Composite hydrogel optical fiber with light-controlled drug release function and preparation method and application thereof

Abstract

This invention belongs to the field of biomedical materials technology, specifically disclosing a composite hydrogel optical fiber with photocontrolled drug release function, its preparation method, and its applications. The preparation method includes the following steps: preparing a hydrogel optical fiber substrate; preparing a lipid nanoparticle dispersion loaded with a photosensitizer; mixing the dispersion with a thiol-polyethylene glycol-thiol precursor solution and a polyethylene glycol precursor solution capped with a four-arm maleimide containing a photoinitiator, respectively, to obtain a first precursor mixture and a second precursor mixture; mixing the mixture in situ at the end of the hydrogel optical fiber substrate and allowing it to stand to obtain a photoresponsive drug delivery composite hydrogel optical fiber. This composite hydrogel optical fiber achieves effective transmission of light signals in situ within the tumor and controllable release and activation of the photosensitizer locally within the tumor, exhibiting good spatiotemporal controllability, biosafety, and application scalability. It can be used for local drug delivery, photomediated therapy, and other precise spatiotemporal controllable biomedical optical applications.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, specifically relating to composite hydrogel optical fibers with light-controlled drug release function, their preparation methods, and applications. Background Technology

[0002] Many disease states (including but not limited to tumor-related lesions, deep tissue damage, local inflammatory responses, and abnormal microenvironments) require precise treatments that are localized, controllable, and have low systemic toxicity. For complex diseases, such as malignant tumors, innovation in treatment methods has always been a crucial research direction in the biomedical field. While commonly used clinical methods such as surgery, radiotherapy, and systemic chemotherapy are widely applied, they generally suffer from high invasiveness, significant systemic toxicity, and insufficient local selectivity. These methods can easily cause irreversible damage to normal tissues and are difficult to implement for precise, minimally invasive interventions targeting deep or occult lesions.

[0003] In recent years, phototherapy technologies (including photodynamic therapy, photothermal therapy, and photoimmunomodulation) have gradually become an important research direction for local disease treatment and biomodulation due to their excellent spatiotemporal controllability, minimal invasiveness, and repeatability. These technologies typically activate functional molecules or materials using specific wavelengths of light, inducing local photochemical, photothermal, or other photoresponsive effects, thereby achieving precise regulation of biological processes. However, existing phototherapy systems still face the following key challenges in practical applications: First, the stable delivery and controllable release of phototherapy agents in the target area are limited, easily affected by the complex internal environment, leading to premature diffusion, inactivation, or uneven distribution, making it difficult to maintain effective local concentrations. Second, biological tissues exhibit significant absorption and scattering of light, limiting the effective transmission of external light sources in deep tissues, resulting in insufficient activation of photoresponsive functions in deep regions.

[0004] To address the aforementioned challenges, hydrogel materials, due to their excellent biocompatibility, water content, and tunable network structure, are widely used in local drug delivery and tissue engineering. However, traditional hydrogel delivery systems generally lack optical signal transmission capabilities, and their drug release process is difficult to precisely control in time and space. Hydrogel optical fibers with optical waveguide properties offer a new solution for optical transmission in deep tissues, enabling low-loss transmission of external optical signals to the target area. However, current research on hydrogel optical fibers largely focuses on single optical transmission functions, lacking effective integration with photoresponsive drug delivery systems and functional therapeutic units. This hinders the synergistic control between "optical transmission—optically controlled release—optically responsive activation," thus limiting their application in precision medicine and biomedical optics. Summary of the Invention

[0005] This invention aims to provide a composite hydrogel fiber with photocontrolled drug release function, its preparation method and application. The composite hydrogel fiber system can realize high spatiotemporal precision photocontrolled drug release and photoactivated therapy in local tissues / lesions, exhibiting good spatiotemporal controllability, biosafety and application scalability. It can be used in local drug delivery, photomediated therapy and other precise spatiotemporal controllable biomedical optical applications.

[0006] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows: Composite hydrogel optical fibers with photocontrolled drug release function include: A hydrogel optical fiber body, wherein the hydrogel optical fiber body has a core and a cladding structure; A photoresponsive functional structure is disposed at the end of the hydrogel optical fiber body. The photoresponsive functional structure is a hydrogel that can undergo a change from a gel state to a sol state under illumination of a specific wavelength of light. The nanophototherapy agent, loaded in the photoresponsive functional structure, can be activated under light irradiation and generate reactive oxygen species or photochemical responses.

[0007] This invention also provides a method for preparing a composite hydrogel optical fiber with photocontrolled drug release function, comprising the following steps: S1. Prepare the hydrogel optical fiber substrate; S2. Prepare a lipid nanoparticle dispersion loaded with photosensitizer; S3. The lipid nanoparticle dispersion obtained in S2 is mixed with a thiol-polyethylene glycol-thiol precursor solution and a polyethylene glycol precursor solution with four-arm maleimide end-capped containing a photoinitiator, respectively, to obtain a first precursor mixture and a second precursor mixture. S4. The first precursor mixture and the second precursor mixture obtained in S3 are mixed in situ at the end of the hydrogel fiber body obtained in S1, and left to stand to obtain a composite hydrogel fiber with light-controlled drug release function.

[0008] Preferably, in step S1, the preparation of the hydrogel optical fiber body specifically includes the following steps: S11. Preparation of hydrogel fiber core: The hydrogel precursor solution is injected into a tubular mold and gelled through enzymatic cross-linking, physical gelation or chemical cross-linking reaction to form a hydrogel fiber core. S12. Preparation of hydrogel optical fiber body: The hydrogel optical fiber core is sequentially immersed in a solution containing crosslinkable polysaccharides and a solution of divalent or polyvalent metal ions to obtain a cladding structure uniformly attached to the surface of the core. S13. After washing with deionized water, the hydrogel optical fiber body is obtained.

[0009] Preferably, in S11, the hydrogel precursor solution is any one of silk fibroin, hyaluronic acid, gelatin, polyvinyl alcohol, polyacrylamide, polyacrylic acid, polyethylene glycol, sulfobetaine polymers, carboxybetaine polymers, or their composite hydrogels, and the hydrogel precursor solution is formed by enzymatic crosslinking, freeze-thaw cycle physical gelation, or light / thermal triggered chemical crosslinking.

[0010] Preferably, the hydrogel precursor solution is silk fibroin hydrogel with a mass fraction of 5%-20%; the preparation of the hydrogel optical fiber core specifically involves: adding horseradish peroxidase and hydrogen peroxide to a final concentration of 0.05-0.2 mg / mL in an aqueous solution of silk fibroin, and carrying out an enzymatic cross-linking reaction at 25°C for 0.5-2 h, followed by dehydration by soaking in 20-60% ethanol for 5-20 min.

[0011] Preferably, in S12, the cross-linkable polysaccharide includes alginate and carboxymethyl cellulose, and the divalent or polyvalent metal ion solution includes calcium chloride solution; the silk fibroin hydrogel core is immersed in a 1-2% sodium alginate solution for 1-3 seconds, then dried for 3-5 minutes, and then immersed in a 0.1M calcium chloride solution for 0.5-2 minutes.

[0012] Preferably, in step S2, the preparation of the lipid nanoparticle dispersion loaded with the photosensitizer includes the following steps: S21. Dissolve the lipid component and the hydrophobic photosensitizer in an organic solvent at a mass ratio of 0.8-40:1 to obtain an organic phase solution; S22. The organic phase solution obtained in S21 is injected into the aqueous phase solution to obtain a lipid nanoparticle dispersion loaded with photosensitizer.

[0013] Preferably, in S21, the lipid component is composed of phospholipids, cholesterol, or their derivatives; the hydrophobic photosensitizer includes porphyrin compounds, phthalocyanine compounds, organic dye molecules, or their derivatives.

[0014] Preferably, the composite hydrogel optical fiber with photocontrolled drug release function can further regulate the photoresponsive functional structure under light stimulation by changing the light exposure time and light intensity, thereby activating the nano-phototherapy agent and generating reactive oxygen species or photochemical responses.

[0015] The present invention also provides the application of composite hydrogel optical fibers with photocontrolled drug release function in the preparation of medical devices for local drug delivery, photomediated therapy or in situ photodynamic therapy of tumors.

[0016] Compared with the prior art, the present invention has the following advantages and technical effects: (1) The present invention constructs a composite hydrogel fiber that integrates optical signal transmission, optical response structure regulation and nano-functional delivery, realizing the synergistic regulation between optical transmission, optical control release and optical response function activation, and improving the spatiotemporal controllability of the local optical response process.

[0017] (2) The present invention uses hydrogel optical fiber with core-cladding structure as a flexible optical waveguide system, which can transmit external optical signals to the target area with low loss, thereby improving the light utilization efficiency and photoresponse activation capability in deep tissues.

[0018] (3) The present invention introduces a photoresponsive functional structure in a local area of ​​hydrogel optical fiber, which can induce changes in the hydrogel network structure under specific light stimulation conditions, realize the in-situ controllable release of drugs or functional molecules, and improve the accuracy and safety of local delivery.

[0019] (4) This invention achieves spatiotemporal coupling between the local release of functional molecules and the photo-response activation process through a time-sequential photomodulation method, which can effectively improve the precision and controllability of local treatment or biological regulation process.

[0020] (5) The nano-phototherapy agent in this invention can realize photodynamic, photothermal or multi-mode photoresponse functions according to application requirements, and can work synergistically with the photoresponsive hydrogel system to improve the local photoresponsive therapy or biological regulation effect.

[0021] (6) The composite hydrogel fiber system constructed in this invention has good biocompatibility, tissue adaptability and material compatibility, and can be applied to local drug delivery, photoresponsive therapy, tissue microenvironment regulation and other biomedical optical application scenarios that require precise spatiotemporal control.

[0022] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0023] Figure 1 Examples 1 show the physical image of the hydrogel optical fiber and a statistical diagram of its dimensions. Figure 1 In the image, 'a' represents a physical image of a hydrogel optical fiber; the scale bar is 5 mm. Figure 1 In the image, b is a hydrogel fiber optic micrograph with a scale bar of 200 μm. Figure 1 In the graph, 'c' represents the fiber size statistics. Figure 2 This is a comparison diagram of the hydrogel optical fiber body of Example 1 and the bare silk fibroin fiber of Comparative Example 1. Figure 2 In this context, 'a' represents the optical signal transmission result. Figure 2 In the figure, b represents the optical transmission results of Example 1 under different bending angles; Figure 3The image shows the optical loss test results of the hydrogel optical fiber body in Example 1. Figure 4 The graph shows the comparison of the mechanical properties of silk fibroin hydrogel fibers treated with alcohol dehydration in Example 1 and silk fibroin hydrogel fibers not treated with alcohol in Comparative Example 2. Figure 5 The figure shows the physicochemical characterization results of the lipid nanoparticle dispersion (LNP-Ce6) prepared in Example 2. Figure 5 In the diagram, 'a' represents the particle size distribution. Figure 5 In the diagram, b represents the potential diagram. Figure 5 In the figure, 'c' represents the stability statistics of different solvents over 7 days. Figure 6 This is a flowchart illustrating the fabrication process of the photoresponsive drug delivery composite hydrogel fiber in Example 3. Figure 7 The results are from biocompatibility testing, among which... Figure 7 In this context, 'a' represents the viability of CCK-8 cells. Figure 7 b represents cell viability staining in 48h extract culture, with a scale bar of 200μm. Figure 8 This is a schematic diagram of the formation and degradation process of UV-responsive hydrogels. Figure 9 The light micrographs of the hydrogel degradation process prepared for the verification example are shown in the image. The scale bar is 200 μm. Figure 9 In the diagram, 'a' represents the light microscope image without ultraviolet light. Figure 9 In the image, b is the optical micrograph of ultraviolet light guided by an optical fiber for 10 minutes. Figure 9 In the image, 'c' represents the optical micrograph of ultraviolet light guided by an optical fiber for 20 minutes. Figure 9 In the middle d, it is the optical micrograph of ultraviolet light guided by optical fiber for 20 min (with gentle blowing with a dropper), with a scale bar of 200 μm; Figure 10 The LNP-Ce6 release characteristic is triggered by photo-controlled degradation, in which, Figure 10 In the figure, 'a' represents the release kinetic curve. Figure 10 In this context, b represents the particle size of the nanoparticles before and after release. Figure 11 For the effects of photodynamic therapy, among which, Figure 11 In the figure, 'a' represents the CCK-8 cell viability statistics. Figure 11 b in the image represents the cell viability staining results after treatment with 10 μg / mL Ce6, with a scale bar of 50 μm. Figure 12 This is a schematic diagram of light-controlled degradation drug release. Figure 13 For the effectiveness of tumor treatment, among which, Figure 13 In this context, 'a' represents the change in mouse body weight after treatment. Figure 13In this context, 'b' represents the relative size of the tumor volume in the tumor-bearing mouse after treatment. Figure 14 This is a statistical diagram of the main fiber dimensions of the hydrogel optical fiber in Example 4, wherein... Figure 14 In the image, 'a' represents a hydrogel fiber optic microscope image with a scale bar of 200 μm. Figure 14 In the graph, b represents the statistical data of fiber diameter. Figure 15 The light guiding effect of the hydrogel optical fiber body in Example 4 under different bending angles is shown below. Figure 15 The light guiding effect when 'a' is 0 degrees. Figure 15 The light guiding effect when b is 30 degrees. Figure 15 The light guiding effect when c is at 45 degrees. Figure 15 The light guiding effect when d is 90 degrees. Figure 15 The light guiding effect when e is at 180 degrees. Figure 15 The middle f represents the light-guiding effect during knotting; Figure 16 The image shows the optical loss test results of the hydrogel optical fiber body in Example 4. Detailed Implementation

[0024] The technical solution of the present invention will be further described below with reference to the accompanying drawings and embodiments.

[0025] Unless otherwise defined, the technical or scientific terms used in this invention shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention pertains.

[0026] Source of experimental materials: In this invention, unless otherwise specified, all other test materials and instruments are conventional test materials in the field and can be purchased through commercial channels.

[0027] Example 1 The hydrogel optical fiber body is prepared by the following steps: S11. After degumming natural silk, it is dissolved in 9.3M lithium bromide solvent, filtered, and the insoluble matter is discarded. The solvent is replaced by ultrafiltration to obtain an aqueous solution of silk fibroin. The specific preparation method of the aqueous solution of silk fibroin includes the following steps: Silkworm cocoons were boiled in sodium carbonate solution (0.05M) for 30 minutes to remove sericin. The degumming process was repeated twice. The degummed silk fibroin was repeatedly washed with a large amount of deionized water and dried at room temperature. The dried silk fibroin was dissolved in 9.3M lithium bromide solution and stirred at 60℃ for 4 hours to obtain a homogeneous and clear silk fibroin solution.

[0028] First, the obtained silk fibroin solution was filtered through a 300-mesh filter, then centrifuged at 9000 rpm for 20 min, repeated twice to remove insoluble impurities. Subsequently, it was dialyzed for 3 days at 4°C using a dialysis bag with a molecular weight cutoff of 10 kDa to remove lithium bromide, yielding an aqueous silk fibroin solution. Finally, the solution was concentrated to different mass fractions by ultrafiltration with a molecular weight cutoff of 10 kDa and stored at 4°C for later use.

[0029] Adjust the silk fibroin solution to 10% by mass, add horseradish peroxidase to a final concentration of 0.1 mg / mL, and then add hydrogen peroxide to a final concentration of 7 mM to obtain the prepolymer solution. S12. The prepolymer obtained in S11 is injected into a tubular mold with an inner diameter of 800 μm and crosslinked at 25°C for 1.5 h. Then, the silk fibroin hydrogel is pushed out of the mold using a syringe with water. Finally, it is soaked in 40% ethanol for 10 min and washed with deionized water to obtain silk fibroin hydrogel fibers. S13. Immerse the silk fibroin hydrogel fiber obtained in S12 in a 2% sodium alginate solution for 1 second, remove it and dry it for 3 minutes, then immerse it in a 0.1M calcium chloride solution for 1 minute, wash it with deionized water, and obtain the hydrogel optical fiber body.

[0030] Actual product images and fiber size statistics charts, such as Figure 1 As shown.

[0031] Depend on Figure 1 It can be seen that the prepared hydrogel optical waveguide fiber is soft and transparent, with a core-cladding structure. The fiber core diameter is about 812.21 μm, and the overall fiber diameter is 978.79 μm, which meets the requirements of practical applications.

[0032] Comparative Example 1 The preparation method of naked silk fibroin fiber includes the following steps: S11. After degumming, natural silk is dissolved in 9.3M lithium bromide solvent, filtered, and the insoluble matter is discarded. The lithium bromide is removed by dialysis to obtain an aqueous solution of silk fibroin. The specific preparation method of the aqueous solution of silk fibroin includes the following steps: Silkworm cocoons were boiled in sodium carbonate solution (0.05M) for 30 minutes to remove sericin. The degumming process was repeated twice. The degummed silk fibroin was repeatedly washed with a large amount of deionized water and dried at room temperature. The dried silk fibroin was dissolved in 9.3M lithium bromide solution and stirred at 60℃ for 4 hours to obtain a homogeneous and clear silk fibroin solution.

[0033] First, the obtained silk fibroin solution was filtered through a 300-mesh filter, then centrifuged at 9000 rpm for 20 min, repeated twice to remove insoluble impurities. Subsequently, it was dialyzed for 3 days at 4°C using a dialysis bag with a molecular weight cutoff of 10 kDa to remove lithium bromide, yielding an aqueous silk fibroin solution. Finally, it was concentrated to different mass fractions by ultrafiltration with a molecular weight cutoff of 10 kDa and stored at 4°C for later use.

[0034] Adjust the silk fibroin solution to 10% by mass, add horseradish peroxidase to a final concentration of 0.1 mg / mL, and then add hydrogen peroxide to a final concentration of 7 mM to obtain the prepolymer solution. S12. The prepolymer obtained in S11 is injected into a tubular mold with an inner diameter of 800 μm and crosslinked at 25°C for 1.5 h. Then, the silk fibroin hydrogel is pushed out of the mold using a syringe with water. Finally, it is soaked in 40% ethanol for 10 min and washed with deionized water to obtain naked silk fibroin fibers.

[0035] Comparative Example 2 The preparation method of un-alcohol-dehydrated silk fibroin hydrogel fibers includes the following steps: S11. After degumming natural silk, it is dissolved in 9.3M lithium bromide solvent, filtered, and the insoluble matter is discarded. The solvent is replaced by ultrafiltration to obtain an aqueous solution of silk fibroin. The specific preparation method of the aqueous solution of silk fibroin includes the following steps: Silkworm cocoons were boiled in sodium carbonate solution (0.05M) for 30 minutes to remove sericin. The degumming process was repeated twice. The degummed silk fibroin was repeatedly washed with a large amount of deionized water and dried at room temperature. The dried silk fibroin was dissolved in 9.3M lithium bromide solution and stirred at 60℃ for 4 hours to obtain a homogeneous and clear silk fibroin solution.

[0036] First, the obtained silk fibroin solution was filtered through a 300-mesh filter, then centrifuged at 9000 rpm for 20 min, repeated twice to remove insoluble impurities. Subsequently, it was dialyzed for 3 days at 4°C using a dialysis bag with a molecular weight cutoff of 10 kDa to remove lithium bromide, yielding an aqueous silk fibroin solution. Finally, the solution was concentrated to different mass fractions by ultrafiltration with a molecular weight cutoff of 10 kDa and stored at 4°C for later use.

[0037] Adjust the silk fibroin solution to 10% by mass, add horseradish peroxidase to a final concentration of 0.1 mg / mL, and then add hydrogen peroxide to a final concentration of 7 mM to obtain the prepolymer solution. S12. The prepolymer obtained in S11 is injected into a tubular mold with an inner diameter of 800 μm and crosslinked at 25°C for 1.5 h. Then, the silk fibroin hydrogel is pushed out of the mold with a syringe containing water and washed with deionized water to obtain un-alcohol-dehydrated silk fibroin hydrogel fibers.

[0038] The hydrogel optical fiber body prepared in Example 1 and the bare silk fibroin fiber prepared in Comparative Example 1 were respectively connected to bare silica fiber to conduct light in three wavelength bands: 450, 530, and 660 nm. The results are as follows: Figure 2 As shown.

[0039] Depend on Figure 2 It can be seen that, compared with the bare silk fibroin fiber of Comparative Example 1, the hydrogel optical fiber body of Example 1 can more effectively restrict the propagation of light within the fiber, reduce light leakage and scattering, and enable the optical signal to be transmitted over a longer distance, as shown in the figure. Figure 2 (a) in the middle.

[0040] The light-guiding effect of fibers bent at different angles (30 degrees, 60 degrees, 90 degrees, 180 degrees, and knotted, from left to right) was demonstrated. It was found that the optical signal could be stably transmitted along the fiber core at all bending angles. This result indicates that the hydrogel optical fiber body constructed in Example 1 still possesses good light-guiding performance under bending operations, and can meet the light transmission requirements of photodynamic therapy in complex in vivo environments. Figure 2 (b) in the middle.

[0041] Optical loss tests were conducted on the hydrogel fiber substrate of Example 1 at 450, 530, and 660 nm (the specific experimental protocol is referenced from CHOI M et al. (2015)). The results are as follows: Figure 3 As shown.

[0042] Depend on Figure 3 The measured optical losses were 0.81, 0.60, and 0.52 dB / cm, respectively. The optical loss gradually decreased with increasing wavelength because the material has strong absorption and scattering of short-wavelength light. The low optical loss indicates that light can be stably transmitted along the fiber core. 660nm light, as a commonly used excitation wavelength for photodynamic therapy, has the lowest loss, ensuring sufficient light energy is delivered to the lesion site, thus achieving a highly effective treatment.

[0043] The mechanical properties (Young's modulus) of the silk fibroin hydrogel fibers prepared in Example 1 and the un-alcohol-dehydrated silk fibroin hydrogel fibers prepared in Comparative Example 2 were tested. The results are as follows: Figure 4As shown, compared with the silk fibroin hydrogel fiber prepared in Comparative Example 2 (without alcohol dehydration), the Young's modulus of the silk fibroin hydrogel fiber in Example 1 increased to 7.11 times. The Young's modulus of the silk fibroin hydrogel in Example 1 reached approximately 440.24 kPa, indicating that ethanol treatment can significantly enhance its structural stability. Since the Young's modulus of hydrogel optical fibers implanted into target tissues is typically in the kPa range, the requirements for implantation materials are mainly to maintain structural integrity and good mechanical compatibility, rather than high strength load-bearing capacity. Therefore, the silk fibroin hydrogel at a mechanical level of 440.24 kPa can maintain the stability of the optical fiber structure while ensuring flexible implantation adaptability, thus meeting its light-guiding function requirements.

[0044] Example 2 The preparation of a lipid nanoparticle dispersion loaded with a photosensitizer includes the following steps: S21. Lipid nanoparticles (LNP) were dissolved in anhydrous ethanol, and then 5.5 mg of dihydroporphyrin e6 (Ce6) was added to obtain an organic phase solution. The LNP consisted of 6.2849 mg of ionizable lipid SM102 (molar ratio of 50%), 1.39855 mg of phospholipid DSPC (molar ratio of 10%), 2.63485 mg of cholesterol Cholesterol (molar ratio of 38.5%), and 0.661 mg of PEG2000 (molar ratio of 1.5%), dissolved in 1 mL of anhydrous ethanol to prepare a solution with a total concentration of 17.7 mM.

[0045] S22. Inject 1 mL of the organic phase solution obtained in S21 into 3 mL of PBS solution (phosphate buffer solution) to obtain a lipid nanoparticle dispersion loaded with photosensitizer (LNP-Ce6).

[0046] The physicochemical properties of LNP-Ce6 prepared in Example 2 were characterized using the following experimental procedures: 5 μL of LNP-Ce6 solution was added to 1 mL of PBS solution for particle size determination; Ce6, LNP, and LNP-Ce6 were added to 5 mM Hepes solution at pH 7 for potential measurement; 5 μL of LNP-Ce6 was added to 1 mL of PBS, H2O, and DMEM (Dürbeco modified Eagle medium), respectively, and incubated for 7 days, with particle size measured daily to assess the stability of the nanoparticles. The results are as follows: Figure 5 As shown.

[0047] Depend on Figure 5The prepared nanoparticles have a diameter of 178.74 nm and exhibit good particle size distribution. The potential of Ce6 is -38.57 mV, that of LNP is 3.81 mV, and that of LNP-Ce6 is -10.37 mV. After coating Ce6, the potential of Ce6 decreases significantly, which can indicate the success of the coating to some extent. The particle size of LNP-Ce6 nanoparticles remains almost unchanged in different solvents over 7 days, indicating that the nanoparticles have a certain degree of stability.

[0048] Example 3 The process flow diagram for preparing composite hydrogel optical fibers with photocontrolled drug release function is as follows: Figure 6 As shown, the specific steps include the following: (1) Dissolve 8.3 mg of mercapto-polyethylene glycol-mercapto (HS-PEG-SH-2K(Mn≈2000)) in 0.25 mL of PBS solution to prepare a mercapto-polyethylene glycol-mercapto precursor solution; dissolve 41.7 mg of four-arm maleimide-terminated polyethylene glycol (4-arm PEG-MAL-20K(Mn≈20,000)) in 0.25 mL of PBS solution, add 5 mg of photoinitiator LAP, and mix to obtain a four-arm maleimide-terminated polyethylene glycol precursor solution containing photoinitiator. (2) The 0.25 mL lipid nanoparticle dispersion (LNP-Ce6) obtained in Example 2 was mixed with 0.25 mL mercapto-polyethylene glycol-mercapto precursor solution and 0.25 mL of polyethylene glycol precursor solution with four-arm maleimide end capping containing photoinitiator to obtain the first precursor mixture and the second precursor mixture, respectively. (3) Take the first precursor mixture and the second precursor mixture obtained above at a volume ratio of 1:1 and mix them in situ at the end of the hydrogel fiber body obtained in Example 1. Let it stand at room temperature for 20 minutes to obtain a composite hydrogel fiber with light-controlled drug release function.

[0049] Silk fibroin, calcium alginate, and photo-controlled degradation block hydrogels were prepared separately, and the specific preparation methods are as follows: Silk fibroin hydrogel: The preparation method is the same as in Example 1, except that in S12, a cylindrical mold with a diameter of 1 cm and a height of 7 mm is used to prepare the silk fibroin hydrogel.

[0050] Calcium alginate hydrogel: Using 1 mL of EDTA-Ca (calcium sodium ethylenediaminetetraacetate) as a solvent, add 200 mg of sodium alginate powder, shake thoroughly, and then place in a 37°C oven to dissolve the sodium alginate. Place in a 4°C refrigerator for 12 hours to remove air bubbles, thus obtaining the prepolymer solution. Place the prepared prepolymer solution in a cylindrical mold with a diameter of 1 cm and a height of 7 mm, add 10 μL of glacial acetic acid, let stand for 2 hours, and wash with deionized water to remove excess calcium ions and glacial acetic acid, obtaining a homogeneous calcium alginate hydrogel.

[0051] Photodegradable hydrogel: 8.3 mg of thiol-polyethylene glycol-thiol (HS-PEG-SH-2K (Mn ≈ 2000)) was dissolved in 0.5 mL of PBS solution to prepare a thiol-polyethylene glycol-thiol precursor solution; 41.7 mg of four-arm maleimide-terminated polyethylene glycol (4-arm PEG-MAL-20K (Mn ≈ 20,000)) was dissolved in 0.5 mL of PBS solution, and 5 mg of photoinitiator LAP was added to obtain a four-arm maleimide-terminated polyethylene glycol precursor solution containing photoinitiator. The two were mixed at a volume ratio of 1:1 in a cylindrical mold with a diameter of 1 cm and a height of 7 mm to obtain a photodegradable hydrogel.

[0052] The hydrogels prepared above were extracted in DMEM high-glucose medium for different times (12, 24, 48 h) to obtain extracts containing hydrogel degradation products. The concentration of the extracts was 0.2 g / mL.

[0053] The extracts from the different sources were used to culture mouse embryonic fibroblast 3T3 cells. The cells were cultured at 37°C and 5% carbon dioxide for 24 hours without direct contact with the hydrogel, and the growth status of the cells was then observed.

[0054] The biosafety of cells under different treatment conditions was assessed by cell viability assay and cell viability staining, thereby verifying the safety of the composite hydrogel optical fiber in biological systems. The results are as follows: Figure 7 As shown.

[0055] Depend on Figure 7 It can be seen that the viability of CCK-8 cells (where CCK is cholecystokinin) was close to 100% after different extraction times with the three hydrogels, and the cell viability staining results after 48 hours of extraction showed that the cell viability was not significantly affected by the hydrogel, indicating that the selected hydrogel material has good biocompatibility.

[0056] Verification Example (1) Dissolve 8.3 mg of mercapto-polyethylene glycol-mercapto (HS-PEG-SH-2K(Mn≈2000)) in 0.25 mL of PBS solution to prepare a mercapto-polyethylene glycol-mercapto precursor solution; dissolve 41.7 mg of four-arm maleimide-terminated polyethylene glycol (4-arm PEG-MAL-20K(Mn≈20,000)) in 0.25 mL of PBS solution, add 5 mg of photoinitiator LAP, and mix to obtain a four-arm maleimide-terminated polyethylene glycol precursor solution containing photoinitiator. (2) Mix 0.25 mL of PBS solution with 0.25 mL of mercapto-polyethylene glycol-mercapto precursor solution and 0.25 mL of polyethylene glycol precursor solution with four-arm maleimide end capped with photoinitiator to obtain the first precursor mixture and the second precursor mixture, respectively.

[0057] First, the effect of the hydrogel on UV-responsive degradation was verified. 0.5 mL of the first precursor mixture and 0.5 mL of the second precursor mixture obtained above were placed in a glass bottle at a volume ratio of 1:1, mixed at room temperature and allowed to stand for 20 min.

[0058] like Figure 8 As shown, the two rapidly undergo covalent cross-linking via a specific thiol-alkene click reaction, forming a transparent hydrogel with a stable three-dimensional network structure. When the prepared gel is irradiated with ultraviolet (UV) light, the hydrogel transforms from its original rigid columnar structure into a soft, flowable state, indicating that its network structure has been effectively disrupted. This is because, under UV excitation, the free radicals generated by the photoinitiator attack the thioether bonds (CS bonds) in the hydrogel, causing the cross-linking points to break. This leads to irreversible breakage and recombination of the originally stable Michael addition cross-linked structure, resulting in the material degrading from a gel state to a sol state.

[0059] Subsequently, the 0.5 mL first precursor mixture and 0.5 mL second precursor mixture obtained above were mixed in situ at the end of the hydrogel fiber body described in Example 1 at a volume ratio of 1:1, and allowed to stand at room temperature for 20 min to obtain a composite hydrogel fiber.

[0060] The ultraviolet light response test was conducted, and the results were as follows: Figure 9 As shown, without UV irradiation, the hydrogel exhibits a regular block shape and a complete network structure. With increasing UV irradiation time, the hydrogel edges gradually become blurred and swelling occurs, indicating that the gel network is breaking down and the structure is becoming loose. This demonstrates that the gel is structurally stable without light irradiation, but can undergo controlled localized degradation under light conditions.

[0061] The experimental method for verifying the feasibility of the photoresponsive drug delivery hydrogel provided in Example 3, which is used to evaluate the effects of the photoresponsive drug delivery hydrogel and its release products on cells, is as follows: 1. The photoresponsive drug delivery hydrogel is placed in an in vitro environment, and under cell-free conditions, it is irradiated with ultraviolet light to induce degradation or disruption of the hydrogel's network structure, thereby releasing LNP-Ce6. For example... Figure 10 As shown.

[0062] Depend on Figure 10 It can be seen that under ultraviolet light irradiation, the drug is rapidly released within the first two minutes and reaches its maximum value at 15 minutes, and the particle size of the nanoparticles remains almost unchanged before and after release.

[0063] 2. The hydrogel treated with ultraviolet light was placed in DMEM high sugar medium for extraction to obtain an extract containing hydrogel degradation products and releases.

[0064] 3. The extract was used to culture C6 glioma cells. The cells were cultured at 37°C and 5% carbon dioxide for 24 hours without direct contact with the hydrogel and without light exposure, in order to evaluate the effects of hydrogel degradation products and releases on cell growth.

[0065] After 24 hours, the culture medium was removed and washed once with PBS, then fresh culture medium was added, and red light was applied at 20 mW / cm². 2 The feasibility of photodynamic therapy after 2 minutes of light exposure, followed by 20 hours of culture, for CCK-8 cell viability testing and cell viability staining for controlled drug release was investigated. Results are as follows... Figure 10 As shown.

[0066] Depend on Figure 11 It was found that photodynamic therapy with different concentrations of LNP-Ce6 (based on Ce6 concentration) resulted in decreased cell viability in tumor cells, with higher concentrations showing better efficacy. Cell viability staining and light microscopy at a concentration of 10 μg / ml further demonstrated the good therapeutic effect of photodynamic therapy, indicating that photoresponsive drug delivery is feasible.

[0067] The composite hydrogel optical fiber with photocontrolled drug release function prepared in Example 3 was used to achieve photodynamic therapy of tumors. The specific experimental protocol is as follows: 1. A photoresponsive drug delivery composite hydrogel fiber was placed under the armpit of the forelimb of a tumor-bearing mouse to be treated, so that the photoresponsive degradation controlled-release hydrogel coated at the front end of the fiber could directly contact the tumor tissue.

[0068] 2. By introducing 360nm ultraviolet light through a composite hydrogel optical fiber, the photoresponsive degradation controlled-release hydrogel at the front end of the optical fiber is induced to degrade or change its network structure, thereby enabling the photosensitizer loaded therein to be released in situ at the tumor site.

[0069] 3. After the photosensitizer release reaches the predetermined release level, 660nm red light is introduced through a composite hydrogel optical fiber to irradiate the tumor area, activating the photosensitizer released into the tumor tissue, causing it to generate reactive oxygen species or other photodynamic effects, which kill tumor cells.

[0070] 4. During treatment, the release process of the photosensitizer and the effect of photodynamic therapy can be controlled by adjusting the light exposure time and intensity. A schematic diagram of light-controlled degradation and drug release is shown below. Figure 12 As shown.

[0071] 5. After treatment, the efficacy of the composite hydrogel fiber-mediated photodynamic therapy can be evaluated using methods such as tumor volume changes, cell viability detection, histological analysis, or other biological assessments. The treatment effect is as follows: Figure 13 As shown.

[0072] Depend on Figure 13 It can be seen that the mice did not experience a significant decrease in body weight during the treatment process, while the tumor volume in the treatment group decreased, indicating that this method can achieve a good tumor treatment effect.

[0073] Example 4 This embodiment provides another method for preparing a hydrogel optical fiber body, which uses a copolymer hydrogel of polyethylene glycol diacrylate (PEGDA) and acrylamide (AM) as the core material (PEGDA:PAM=4:6) and is cured by ultraviolet light.

[0074] The preparation method of the hydrogel optical fiber body includes the following steps: S11. Mix PEGDA (40% concentration), acrylamide, photoinitiator I2959, and water in the following ratio: PEGDA 1.6g, acrylamide 2.4g, I2959 100mg, and water 5.9mL. Stir thoroughly to dissolve and obtain the prepolymer solution.

[0075] S12. Inject the prepolymer liquid into a circular mold with an inner diameter of 600 μm, and irradiate it with ultraviolet light (wavelength 365 nm, power 100%) for 30 s to solidify and form a copolymer hydrogel fiber core.

[0076] S13. Following the same method as step S13 in Example 1, calcium alginate hydrogel is wrapped around the outer layer of the copolymer hydrogel core to obtain a core-cladding structure hydrogel optical fiber.

[0077] The prepared core-cladding hydrogel optical fiber was characterized as follows: (1) The fiber morphology was observed under a microscope, and the results are as follows: Figure 14 As shown, the core diameter was measured to be approximately 585 μm, and the total fiber diameter was approximately 807 μm.

[0078] (2) Light guiding tests were conducted on fibers with different bending angles (30 degrees, 45 degrees, 90 degrees, 180 degrees, and knots). The results are as follows: Figure 15 As shown, the optical signal can be stably transmitted along the fiber core under different bending angles, indicating that the optical fiber still has good light guiding performance under bending conditions.

[0079] (3) The optical loss at wavelengths of 450nm, 530nm and 660nm was tested respectively, and the results are as follows: Figure 16 As shown, the measured optical losses were 0.248 dB / cm, 0.214 dB / cm, and 0.198 dB / cm, respectively. It can be seen that the optical loss decreases with increasing wavelength, with the lowest loss at 660 nm, which is beneficial for the effective transmission of excitation light in photodynamic therapy.

[0080] The above results show that using photocrosslinked PEGDA-PAM copolymer as the fiber core can also yield hydrogel fiber bodies with good flexibility and light guiding properties, which can be used for the subsequent preparation of composite photoresponsive functional layers.

[0081] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. A composite hydrogel optical fiber with photocontrolled drug release function, characterized in that, include: A hydrogel optical fiber body, wherein the hydrogel optical fiber body has a core and a cladding structure; A photoresponsive functional structure is disposed at the end of the hydrogel optical fiber body. The photoresponsive functional structure is a hydrogel that can undergo a change from a gel state to a sol state under illumination of a specific wavelength of light. The nanophototherapy agent, loaded in the photoresponsive functional structure, can be activated under light irradiation and generate reactive oxygen species or photochemical responses.

2. A method for preparing a composite hydrogel optical fiber with photocontrolled drug release function as described in claim 1, characterized in that, Includes the following steps: S1. Prepare the hydrogel optical fiber substrate; S2. Prepare a lipid nanoparticle dispersion loaded with photosensitizer; S3. The lipid nanoparticle dispersion obtained in S2 is mixed with a thiol-polyethylene glycol-thiol precursor solution and a polyethylene glycol precursor solution with four-arm maleimide end-capped containing a photoinitiator, respectively, to obtain a first precursor mixture and a second precursor mixture. S4. The first precursor mixture and the second precursor mixture obtained in S3 are mixed in situ at the end of the hydrogel fiber body obtained in S1, and left to stand to obtain a composite hydrogel fiber with light-controlled drug release function.

3. The preparation method according to claim 2, characterized in that, In step S1, the preparation of the hydrogel optical fiber body specifically includes the following steps: S11. Preparation of hydrogel fiber core: The hydrogel precursor solution is injected into a tubular mold and gelled through enzymatic cross-linking, physical gelation or chemical cross-linking reaction to form a hydrogel fiber core. S12. Preparation of hydrogel optical fiber body: The hydrogel optical fiber core is sequentially immersed in a solution containing crosslinkable polysaccharides and a solution of divalent or polyvalent metal ions to obtain a cladding structure uniformly attached to the surface of the core. S13. After washing with deionized water, the hydrogel optical fiber body is obtained.

4. The preparation method according to claim 3, characterized in that, In S11, the hydrogel precursor solution is any one of silk fibroin, hyaluronic acid, gelatin, polyvinyl alcohol, polyacrylamide, polyacrylic acid, polyethylene glycol, sulfobetaine polymers, carboxybetaine polymers, or composite hydrogels thereof, and the hydrogel precursor solution is formed by enzymatic crosslinking, freeze-thaw cycle physical gelation, or light / thermal triggered chemical crosslinking.

5. The preparation method according to claim 4, characterized in that, The hydrogel precursor solution is a silk fibroin hydrogel with a mass fraction of 5%-20%. The preparation of the hydrogel optical fiber core is as follows: add horseradish peroxidase and hydrogen peroxide with a final concentration of 0.05-0.2 mg / mL to the silk fibroin aqueous solution, and carry out an enzymatic cross-linking reaction at 25°C for 0.5-2 h. Subsequently, it also includes dehydration by soaking in 20-60% ethanol for 5-20 min.

6. The preparation method according to claim 3, characterized in that, S12 contains cross-linkable polysaccharides, including alginate and carboxymethyl cellulose, and divalent or polyvalent metal ion solutions, including calcium chloride solution. The silk fibroin hydrogel core is sequentially immersed in a solution containing cross-linkable polysaccharides and a solution containing divalent or polyvalent metal ions, specifically: first, the silk fibroin hydrogel core is immersed in a 1-2% sodium alginate solution for 1-3 seconds, then removed and dried for 3-5 minutes, and then immersed in a 0.1M calcium chloride solution for 0.5-2 minutes.

7. The preparation method according to claim 2, characterized in that, In step S2, a lipid nanoparticle dispersion loaded with a photosensitizer is prepared, including the following steps: S21. Dissolve the lipid component and the hydrophobic photosensitizer in an organic solvent at a mass ratio of 0.8-40:1 to obtain an organic phase solution; S22. The organic phase solution obtained in S21 is injected into the aqueous phase solution to obtain a lipid nanoparticle dispersion loaded with photosensitizer.

8. The preparation method according to claim 7, characterized in that, In S21, the lipid component consists of phospholipids, cholesterol, or their derivatives; the hydrophobic photosensitizers include porphyrin compounds, phthalocyanine compounds, organic dye molecules, or their derivatives.

9. The composite hydrogel optical fiber with photocontrolled drug release function according to claim 1, characterized in that, The composite hydrogel optical fiber with photocontrolled drug release function can further regulate the photoresponsive functional structure by changing the light exposure time and light intensity under light stimulation, thereby activating the nano-phototherapy agent to generate reactive oxygen species or photochemical response.

10. The application of the composite hydrogel optical fiber with photocontrolled drug release function as described in claim 1 in the preparation of medical devices for local drug delivery, photomediated therapy or in situ photodynamic therapy of tumors.

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