A hydrogel with photothermal performance and a preparation method thereof

Abstract

The present application relates to the field of biological materials, in particular to a hydrogel with photothermal performance and a preparation method thereof, which is prepared by a photosensitizer molecule-oxidized sodium alginate with degradable natural polymer sodium alginate, tissue engineering carrier material chitosan and photosensitizer small molecules participating in the reaction. The hydrogel is convenient to synthesize, low in cost, has near-infrared laser photothermal response characteristics, can be rapidly heated by irradiation of near-infrared laser, and has good application prospect in the medical field.

Description

Technical Field

[0001] This invention relates to the field of medical polymer materials and biomaterials technology, and in particular to a method for preparing a hydrogel with photothermal therapy function. Background Technology

[0002] Cancer, with its low cure rate and high recurrence rate, continues to threaten people's lives and trouble everyone. Traditional anticancer drug treatments are often severely limited by low efficacy, poor selectivity, drug resistance in normal tissues and organs, and side effects. Currently, tumor treatment in my country still primarily relies on surgical resection; however, most surgeries cannot completely remove the tumor, leading to recurrence, and postoperative wound healing requires a considerable amount of time. To remove residual tumor tissue, we need a minimally invasive method and treatment approach. Photothermal therapy, which can target specific areas and provides gentle treatment, is undoubtedly a suitable choice.

[0003] Hydrogels are promising biomaterials, consisting of a three-dimensional network structure formed by cross-linking linear polymer chains, exhibiting excellent water absorption capabilities. Furthermore, hydrogels exhibit low surface protein and cell adhesion, and their high water content closely resembles that of body tissues filled with aqueous fluids. Their soft, wettable surface and tissue affinity significantly reduce irritation to the human body. These properties enable them to load a range of tumor therapeutic agents, thus facilitating their medical applications. Summary of the Invention

[0004] The purpose of this invention is to address the shortcomings of existing technologies by proposing a method for preparing a hydrogel with photothermal therapy function. To achieve the above objective, this invention adopts the following technical solution:

[0005] 1) Dissolve 1g of sodium alginate in deionized water, and modify the sodium alginate by adding sodium periodate solution under room temperature and light-protected conditions. New characteristic absorption peaks were measured using an infrared spectrometer.

[0006] 2) Sodium alginate is a natural polymer with high viscosity and biodegradability. It has strong hydrophilicity and good biocompatibility, and can form a very viscous and homogeneous solution. It can also be used as a tissue engineering material.

[0007] 3) Place the solution obtained in the above steps in the freezer compartment of the refrigerator to prevent it from changing.

[0008] 4) The synthesis steps of photosensitizer molecules are as follows:

[0009] 5) Dissolve 3.685g of N-phenyl-p-phenylenediamine and 4.365g of di-tert-butyl dicarbonate in 20mL of tert-butanol solution and stir at room temperature for 6h.

[0010] 6) Add 0.568 g of the compound obtained in the above steps to a round-bottom flask containing 0.117 g of dibromo-terephthalaldehyde, 0.056 g of Ruphos, 0.849 g of potassium phosphate and 0.027 g of Pd2(dba)3. Add 3 mL of toluene under an argon atmosphere and reflux at 110 °C for 24 h.

[0011] 7) Add 107 mg of the compound obtained in the above steps to 74 mg of malononitrile-modified rhodanine and 3 mL of a 1, photosensitizer molecule-dioxane solution, and stir until homogeneous. Then add 0.4 mL of triethylamine to the mixture and react at 110 °C for 6 h.

[0012] 8) Add 300 mg of the compound obtained in the above steps to a mixed solution of 10 mL trifluoroacetic acid and 10 mL dichloromethane, and stir at room temperature to obtain photosensitizer molecules (compound 4).

[0013] 9) To optimize the above steps, the time and amount of trifluoroacetic acid added must be strictly controlled. After the reaction is complete, saturated sodium bicarbonate solution and water are added for repeated extraction to completely remove trifluoroacetic acid.

[0014] 10) Dissolve the photosensitizer molecule obtained in the above steps in tetrahydrofuran solution, and then add it to the deionized aqueous solution after the reaction in step 1). Stir at room temperature to obtain the photosensitizer molecule - sodium alginate oxide. In the infrared spectrum, the photosensitizer molecule - sodium alginate oxide exhibits new characteristic absorption peaks, which are the absorption peaks unique to carbon-nitrogen double bonds and carbon-nitrogen triple bonds.

[0015] 11) To remove tetrahydrofuran from the mixed solution, after the reaction is complete, perform vacuum rotation, followed by repeated washing with deionized water by centrifugation. Dialysis can also be performed.

[0016] 12) Take 1 mL of 14% sodium alginate aqueous solution from step 1) and add it to the above steps to form a homogeneous aqueous dispersion. Then add 1 mL of 7% chitosan aqueous solution and stir at room temperature for 15-30 min to ensure thorough mixing. Let stand to form a hydrogel. Use a UV spectrophotometer to measure the absorbance values ​​of different components of the hydrogel under UV absorption. Attached Figure Description

[0017] Figure 1 This is a synthetic route diagram of the photosensitizer molecule (compound 4) of the present invention.

[0018] Figure 2The infrared spectra of sodium alginate, oxidized sodium alginate, and photosensitizer molecule-oxidized sodium alginate in this invention are shown.

[0019] Figure 3 This is a UV absorption diagram of different components of the hydrogel.

[0020] Figure 4 The graph shows the hydrogel before and after gelation, from solution to gel state.

[0021] Figure 5 This is a graph showing the temperature change of hydrogels with different concentrations of photosensitizer molecules under light irradiation. Detailed Implementation

[0022] This invention provides a hydrogel with photothermal properties, which is composed of sodium oxidized alginate, chitosan, and photosensitizer molecules - sodium oxidized alginate.

[0023] The specific preparation method of the photosensitizer molecule, sodium alginate, is as follows:

[0024] Prepare a 1% (w / w) aqueous solution of 1g sodium alginate, then add 10mL of 0.5M sodium periodate solution and stir for 24h at room temperature in the dark. After 24h, add 3mL of ethylene glycol and stir for 15min to terminate the oxidation reaction. Add 0.3g of sodium chloride and mix thoroughly, then add 200mL of ethanol to precipitate the product. Filter, dissolve the product in deionized water, and precipitate again with ethanol. Repeat this process three times, then freeze-dry. Under infrared spectroscopy, the modified oxidized sodium alginate shows a new absorption peak at 1710nm compared to sodium alginate; this is a characteristic absorption peak of the aldehyde group.

[0025] Synthesis of compound 1.

[0026] In a 50 mL single-necked round-bottom flask, N-phenyl-p-phenylenediamine (3.685 g, 20 mmol), di-tert-butyl dicarbonate (4.365 g, 20 mmol), and tert-butanol (20 mL) were added and stirred at room temperature for 6 h. The mixture was then separated using a silica gel column chromatography (eluent: dichloromethane / petroleum ether = 5:1) to finally obtain compound 1.

[0027] The molecular formula of compound 1 is shown below:

[0028] Synthesis of compound 2.

[0029] In a 25 mL double-necked round-bottom flask, 2,5-dibromo-terephthalaldehyde (0.117 g, 0.40 mmol), compound 1 (0.568 g, 2.00 mmol), Ruphos (0.056 g, 0.12 mmol), potassium phosphate (0.849 g, 4.00 mmol), and Pd2(dba)3 (0.027 g, 0.03 mmol) were added. Toluene (3 mL) was added under argon atmosphere, and the mixture was refluxed at 110 °C for 24 h. The mixture was extracted with dichloromethane / water, and the organic phase was evaporated to dryness and separated by silica gel column chromatography (eluent: dichloromethane) to give compound 2.

[0030] The molecular formula of compound 2 is shown below:

[0031] Synthesis of compound 3.

[0032] Compound 2 (107 mg, 0.154 mmol), malononitrile-modified rhodanine (74 mg, 0.308 mmol), and 1,4-dioxane (3 mL) were added to a 50 mL single-necked round-bottom flask. After stirring for ten minutes, triethylamine (0.4 mL) was added to the mixture, and the reaction was carried out at 110 °C for 6 h. After the reaction was completed, the solvent was removed by rotary evaporation, and the crude product was recrystallized from dichloromethane / ethanol to give compound 3.

[0033] The molecular formula of compound 3 is as follows:

[0034] Synthesis of photosensitizer compound 4.

[0035] Compound 3 (300 mg, 317 mmol), trifluoroacetic acid (10 mL), and dichloromethane (10 mL) were added to a 100 mL single-necked round-bottom flask and stirred at room temperature for 4 h. The mixture was washed with saturated sodium bicarbonate solution until the pH reached 8-9. The solvent was removed, and the mixture was dried to obtain compound 4.

[0036] The molecular formula of photosensitizer compound 4 is as follows:

[0037] Following the synthesis steps described above, 20 mg of oxidized sodium alginate was dissolved in 5 mL of ultrapure water. Compound 4 (5 mg) was added to 5 mL of tetrahydrofuran, and then added to the oxidized sodium alginate solution at room temperature. The mixture was reacted for 6 h under stirring. After the reaction was complete, the mixture was evaporated on a rotary evaporator to remove the organic solvent (THF). To remove any remaining trace amount of tetrahydrofuran, the aqueous dispersion of the photosensitizer molecule-oxidized sodium alginate was centrifuged and washed three times. Finally, the photosensitizer molecule-oxidized sodium alginate was obtained. Under infrared spectroscopy, the photosensitizer molecule-oxidized sodium alginate showed new absorption peaks at 1664 nm and 2217 nm, which are the absorption peaks unique to carbon-nitrogen double and triple bonds, respectively.

[0038] Preparation of hydrogels containing sodium oxidized alginate, chitosan, and photosensitizer molecules - sodium oxidized alginate.

[0039] Take 1 mL of a 14% (w / w) sodium alginate aqueous solution and add it to the photosensitizer molecule (sodium alginate) to form a homogeneous aqueous dispersion. Then add 1 mL of a 7% (w / w) chitosan aqueous solution and stir at room temperature for 15-30 min to ensure thorough mixing. Let stand to form a hydrogel. Use a UV spectrophotometer to measure the absorbance values ​​of different components of the hydrogel under UV absorption. The graph shows that chitosan and sodium alginate have no absorption peaks, the photosensitizer molecule (compound 4) has an absorption peak at 605 nm, and the absorption peaks of the hydrogel and the photosensitizer molecule (sodium alginate) are both around 700 nm, indicating a gradual red shift in absorption peaks.

[0040] Using the method of the present invention, such as Figure 5 It can be seen that when irradiated for 300 seconds under the same light power, the temperature of hydrogels containing different amounts of photosensitizer molecules changes. When the photosensitizer molecule content is 5 mg, the temperature of the hydrogel is about 67.5℃; when the content is 2.5 mg, the temperature is about 47.4℃; when the content is 1.25 mg, the temperature is about 45.3℃; and when the content is 0.625 mg, the temperature is about 35.5℃. The results show that the temperature of the hydrogel gradually increases with the increase of the photosensitizer molecule content.

Claims

1. A method for preparing a hydrogel with photothermal properties, characterized in that, The structural formula of the photosensitizer molecule is: The synthesis process of the hydrogel is as follows: First, the oxidized sodium alginate solution reacts with photosensitizer molecules to obtain photosensitizer molecules - oxidized sodium alginate compound; then, the oxidized sodium alginate reacts with photosensitizer molecules - oxidized sodium alginate compound and chitosan to obtain the hydrogel.

2. The method for preparing a hydrogel with photothermal properties according to claim 1, characterized in that: 20 mg of oxidized sodium alginate was dissolved in 5 mL of ultrapure water. 5 mg of the above photosensitizer molecule was added to 5 mL of tetrahydrofuran and then added to the oxidized sodium alginate solution at room temperature. The mixture was reacted for 6 h under stirring.

3. The method for preparing a hydrogel with photothermal properties according to claim 1, characterized in that: Take 1 mL of 14% sodium alginate aqueous solution and add it to the photosensitizer molecule - sodium alginate to form a uniform aqueous dispersion. Then add 1 mL of 7% chitosan aqueous solution and stir at room temperature for 15-30 min to mix the two thoroughly. Let stand to form a hydrogel.

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