizer solid in 396 μL of water, add 4 μL of glutaraldehyde, and mix thoroughly to obtain an injectable photothermal hydrogel containing 5% photosensitizer.

[0033] Using a power density of 600 mW / cm 2 A laser irradiates 100 μL of injectable photothermal hydrogel containing 7.5%, 5%, 2.5%, and 1% photosensitizers, and the temperature changes as follows: Figure 5 As shown.

Claims

1. A method for preparing a photothermal responsive hydrogel, comprising the following steps: Step 1: Add 2,5-bis(diphenylamino)terephthalaldehyde and rhodanine-3-acetic acid to 1,4-dioxane and stir. Then slowly add triethylamine and stir under reflux at 110°C for 7 hours. After the reaction system cools down, remove the solvent under reduced pressure and recrystallize to obtain the photosensitizer. Step 2: Add NHS and EDC to the photosensitizer ethanol solution, heat and stir at 60°C for 1 hour, and cool to obtain the first solution; Step 3: Add chitosan to water, slowly add nitric acid, heat and stir at 80°C for 1.5 hours, and cool to obtain the second solution; Step 4: Slowly add the first solution to the second solution, heat and stir at 80°C under argon for 7 hours, cool and freeze dry to obtain chitosan-grafted photosensitizer solid; Step 5: Dissolve the chitosan-grafted photosensitizer solid in water, add a crosslinking agent, and obtain an injectable photothermal hydrogel.

2. The method for preparing a photothermal responsive hydrogel according to claim 1, characterized in that, The chitosan is 95% chitosan, 85% chitosan, low-viscosity chitosan, or carboxymethyl chitosan.

3. The method for preparing a photothermal responsive hydrogel according to claim 1, characterized in that, In step two, the molar ratio of photosensitizer to NHS and EDC is 1:10:3.

2.

4. The method for preparing a photothermal responsive hydrogel according to claim 1, characterized in that, In step three, the volume ratio of water to nitric acid is 80:

1.

5. The method for preparing a photothermal responsive hydrogel according to claim 1, characterized in that, The molar ratio of the photosensitizer to chitosan is 1:0.06 to 1.

2.

6. The method for preparing a photothermal responsive hydrogel according to claim 1, characterized in that, The crosslinking agent in step five is glutaraldehyde, adipaldehyde, heptaaldehyde, or octanaldehyde.

7. A photothermal responsive hydrogel obtained by the preparation method according to any one of claims 1-6.

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