CN109504648B - Application of composite supermolecule hydrogel based on nanogold as biomedical material - Google Patents

Application of composite supermolecule hydrogel based on nanogold as biomedical material Download PDF

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CN109504648B
CN109504648B CN201710834688.7A CN201710834688A CN109504648B CN 109504648 B CN109504648 B CN 109504648B CN 201710834688 A CN201710834688 A CN 201710834688A CN 109504648 B CN109504648 B CN 109504648B
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CN109504648A (en
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刘文广
吴元昊
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Hunan Jinrun Health Technology Co., Ltd.
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Tianjin University
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Abstract

The invention discloses application of a composite supramolecular hydrogel based on nano-gold as a biomedical material, which is characterized in that spherical gold nanoparticles with different particle sizes are prepared by taking sodium citrate as a reducing agent, a nano-film is formed on the surfaces of the gold nanoparticles by utilizing dopamine self-polymerization reaction in an alkaline environment, then the gold nanoparticles wrapped by dopamine, acryloyl glycinamide and acrylamide are taken as raw materials, the nano-composite supramolecular hydrogel with different particle sizes is prepared by free radical polymerization in the presence of an initiator, and the nano-composite supramolecular hydrogel is taken as a filling material for relapse treatment after breast cancer surgery. The hydrogel has high critical dissolving temperature, can generate gel-sol conversion when the temperature is higher than the critical dissolving temperature, can regulate and control the thermoplasticity and the injectability of the gel through near infrared light, can effectively kill cancer cells to control the recurrence and the metastasis of breast cancer through the photothermal effect generated after filling, has good biocompatibility, and the preparation methods of the monomer and the hydrogel are simple and easy.

Description

Application of composite supermolecule hydrogel based on nanogold as biomedical material
Technical Field
The invention relates to a preparation method and application of hydrogel, in particular to a preparation method and application of a PAAm-PNAGA-AuNPs-PDA (PAAm-PNAGA-AuNPs-PDA) hydrogel compounded by acrylamide and acryloyl glycinamide and dopamine-gold nanoparticles, which has the functions of high stability, temperature sensitivity, thermoplasticity, photothermal conversion and the like, and can be used as a filling material after a breast cancer operation to prevent the recurrence and transfer of the breast cancer under the regulation and control of near infrared light.
Background
Hydrogels are high molecular weight polymeric materials that are hydrophilic and insoluble in water, and that have a cross-linked structure that can absorb a large amount of water (typically greater than 50% of the total mass). Because the polymer chains are not dissolved in water due to the physical crosslinking and chemical crosslinking effects, the polymer chains can only swell and keep a certain shape, and meanwhile, the polymer chains also have good water permeability and biocompatibility, and can reduce adverse reactions when used as a human body implant. Therefore, the hydrogel is widely applied as an excellent biomedical material. The stimulus-responsive hydrogel can change the structure or property of the hydrogel through stimulation so as to achieve the aim of multifunctional response, and is a hot point of research at present. The near-infrared response type hydrogel is a stimulation-response hydrogel with wide application prospect, and can realize multi-aspect response purpose by accurately controlling the irradiation intensity, the irradiation time and the irradiation site of the light source.
The near-infrared stimuli-responsive hydrogel is an intelligent hydrogel which can generate volume transformation or phase transformation after being irradiated by near-infrared light, belongs to a light stimulus-responsive hydrogel, can act on a specific part of a human body under the condition of light irradiation, can be used as a remote control release system (Li W, Wang J, Ren J, Qu X.3D Graphene oxide-polymer hydrogel: near-extracted light-sampled active scaffold for reversible cell capture and on-demand release.Adv.Mat.2013, 25,6737-6743) due to the property of avoiding interventional injury because the nano hydrogel does not directly contact with the stimulation part. The traditional light stimulation response type hydrogel contains light active groups such as azobenzene, spiropyran, triphenylmethane and other light response polymers, and the active groups change in configuration or form charged groups after being illuminated, so that the conformation or the hydrophilicity and hydrophobicity of polymer molecular chains change, and the volume phase transformation of the nano hydrogel is caused (Li M-H, Keller P, Stimuli-responsive polymer vectors, Soft mate.2009, 5, 927-one 937). However, the light which triggers the volume phase transition of the photostimulation-responsive nano hydrogel is ultraviolet light or blue light, and the light with shorter wavelength can cause certain damage to biological tissues or cells, so that the clinical application is greatly limited. However, the reports of the conventional near-infrared response materials focus on graphene oxide, nanogold, carbon nanotubes, polypyrrole and the like, but the application of these materials in the biomedical field is limited due to the problems of cytotoxicity, low light-heat conversion efficiency and the like (Zhang Z, Wang J, Nie X, et al.
The side chain of the polymer molecular chain of acryloyl glycinamide (NAGA) is provided with two amide groups, strong hydrogen bond action is generated among molecules, so that a formed physical cross-linking network enables the gel to have good mechanical strength and toughness, and the hydrogen bond formed by the bisamide groups can be destroyed and reconstructed at a higher temperature, after the hydrophilic monomer acrylamide and the NAGA are copolymerized, the gel has a high critical dissolving temperature, gel-sol transformation can be generated, and the temperature sensitivity and the injectability of the supermolecule gel are endowed. Gold nanoparticles have excellent optical properties, and when the wavelength of incident light is resonantly coupled to the oscillation frequency of free electrons, Surface plasmon resonance (LSPR) occurs, showing strong absorption peaks in the UV-visible spectrum (Liz-Marz a n L, Tailored Surface Plasmons through the Morphology and Assembly of Metal nanoparticies. Langmuir,2006,22, 32-41.). Gold nanoparticles can all exhibit different optical properties by controlling the size, shape, composition, structure, self-assembly and their cladding. In recent years, polydopamine has been widely used in the biomedical field as a novel coating material through studies on the phenomenon that mussels adhere to solid surfaces. Just because polydopamine contains abundant functional groups on the surface, it has certain functions in various directions such as cell imaging, free radical scavenging, drug delivery, tumor diagnosis and photothermal therapy (Liu, Y, Ai K, Lu L. multidopamine and its derivative materials: synthesis and simulation applications in energy, environmental, and biological fields. chem. Rev.2014,114, 5057-5115). The gold nanoparticles coated with dopamine greatly improve the photo-thermal conversion efficiency by changing the synergistic effect of the optical refractive index and the light absorption, and the polydopamine can fix the nanoparticles in a gel network through the Michael addition reaction, so that the stability of the nanoparticles in the gel is improved.
Breast Cancer is one of the most common female malignancies today, the incidence of which remains on the rise every year, and breast Cancer has dominated the first female Cancer incidence worldwide (Siegel R, Ma J, Zou, Z Cancer statistics. ca Cancer J Clin,2014,64, 9-29). Although surgical resection of breast cancer has significantly reduced the mortality of breast cancer in recent years with the development of modern medicine, the problem of recurrence and metastasis of breast cancer remains ineffectively solved and is the biggest difficulty and challenge in clinical treatment efforts. At present, clinical postoperative treatment modes are mainly oral medicines, and the low side effect rate and the side effects of the medicines cannot achieve effective treatment effects.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide application of a nano-gold-based composite supramolecular hydrogel as a biomedical material, wherein acryloyl glycinamide (NAGA) and acrylamide (AAm) are used as monomers to load dopamine-gold nanoparticles.
The technical purpose of the invention is realized by the following technical scheme:
the composite supermolecule hydrogel based on the nano-gold is composed of copolymerized hydrogel and dopamine-coated gold nanoparticles, wherein: the copolymerization hydrogel is formed by copolymerizing acrylamide and acryloyl glycinamide in a water phase, dopamine-coated gold nanoparticles are dispersed in the water phase, and the dopamine-coated gold nanoparticles are dispersed and fixed in the copolymerization hydrogel through copolymerization in the water phase.
During preparation, acrylamide, acryloyl glycinamide, an initiator and dopamine-coated gold nanoparticles are uniformly dispersed in a water phase, the initiator is used for initiating polymerization of carbon-carbon unsaturated bonds on the acrylamide and the acryloyl glycinamide, and the copolymerization hydrogel is prepared through free radical polymerization under the anaerobic condition and the dopamine-coated gold nanoparticles are dispersed and fixed in the copolymerization hydrogel.
The mass ratio of acrylamide to acryloyl glycinamide is (1-3): (5-10), preferably (1-2): (5-6). In the aqueous phase, the solids content is from 10 to 25%, preferably from 15 to 20% (i.e. the ratio of the mass of acrylamide, acryloyl glycinamide charged to the mass of water, mg/mg).
The preparation of the hydrogel is carried out by using 3-10%, preferably 5-10% of the amount of the initiator based on the mass of the two comonomers, and the initiator is selected from thermal initiators under aqueous phase conditions commonly used in the field of high molecular polymerization, such as Ammonium Persulfate (APS) and potassium persulfate (KPS), or photoinitiators, such as 2-hydroxy-2-methyl-1-phenyl-1-propanone (Irgacure 1173). The thermal initiator is selected by first removing oxygen from the reaction system with an inert gas (e.g., nitrogen, argon or helium) to avoid inhibition of polymerization, and then heating the reaction system to a temperature above the initiation temperature of the initiator used and for a relatively long time (e.g., 1 hour or more or longer (1-5 hours) depending on the activity and amount of the initiator, so as to promote the initiator to generate enough free radicals for a long time to initiate the reaction system for continuous free radical polymerization, thereby finally preparing the hydrogel of the present invention. Selecting a photoinitiator, wherein the photoinitiator is 2-hydroxy-2-methyl-1-phenyl-1-acetone (Irgacure 1173), selecting a transparent closed reaction vessel, initiating free radical polymerization under the condition of ultraviolet irradiation, and because the photoinitiation efficiency is higher than that of thermal initiation, and because the irradiation time is adjusted according to the activity and the dosage of the selected initiator, the irradiation time can be shorter than the heating time of thermal initiation, such as 20 minutes or longer (30min-1h), and compared with the thermal initiation, the experimental time can be greatly reduced.
The particle diameter of the dopamine-coated gold nanoparticles is 10-20 nm, and the mass percentage of the dopamine-coated gold nanoparticles in the aqueous phase is 1-10 wt%, preferably 2-5 wt%.
The dopamine-coated gold nanoparticles are prepared by a seed growth method, nano-gold is prepared by reacting sodium citrate serving as a reducing agent with chloroauric acid serving as a raw material, the supernatant is centrifuged, then a pH 8-8.5 Tris buffer solution is added, dopamine is dissolved in the gold-containing nanoparticle solution and ultrasonically stirred, and the dopamine-coated gold nanoparticles with core-shell structures are formed by being oxidized, self-polymerized and coated on the surfaces of the gold nanoparticles. In the seed growth method, the sodium citrate and the chloroauric acid are repeatedly reacted in multiple steps to control the particle size of the generated gold nanoparticles; the thickness of the dopamine coating layer can be adjusted by adjusting the dopamine content.
In the technical scheme of the invention, acrylamide (AAm) and acryloyl glycinamide (NAGA) are taken as monomers to prepare the hydrogel, amide groups on a side chain of a molecular chain of the hydrogel can generate strong intermolecular hydrogen bond action, a stable physical crosslinking network is provided, and the hydrogel can be used as an effective dynamic reversible gel network to realize gel-sol conversion of the hydrogel at a certain temperature. Free radicals provided by Ammonium Persulfate (APS) initiator can not only initiate the reaction between AAm and NAGA monomers, but also promote the self-polymerization of dopamine, and poly-dopamine can generate Michael addition reaction with amino on polyacrylamide to fix nanoparticles in a gel network,
in the preparation scheme, after the reaction is finished, the copolymer is taken out of the reaction container, and after the monomers, the initiator, the cross-linking agent and the solvent which do not participate in the reaction are removed, the copolymer is soaked in water until the swelling balance is achieved (for example, the copolymer is soaked for 7 days, the water is replaced every 12 hours every day, and the swelling balance is achieved).
The application of the composite supermolecule hydrogel based on the nano-gold as the near-infrared response type material has the sol-gel transition temperature of 50-55 ℃ and the laser intensity of 2mW/cm2Irradiating the gel at wavelength of 808nm, and after irradiating for 10min, raising the temperature to the sol-gel transition temperature to realize the gel-sol transition.
The nano-gold-based composite supramolecular hydrogel is applied as a biomedical material, a cell scaffold, a medicine for treating breast cancer and a breast cancer postoperative filling material, and prevents recurrence and metastasis of breast cancer under near-infrared light regulation.
The temperature-sensitive nano-composite hydrogel provided by the invention is prepared by taking acrylamide (AAm) and acryloyl glycinamide (NAGA) as raw materials and compounding dopamine-gold nanoparticles under the initiation of an initiator, and has the advantages of temperature sensitivity, photo-thermal property, injectability and good biocompatibility due to the synergistic effect of hydrogen bonds and the nanoparticles. According to the scheme of the invention, the breast cancer cells of the mouse are inoculated on the right breast mammary gland of the mouse, surgical excision is carried out after the tumor grows, then gel is injected to the excision part after surgery, the filling shape and the photothermal property of the gel are adjusted through near infrared light irradiation, so that the gel is effectively attached to the cavity after surgery, and the cancer cells are killed at local high temperature to prevent the recurrence and the metastasis of the breast cancer.
Drawings
FIG. 1 is a transmission electron micrograph of several gold nanoparticles of the present invention, wherein the gold nanoparticles: A)10nm, B)20nm, gold nanoparticles coated with polydopamine: C)10nm, D)20 nm.
FIG. 2 is a Fourier infrared spectrum of PAAm-PNAGA and PAAm-PNAGA-AuNPs-PDA hydrogel in the present invention, wherein 1 is PAAm-PNAGA-AuNPs-PDA, and 2 is PAAm-PNAGA.
FIG. 3 is a spectrum diagram of ultraviolet absorption spectra of nanoparticles of different particle sizes in the present invention.
FIG. 4 is a graph of photothermal conversion of hydrogels containing different nanoparticles over time (i.e., gel photothermal conversion curves) in accordance with the present invention.
FIG. 5 is a graph of rheological measurements of different hydrogels of the present invention at a fixed frequency and strain as a function of temperature: A) PNAGA-AAm; B) PNAGA-AAmAUNPs; C) PNAGA-AAmAUNPs-PDA.
FIG. 6 shows that the amount of the PNAGA-AAm-AuNPs-PDA hydrogel is 2mW/cm2Schematic diagram of gel-sol transition with time under laser irradiation with wavelength of 808 nm.
FIG. 7 is a graph showing the results of cytotoxicity tests of PAAm-PNAGA-AuNPs-PDA hydrogel of the present invention.
FIG. 8 is a thermal image of different hydrogels of the present invention at the post-operative filling site of mouse breast cancer with laser irradiation.
FIG. 9 is a graph showing the gel swell of various hydrogels of the present invention.
Detailed Description
The technical scheme of the invention is further explained by combining specific examples.
Gold nanoparticles with different particle sizes are synthesized by a seed growth method, taking the particle size of 10nm as an example. 150mL of a 2.2mM sodium citrate solution was heated to boiling for 15min, and 1mL of a 25mM chloroauric acid solution was added and reacted for 10 min. After the solution turned into wine red, the solution was cooled to 90 ℃ and 1mL of 60mM sodium citrate solution and 1mL of 25mM chloroauric acid solution were added to react for 30min, thereby obtaining nanogold with a particle size of 10 nm. And then repeating the steps to obtain the gold nanoparticles with different particle sizes, and if 1mL of 25mM chloroauric acid and 150mL of 2.2mM sodium citrate solution are added, repeating the steps for 3 times to obtain the gold nanoparticles with the particle size of 20 nm. The newly synthesized gold nanoparticle solution was centrifuged for 10min, and the supernatant was discarded and dispersed in 1mL of deionized water. Adding 2mg of dopamine hydrochloride, stirring and dissolving, then adjusting the pH value to 8.5 by using a Tris buffer solution, ultrasonically stirring for 30min, and then centrifugally collecting precipitates to obtain the dopamine-coated core-shell structured nanoparticles. Obtaining 10nm and 20nm gold nanoparticles according to the same steps, wrapping dopamine, performing an ultraviolet and visible light absorption test, taking 1mL of nanoparticle aqueous solution, performing ultrasonic dispersion uniformly, and testing absorbance and absorption peak at a speed of 1nn/s within a wavelength range of 200-1000 nm. As shown in figure 1, the particle size of the gold nanoparticles is 10nm and 20nm, and the gold nanoparticles can still keep a better dispersion condition after being wrapped by polydopamine. AuNPs-X represents gold nanoparticles, and X is the particle size of the gold nanoparticles; AuNPs-PDA-X represents gold nanoparticles wrapped by dopamine, and X is the particle size of the gold nanoparticles. As shown in figure 3, gold nanoparticles with the particle diameters of 10nm and 20nm have absorption peaks at 520nm, the absorption peak of the nanoparticles after being wrapped by dopamine is red-shifted, two absorption peaks appear, and the red-shift distance increases along with the increase of the size of the nanoparticles. The AuNPs-PDA-20 respectively has absorption peaks at 560nm and 780nm, the characteristic peaks are in a near infrared region, the laser wavelength range is closer, and the more excellent photo-thermal conversion efficiency can be shown. We then used 20nm gold nanoparticles as the final nanoparticle size, taking into account the near-infrared light response and the photothermal conversion efficiency.
Acrylamide (25mg) and acrylamidoglycinamide (125mg) were dissolved in an aqueous solution of nanoparticles (dopamine-coated gold nanoparticles mass/sum of dopamine-coated gold nanoparticles and water mass) at a mass percentage of 2 wt%, and 15mg of Ammonium Persulfate (APS) as an initiator was added. And (3) filling nitrogen into the mixed solution to remove oxygen, injecting the mixed solution into a closed mold, and curing the mold at room temperature for 12 hours to ensure that the free radical polymerization is fully initiated. The mold was then opened and the gel removed, soaked in deionized water for 3-4 days (24 hours per day) to reach equilibrium swelling, and the deionized water was changed every 12 hours. According to the phase synchronization steps, nano particles with different particle diameters are utilized to obtain the nano composite gel, and the experimental processes of photo-thermal conversion, rheological test, gel-sol conversion and the like are carried out. The gel sample is named PAAm-PNAGA-AuNPs-PDA-X, wherein X represents the particle size of gold nanoparticles, and the details are shown in the following table:
Figure BDA0001409500650000061
performing infrared spectrum detection on the PAAm-PNAGA and the PAAm-PNAGA-AuNPs-PDA gel, wherein the characteristic peaks of the PAAm-PNAGA gel are as follows: v-3448 cm-1(NH)，2927cm-1(CH)，1647cm-1(C ═ O). The characteristic peaks of PAAm-PNAGA-AuNPs-PDA gel are as follows: v-3426 cm-1(NH)，2924cm-1(CH)，1639cm-1(C＝O)，1258cm-1(C-N). A new 1258cm appeared in PAAm-PNAGA-AuNPs-PDA gel-1The characteristic peak, which is a C-N stretching vibration peak on the benzene ring of polydopamine, confirms that the PDA and AAm have Michael addition reaction, and the nano particles are fixed in the gel network, as shown in figure 2.
The nano composite hydrogel is subjected to rheological test by adopting the following method, the dried cylindrical gel is weighed to the initial weight and then soaked in deionized water at 37 ℃, the hydrogel is taken out after a certain time interval, the water on the surface of the gel is lightly wiped by using filter paper, then the gel is immediately weighed on a microbalance, the mass is recorded, and three samples are measured in each group. The swelling degree of the gel was calculated by the following formula:
Figure BDA0001409500650000071
wherein m iswetAnd mdryThe wet and dry weights of the gel are shown in FIG. 9. The PNAGA-AAm, PNAGA-AAm-AuNPs and PNAGA-AAm-AuNPs-PDA hydrogels reach swelling balance after being soaked in water for 5 days (24 hours per day), wherein the swelling degree of the PNAGA-AAm-AuNPs and PNAGA-AAm-AuNPs-PDA hydrogels containing the nano particles is reduced, mainly because the nano particles are dispersed in a gel network to increase the crosslinking degree of the gel, and the network is more compact. Compared with PNAGA-AAm-AuNPs-PDA hydrogel which is not wrapped by dopamine, the water absorption rate of the PNAGA-AAm-AuNPs-PDA hydrogel is increased, mainly, water can easily enter a polymer network due to free diffusion of gold nanoparticles, and the nanoparticles are fixed in the network by the dopamine cross-linked hydrogel, so that a more compact three-dimensional network is obtained.
The photo-thermal conversion performance of the nano composite hydrogel under near infrared light is tested by adopting the following method: taking a cylindrical sample with a diameter of 10mm and a height of 8mm, placing the sample in a cuvette, placing a temperature sensor in the gel, using 2w/m2Power (laser intensity 2 mW/cm)2Wavelength 808nm) is irradiated on the gel, and the change rule of the gel temperature along with time is tested. After irradiating for 10min, the temperature is raised by 50 ℃, and the gel can be completely changed into sol. For more visual representation of the photothermal conversion properties of the gel, see figure 4 of the specification.
The nano composite hydrogel is subjected to rheological test by adopting the following method, the size of a test sample is a wafer with the diameter of 3cm and the thickness of 1mm, the compression mode is adopted to test the values of G ' and G ' ' at the temperature range of 30-70 ℃, the fixed stress is 15Pa, the fixed frequency is 1Hz, and the aim of ensuring the test to be in a linear range is achieved. The heating rate is controlled to be 0.1 +/-0.05 ℃. The nano composite hydrogel has the storage modulus and the loss modulus at 50 ℃ to form an intersection point, and the gel-sol transformation is proved to occur, which is shown in the attached figure 5 of the specification. Rheological measurements of fixed frequency and strain as a function of temperature: A) PNAGA-AAm; B) PNAGA-AAmAUNPs; C) PNAGA-AAmAUNPs-PDA. The three gels show a cross-over point in storage modulus (G ') and loss modulus (G') with increasing temperature, representing a gel having a gel-sol transition temperature (or UCST) with UCST temperatures of 58 deg.C, 52 deg.C and 55 deg.C, respectively. When G '> G' is present, a gel state is present, and when G '< G' is present, a sol state is present. This is mainly due to the fact that an increase in temperature leads to the breaking of hydrogen bonds and a decrease in the crosslinking density, whereas after a decrease in temperature hydrogen bonds are restored. After the nanoparticles were added, the UCST of the gel decreased, mainly due to the increased frequency of free motion of the nanoparticles with increasing temperature, resulting in faster hydrogen bond cleavage.
The gel-sol transition of the nano-composite hydrogel of the invention under near infrared light is detected by the following method, and the gel with the diameter of 10mm and the thickness of 8mm is prepared under the condition of 2mW/cm2Under near infrared illumination, the change of the gel morphology is observed. The gel begins to soften and deform when the temperature of the gel reaches 40 ℃ after being irradiated for 1min, partial gel sol transformation occurs, and the gel state can be completely changed into the sol state after being irradiated for 5 min. After cooling to room temperature, the sol can be recovered to gel again, and the gel is proved to have good thermoplasticity and injectability, which is shown in the attached figure 6 of the specification.
The cytotoxicity of the nanocomposite hydrogel of the present invention was examined using the following method. To test the possibility of applying this nanocomposite supramolecular hydrogel to biomaterials, various gel pieces were cut into disks 10mm in diameter and 0.5mm thick, sterilized by soaking in 75% alcohol for 2h, and then washed with PBS, and these gels were placed into the bottom of 48-well plates. 2mL of L929 cell suspension (5X 10)4cells/mL) were seeded into 48-well plates and cultured for 24 hours. Then sucking out the cell culture medium, adding 80 mu L of thiazole blue solution (5mg/mL) and 320 mu L of serum-free cell culture medium, culturing for 4 hours, sucking out the solution, washing for 3 times by PBS, then adding 300 mu L of dimethyl sulfoxide, dissolving the crystal substance, finally measuring the absorbance at 490nm by a microplate reader, and taking the untreated blank cells as a control group according to the experimental result, wherein the final cell survival rate is calculated by the formula of sample absorbance/control group absorbance multiplied by 100%. Also to reduce errors, we have performed three holes for each composite ratioParallel experiments, taking the average and deviation as the measurement results. The experimental result shows that the gel has good biocompatibility and can be used as biological materials such as cell scaffolds and the like, as shown in figure 7.
The following method was used to examine the postoperative filling effect of breast cancer of the nanocomposite hydrogel of the present invention, and 106Injecting 4T1 cells (Jiangsu Kai-Bio technologies Co., Ltd.) into the right breast of Balb/c mouse until the tumor grows to 200mm3At that time, the tumor was excised. And then injecting the nano-composite hydrogel into the cavity part after operation, and changing the shape of the gel by near infrared light irradiation so that the gel is more attached to the filling part. After 24h of filling, the filling site was laser irradiated for 5min, and the gel temperature was 50 ℃ as observed by a thermal imaging machine, which was sufficient to kill the residual tumor cells in the tissue. Compared with a blank group injected with PBS, the temperature is only raised by 2.3 ℃, the gel of the composite gold nanoparticles can reach 43 ℃, but after 48h and 72h of filling, the temperature can only reach 40 ℃ and 37 ℃ after laser irradiation, and the photo-thermal property of the nano composite gel is not changed and can still reach the previous temperature. Experimental results prove that the nano-composite hydrogel has excellent photo-thermal performance, and nano-particles can stably exist in the gel, so that the nano-composite hydrogel is an excellent near-infrared responsive gel, and the details are shown in the attached figure 8 of the specification. The effect of treating the recurrence of breast cancer is evaluated by the following method, after surgical filling, laser irradiation is carried out for 5min every day, mice are killed after 4 weeks, and the recurrence condition of tumors is examined, wherein the mice are divided into a blank non-treatment group, a laser irradiation non-filling group, a gel filling laser irradiation group and 6 groups, and the final recurrence results are respectively 5, 4 and 1, and the result proves that the nanocomposite hydrogel can effectively prevent the recurrence of breast cancer. The nano composite hydrogel with near infrared response is injected to the postoperative part, the shape and the photo-thermal effect of the filling gel can be regulated and controlled through near infrared irradiation, the nano composite hydrogel is used as a proper filling material, cancer cells are killed through the photo-thermal effect, and the recurrence and the metastasis of breast cancer can be effectively controlled.
The preparation of the composite hydrogel can be realized by adjusting the preparation process parameters according to the content of the invention, and the composite hydrogel has near infrared performance which is basically consistent with the embodiment. The invention has been described in an illustrative manner, and it is to be understood that any simple variations, modifications or other equivalent changes which can be made by one skilled in the art without departing from the spirit of the invention fall within the scope of the invention.

Claims (11)

1. The application of the composite supramolecular hydrogel based on the nanogold in the preparation of biomedical materials is characterized in that the composite supramolecular hydrogel based on the nanogold is composed of copolymerized hydrogel and dopamine-coated gold nanoparticles, wherein: the copolymerization hydrogel is formed by copolymerizing acrylamide and acryloyl glycinamide in a water phase, dopamine-coated gold nanoparticles are dispersed in the water phase, and the dopamine-coated gold nanoparticles are dispersed and fixed in the copolymerization hydrogel through copolymerization in the water phase.
2. The use of nanogold-based composite supramolecular hydrogel in the preparation of biomedical materials according to claim 1, wherein the mass ratio of acrylamide to acryloyl glycinamide is (1-3): (5-10).
3. The use of nanogold-based composite supramolecular hydrogel in the preparation of biomedical materials according to claim 2, wherein the mass ratio of acrylamide to acryloyl glycinamide is (1-2): (5-6).
4. The use of nanogold-based composite supramolecular hydrogels according to claim 1 for the preparation of biomedical materials, characterized in that the solid content in the aqueous phase is 10-25%.
5. The use of nanogold-based composite supramolecular hydrogels according to claim 4 for the preparation of biomedical materials, characterized in that the solid content in the aqueous phase is 15-20%.
6. The application of the nanogold-based composite supramolecular hydrogel in preparation of biomedical materials according to claim 1, wherein the particle size of the dopamine-coated gold nanoparticles is 10-20 nm, and the mass percentage of the dopamine-coated gold nanoparticles in the aqueous phase is 1-10 wt%.
7. The application of the nanogold-based composite supramolecular hydrogel in preparation of biomedical materials according to claim 6, wherein the mass percentage of dopamine-coated gold nanoparticles in the aqueous phase is 2-5 wt%.
8. The application of the nanogold-based composite supramolecular hydrogel in preparation of biomedical materials according to claim 1, wherein the using amount of an initiator is 3% -10% of the mass sum of two comonomers, the initiator adopts a thermal initiator or a photoinitiator, the thermal initiator is ammonium sulfate or potassium persulfate, and the photoinitiator is 2-hydroxy-2-methyl-1-phenyl-1-acetone; selecting a thermal initiator, namely firstly removing oxygen in a reaction system by using inert gas to avoid the polymerization inhibition of the thermal initiator, then heating the reaction system to a temperature higher than the initiation temperature of the initiator and keeping the temperature for more than 1h according to the activity and the dosage of the initiator so as to promote the initiator to generate enough free radicals for a long time, initiating the reaction system to continuously generate free radical polymerization reaction, and finally preparing hydrogel; the method is characterized in that a photoinitiator is selected, a transparent closed reaction container is selected, free radical polymerization is initiated under the condition of ultraviolet irradiation, the photoinitiation efficiency is higher than that of thermal initiation, the irradiation time can be shorter than the heating time of thermal initiation when the irradiation time is adjusted according to the activity and the dosage of the selected initiator, the irradiation time is more than 20 minutes, and the experiment time can be greatly reduced compared with that of thermal initiation.
9. The application of the nanogold-based composite supramolecular hydrogel in preparation of biomedical materials as claimed in claim 8, wherein the dosage of the initiator is 5-10% of the mass sum of two comonomers, the inert gas is nitrogen, argon or helium, the thermal initiator is selected, the reaction system is heated to the temperature above the initiation temperature of the initiator and kept for 1-5h, so that the initiator can generate enough free radicals for a long time, the reaction system is initiated to continuously generate free radical polymerization, and finally the hydrogel is prepared; selecting a photoinitiator, selecting a transparent closed reaction container, initiating free radical polymerization under the condition of ultraviolet irradiation, wherein the photoinitiation efficiency is higher than that of thermal initiation, and the irradiation time can be shorter than the heating time of thermal initiation when the irradiation time is adjusted according to the activity and the dosage of the selected initiator, is 30min-1h, so that the experimental time can be greatly reduced compared with the thermal initiation.
10. Use of the nanogold-based composite supramolecular hydrogel in the preparation of biomedical materials according to claim 1, wherein the nanogold-based composite supramolecular hydrogel is used as a cytoskeleton.
11. The application of the nanogold-based composite supramolecular hydrogel in preparation of biomedical materials according to claim 1, wherein the nanogold-based composite supramolecular hydrogel is applied to preparation of a medicine for treating breast cancer, and is used as a filling material after breast cancer operation to prevent recurrence and metastasis of breast cancer under near infrared light regulation.
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