Photothermal-responsive curcumin sustained-release microgels, preparation method and application thereof

Abstract

The application belongs to the field of biomedical materials and biomedical engineering technology, and discloses a photothermal responsive curcumin sustained-release microgel as well as a preparation method and application thereof. The preparation method is as follows: eggshell membrane short fibers are soaked in a dopamine aqueous solution, centrifuged and washed after dark storage, and dopamine-eggshell membrane short fibers are obtained; the dopamine-eggshell membrane short fibers, curcumin and sodium alginate are mixed, dropped into a calcium chloride solution for shaping, and a photothermal responsive curcumin sustained-release microgel is obtained. The microgel has excellent water content, compact microstructure, biocompatibility, blood compatibility and photothermal response function, and can be applied to precise and controllable drug loading.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, and relates to a photothermal responsive curcumin sustained-release microgel, its preparation method and application. Background Technology

[0002] Drug delivery systems are the core carriers for achieving precision disease treatment. Traditional drug delivery materials generally suffer from problems such as burst drug release, uncontrollable release behavior, short local action time, and insufficient biocompatibility, making it difficult to meet the clinical demand for precise spatiotemporal drug delivery. Curcumin, as a natural polyphenol active drug, has various pharmacological activities such as anti-inflammatory, antioxidant, and antitumor effects. However, it has poor water solubility, low in vivo stability, and rapid metabolism, resulting in extremely low bioavailability when administered alone. Therefore, it requires a suitable carrier to achieve stable loading and controlled release.

[0003] In recent years, natural polysaccharide-based hydrogels have become a research hotspot in the field of drug delivery due to their wide availability, excellent biocompatibility, and strong structural designability. Sodium alginate can be rapidly molded into microsphere carriers through ionic cross-linking, but its single system suffers from drawbacks such as weak mechanical properties, insufficient drug controlled-release capability, and lack of external response triggering mechanisms. Eggshell membrane, as a natural bio-derived material, can be combined with polysaccharide matrices to optimize the gel's microstructure and physicochemical properties, thereby improving carrier stability and drug loading efficiency. However, existing polysaccharide-based drug-loaded hydrogels still struggle to achieve precise external control of drug release rates and cannot dynamically adjust the drug delivery rhythm according to the treatment progress, limiting their application in the field of precision drug delivery.

[0004] Therefore, developing a novel carrier material that can efficiently load curcumin, achieve photothermal responsive controlled drug release, and exhibit excellent biocompatibility is of great clinical significance for overcoming the bottleneck of precise drug release regulation. Summary of the Invention

[0005] The purpose of this invention is to provide a photothermal responsive curcumin sustained-release microgel, its preparation method and application. The microgel has suitable water content and swelling properties, excellent biocompatibility and in vitro release characteristics of curcumin as expected, and can be applied to precise and controllable drug delivery.

[0006] In a first aspect, the present invention provides a method for preparing photothermal responsive curcumin sustained-release microgels, the method comprising the following steps:

[0007] S1. The eggshell membrane short fiber is soaked in a light-proof solution of dopamine, allowed to stand in the dark, and then centrifuged and washed to prepare dopamine-eggshell membrane short fiber.

[0008] S2. Mix the dopamine-eggshell membrane short fiber, curcumin and sodium alginate aqueous solution to obtain a mixture;

[0009] S3. The mixture is dropped into a calcium chloride solution to form a photothermal responsive curcumin sustained-release microgel.

[0010] In some embodiments of the present invention, the preparation method of dopamine aqueous solution is as follows: dopamine is dissolved in distilled water and stirred at room temperature in the dark until completely dissolved.

[0011] In some embodiments of the present invention, step S1 specifically involves: soaking eggshell membrane short fibers in a dopamine aqueous solution with a concentration of (0.3-0.5) mg / ml, letting it stand in the dark for 12-16 hours, centrifuging and washing three times to obtain dopamine-eggshell membrane short fibers.

[0012] In some embodiments of the present invention, the ratio of the eggshell membrane short fiber, dopamine, and water is (1-2) g: (15-40) mg: (50-80) ml.

[0013] In some embodiments of the present invention, the sodium alginate aqueous solution is prepared by dissolving sodium alginate in distilled water and stirring at room temperature until completely dissolved.

[0014] In some embodiments of the present invention, step S2 specifically involves: adding dopamine-eggshell membrane short fibers to an aqueous solution of sodium alginate, stirring continuously at room temperature until the dopamine-eggshell membrane short fibers are uniformly dispersed in the system, then adding curcumin and stirring until the curcumin is completely dissolved to obtain a mixture.

[0015] In some embodiments of the present invention, the ratio of sodium alginate, dopamine-eggshell membrane short fiber, curcumin, and water in the mixture is (0.5-0.1) g: (0.5-1) g: (0.05-0.1) g: 100 ml.

[0016] In some embodiments of the present invention, the mixture is added dropwise to the coagulation bath, specifically by using a syringe to uniformly add the mixture dropwise to the coagulation bath at a speed of (50-80) mm / h.

[0017] In some embodiments of the present invention, the coagulation bath is an aqueous solution of CaCl2. Preferably, it is an aqueous solution of CaCl2 with a mass fraction of 2%.

[0018] In some embodiments of the present invention, the settling time is 9 to 12 hours.

[0019] In a second aspect, the present invention provides a photothermal responsive curcumin sustained-release microgel prepared by the above-described preparation method.

[0020] In a third aspect, the present invention provides an application of the photothermally responsive curcumin sustained-release microgel prepared by the above-described preparation method in the preparation of a precise and controllable drug-loaded product.

[0021] In a fourth aspect, the present invention provides a medical material, characterized in that the medical material is obtained by freeze-drying the photothermal responsive curcumin sustained-release microgel as described in claim 7.

[0022] In some embodiments of the present invention, the application of photothermal responsive curcumin sustained-release microgel in the preparation of materials for precise and controllable drug delivery is as follows: by controlling the degree of calcium ion crosslinking and the microsphere molding process, the resulting microgel has a suitable water content and a compact microstructure. At the same time, local temperature rise is achieved through photothermal conversion, thereby triggering changes in the gel network structure and precisely controlling the drug release behavior.

[0023] Compared with the prior art, the present invention has the following technical effects:

[0024] (1) This invention uses a composite construction of eggshell membrane short fibers, sodium alginate and dopamine to endow the microgel drug delivery system with excellent near-infrared photothermal conversion performance. Under light irradiation, the local temperature can be controlled to rise, providing a non-invasive triggering method for precise external regulation of drug release, effectively solving the technical bottleneck of uncontrollable release behavior of traditional drug delivery materials.

[0025] (2) The microgel obtained by the present invention retains the excellent properties of natural polymers, and has excellent water content, dense microstructure and excellent biocompatibility. It has low overall cytotoxicity, can be well adapted to the in vivo drug delivery environment, avoids the safety hazards caused by synthetic materials, and significantly improves the clinical applicability of the drug delivery system.

[0026] (3) This invention realizes the photothermal controllable sustained release of curcumin. The release rate can be flexibly adjusted by light intensity and duration. It maintains long-term sustained release in the absence of light and triggers rapid release under light. It constructs a dual regulation mode that complements the "resting state and activated state", which can meet the precise drug delivery needs of different treatment stages and improve drug delivery efficiency. Attached Figure Description

[0027] To more clearly illustrate the technical solutions of the present invention, the accompanying drawings used in the description of the embodiments or prior art will be briefly introduced below. Obviously, the drawings described below are merely some embodiments of the present invention, and those skilled in the art can obtain other drawings based on these drawings without any creative effort.

[0028] Figure 1 This is a schematic diagram showing the comparison between the photothermal responsive curcumin sustained-release microgel prepared in Example 1 before and after freeze-drying.

[0029] Figure 2 This is a microscopic schematic diagram of the photothermal responsive curcumin sustained-release microgel prepared in Example 2 under an electron microscope;

[0030] Figure 3 This is a schematic diagram of the temperature change curve of the photothermal responsive curcumin sustained-release microgel prepared in Example 3 under near-infrared light irradiation. Detailed Implementation

[0031] The technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of this application.

[0032] In a first aspect, the present invention provides a method for preparing photothermal responsive curcumin sustained-release microgels, the method comprising the following steps:

[0033] S100. Soak eggshell membrane short fibers in a light-protected solution of dopamine for 12-16 hours in the dark to allow dopamine to self-polymerize and adhere to the surface of the eggshell membrane to form a uniform polydopamine functional layer. After centrifugation, wash three times to remove unadsorbed free dopamine and obtain dopamine-eggshell membrane short fibers with photothermal response function.

[0034] S200. Add dopamine-eggshell membrane short fibers to sodium alginate aqueous solution and stir continuously at room temperature until the dopamine-eggshell membrane short fibers are uniformly dispersed in the system. Then add curcumin and stir until curcumin is completely dissolved, so that it is uniformly dispersed in the pores of sodium alginate matrix and dopamine-eggshell membrane short fibers to obtain a uniform mixture, thereby achieving stable drug loading.

[0035] S300. Transfer the above mixture into a syringe, and use a uniform injection pump to drop the mixture into a calcium chloride solution. A dense gel network is formed by cross-linking calcium ions with sodium alginate. After standing to solidify, a photothermal responsive curcumin sustained-release microgel is obtained.

[0036] For example, in step S100, the mass-to-volume ratio of eggshell membrane short fiber, dopamine, and distilled water is (1-2) g: (15-40) mg: (50-80) ml.

[0037] For example, all stirring operations in step S100 are carried out under light-proof and room temperature conditions until dopamine is completely dissolved.

[0038] For example, in step S200, the mass-to-volume ratio of sodium alginate, dopamine-eggshell membrane short fiber, curcumin, and distilled water is (0.5-0.1) g: (0.5-1) g: (0.05-0.1) g: 100 mlg.

[0039] For example, all stirring operations in step S200 are carried out at room temperature until sodium alginate is completely dissolved, dopamine-eggshell membrane short fibers are evenly dispersed, and curcumin is completely dissolved.

[0040] For example, the syringe used in step S300 is 20 ml, the coagulation bath used for drop molding is a 2% CaCl2 aqueous solution, and the mixture is uniformly injected at a speed of (50-80) mm / h and then allowed to stand until the microspheres are fully cross-linked and cured.

[0041] For example, in step S3, after the mixed solution is added dropwise to the calcium chloride solution, it is allowed to stand for 9 to 12 hours to crosslink until the microspheres are fully solidified and formed, thus obtaining a spherical microgel.

[0042] To further illustrate the embodiments of this application, the following description, in conjunction with specific examples and accompanying drawings, provides further details. Figure 1 , Figure 2 This application provides a detailed description of the microgels for precise and controllable drug delivery and their preparation methods, based on embodiments of this application.

[0043] Eggshell membrane short fibers used in the preparation examples:

[0044] Waste eggshells were collected, soaked in water, and the eggshells and eggshell membranes were manually separated. The obtained eggshell membranes were washed clean with water to remove surface moisture, cut into small pieces, transferred to a mortar, and liquid nitrogen was added to completely immerse the sample. The sample was continuously ground while the liquid nitrogen was evaporating. The grinding operation was repeated three times. After drying, the sample was ground again to obtain short eggshell membrane fibers with uniform shape and small particle size.

[0045] Example 1

[0046] 1) Weigh 0.4 g of dopamine and dissolve it in 80 ml of water. Stir until completely dissolved in the dark at room temperature. Then add 0.6 g of eggshell membrane short fiber and let it stand in the dark at room temperature for 12 hours. Centrifuge and wash three times to obtain dopamine-eggshell membrane short fiber.

[0047] 2) Weigh 0.6 g of sodium alginate and dissolve it in 80 ml of water. Stir at room temperature until completely dissolved, then add 0.6 g of dopamine-eggshell membrane short fiber and stir at room temperature until the dopamine-eggshell membrane short fiber is evenly dispersed in the solution. Then weigh 0.08 g of curcumin and add it to the solution and stir until completely dissolved.

[0048] 3) Draw the mixture into a 20 ml syringe, and use a syringe pump to drip the solution into 60 ml of 2% CaCl2 solution at a constant speed of 50 mm / h. Let it stand for 10 hours until the microspheres are fully cross-linked and solidified to obtain the sample of Example 1.

[0049] To verify the water content of the photothermally responsive curcumin sustained-release microgel, a certain mass of the Example 1 sample was weighed, freeze-dried, and then weighed again. Based on the formula, the water content of the Example 1 sample was calculated to be 94.19% ± 0.0046%, which is considered to have good water content. A photograph of the Example 1 sample is shown below. Figure 1 As shown, Figure A is the freeze-dried sample of Example 1, and Figure B is the sample of Example 1 under normal temperature conditions.

[0050] Example 2

[0051] 1) Weigh 0.2 g of dopamine and dissolve it in 50 ml of water. Stir at room temperature in the dark until completely dissolved, then add 1 g of eggshell membrane short fiber. Let stand at room temperature in the dark for 15 hours, centrifuge and wash three times to obtain dopamine-eggshell membrane short fiber.

[0052] 2) Weigh 0.3 g of sodium alginate and dissolve it in 40 ml of water. Stir at room temperature until completely dissolved, then add 0.3 g of dopamine-eggshell membrane short fiber and stir at room temperature until the dopamine-eggshell membrane short fiber is evenly dispersed in the solution. Then weigh 0.04 g of curcumin and add it to the solution and stir until completely dissolved.

[0053] 3) Draw the mixture into a 20 ml syringe, and use a syringe pump to drip the solution into 100 ml of 2% CaCl2 solution at a constant speed of 60 mm / h. Let it stand for 9 hours until the microspheres are fully cross-linked and solidified to obtain the sample of Example 2.

[0054] To verify whether the microstructure of the photothermally responsive curcumin sustained-release microgel was dense, the sample from Example 2 was freeze-dried. The microstructure and surface morphology of the material were observed using scanning electron microscopy (FE-SEM), and photographs were taken. The results are as follows: Figure 2 Image A is an electron microscope image at 50x magnification; image B is an electron microscope image at 5000x magnification. This shows that the composite cross-linking of dopamine-eggshell membrane short fibers and sodium alginate can form a dense and regular microgel, which can not only ensure the stable embedding of drugs during the preparation process, but also achieve precise and controllable release of drugs through network relaxation under photothermal stimulation, providing a reliable structural guarantee for efficient drug loading and intelligent drug delivery.

[0055] Example 3

[0056] 1) Weigh 0.6 g of dopamine and dissolve it in 120 ml of water. Stir until completely dissolved in the dark at room temperature. Then add 0.9 g of eggshell membrane short fiber and let it stand in the dark at room temperature for 16 hours. Centrifuge and wash three times to obtain dopamine-eggshell membrane short fiber.

[0057] 1) Weigh 0.9 g of sodium alginate and dissolve it in 120 ml of water. Stir at room temperature until completely dissolved, then add 0.9 g of dopamine-eggshell membrane short fiber and stir at room temperature until the dopamine-eggshell membrane short fiber is evenly dispersed in the solution. Then weigh 0.12 g of curcumin and add it to the solution and stir until completely dissolved.

[0058] 2) Draw the mixture into a 20 ml syringe, and use a syringe pump to drip the solution into 100 ml of 2% CaCl2 solution at a constant speed of 80 mm / h. Let it stand for 12 hours until the microspheres are fully cross-linked and solidified to obtain the sample of Example 3.

[0059] To verify the photothermal conversion performance of the photothermally responsive curcumin sustained-release microgel, a certain mass of the Example 3 sample was weighed, freeze-dried, and then immersed in a centrifuge tube containing 10 ml of phosphate buffer. The Example 3 sample was continuously irradiated with an 808 nm near-infrared laser at a constant power density for 10 min, with data collected every 1 min to plot a temperature-time curve. Figure 3 The photothermal temperature change curves show that during 10 minutes of near-infrared irradiation, the temperature of the microgel sample group steadily and continuously increased with the extension of irradiation time, gradually rising from approximately 23.7℃ initially to approximately 34.2℃ after 10 minutes of irradiation, with a cumulative temperature rise of approximately 10.5℃. The rate of temperature rise slightly accelerated with the progress of irradiation, indicating that the microgel possesses excellent near-infrared photothermal conversion performance. Under near-infrared light irradiation, the dopamine component can efficiently convert light energy into heat energy, raising the local ambient temperature around the microspheres and triggering the relaxation of the dense microscopic network structure of the microgel. This provides a channel for the diffusion and release of curcumin molecules, thereby achieving photothermally triggered controlled drug release. This photothermal effect provides a non-invasive external control method for drug delivery systems, allowing for precise control of the local temperature rise through irradiation time and power, thereby achieving dynamic regulation of the curcumin release rate and meeting the precise drug delivery needs of different therapeutic scenarios.

[0060] The foregoing description has fully disclosed the specific embodiments of the present invention. It should be noted that any modifications made to the specific embodiments of the present invention by those skilled in the art do not depart from the scope of the claims. Accordingly, the scope of the claims is not limited to the foregoing specific embodiments.

Claims

1. A method for preparing a photothermally responsive curcumin sustained-release microgel, characterized in that, The preparation method includes the following steps: S1. The eggshell membrane short fiber is soaked in a dopamine aqueous solution, allowed to stand in the dark, and then centrifuged and washed to prepare dopamine-eggshell membrane short fiber; S2. Mix the dopamine-eggshell membrane short fiber, curcumin and sodium alginate aqueous solution to obtain a mixture; S3. The mixture is dropped into a calcium chloride solution and allowed to stand to solidify, resulting in a photothermal responsive curcumin sustained-release microgel.

2. The preparation method according to claim 1, characterized in that, Step S1 specifically involves immersing the eggshell membrane short fibers in a dopamine aqueous solution with a concentration of (0.3-0.5) mg / ml for 12-16 hours in the dark, centrifuging, and washing to obtain dopamine-eggshell membrane short fibers.

3. The preparation method according to claim 1, characterized in that, The ratio of the eggshell membrane short fiber to the dopamine aqueous solution is (1-2) g: (50-80) ml.

4. The preparation method according to claim 1, characterized in that, In the mixture, the ratio of sodium alginate, dopamine-eggshell membrane short fiber, curcumin, and water is (0.5-0.1) g: (0.5-1) g: (0.05-0.1) g: 100 ml.

5. The preparation method according to claim 1, characterized in that, In step S3, the step of adding the mixture dropwise to the calcium chloride solution specifically involves: The mixture was added dropwise to the calcium chloride solution at a rate of (50-80) mm / h using a syringe.

6. The preparation method according to claim 1, characterized in that, In step S3, the settling time is 9–12 hours.

7. The photothermal responsive curcumin sustained-release microgel prepared by the preparation method according to any one of claims 1-6.

8. The application of the photothermal responsive curcumin sustained-release microgel as described in claim 7 in the preparation of a precise and controllable drug-loaded product.

9. A medical material, characterized in that, The medical material is obtained by freeze-drying the photothermal responsive curcumin sustained-release microgel as described in claim 7.

Images