CN116023681B - Preparation method and application of acoustic-thermal double-response hydrogel - Google Patents
Preparation method and application of acoustic-thermal double-response hydrogel Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention discloses a preparation method and application of acoustic-thermal dual-responsiveness hydrogel, and belongs to the technical field of medical materials. The acoustic-thermal dual-responsiveness hydrogel mainly comprises sulfhydryl sodium alginate (SA-SH), arginine-modified sodium alginate (Sa-arg), modified titanium dioxide nano-particles (TiO 2@MnO2) and beta-sodium glycerophosphate (beta-GP). After ultrasonic treatment, the hydrogel can generate sol-gel conversion and chemical substances such as ROS, NO, O 2 and the like, can excite the immunoreaction activity of wound or tumor immune cells, promote the apoptosis of the wound or cancer cells and improve the tumor microenvironment, and has synergistic wound healing/anticancer effects. The hydrogel prepared by the method has good biocompatibility, low cost, simple and quick preparation method, high gelling speed, acoustic-thermal dual responsiveness, capability of treating focuses deep in tissues through ultrasonic waves and thermal effects thereof, and great application potential in the fields of antibiosis, wound healing promotion, cancer treatment and the like.
Description
Technical Field
The invention relates to the field of biomedical materials, in particular to a preparation method and application of acoustic-thermal dual-response hydrogel.
Background
Research related to cancer has been one of hot topics in the biomedical field, and as cancer research is advanced, treatment means for cancer are also maturing. There are three currently predominant methods of cancer treatment in the clinic: surgical treatment, radiation therapy and chemotherapy, and targeted therapy. The operation treatment is a cancer treatment means mainly based on operation excision, the principle of the method is simple and takes effect quickly, but a part of normal tissues and organs in a human body can be excised in the process, so that sequelae or dysfunction are caused, and besides, the operation treatment cannot prevent the metastasis and the spread of the cancer and can also cause the recurrence of the cancer. The radiotherapy and the chemotherapy are treatment methods for killing cancer cells by adopting high-energy radioactive rays (radiotherapy) or chemical medicaments (chemotherapy), have strong cancer killing capability, but the normal cells in a human body can be damaged by the high-energy rays or the medicaments during treatment, so that the patients are weak, and the treatment method is a double-edged sword. Whatever treatment thought is, the financial resources and the energy of the patient are all huge tests, so that the development of a novel convenient and efficient cancer treatment strategy has great significance.
The hydrogel is a three-dimensional porous material with excellent hydrophilicity, and the microstructure similar to human tissue endows the three-dimensional porous material with excellent biocompatibility, and can be applied to various biomedical fields, such as antibiosis, antiphlogosis, wound healing promotion, load carrying and the like through design. Hydrogels also have great application potential in cancer treatment, and photothermal therapy (PTT), magnetocaloric therapy (MHT), catalytic therapy and other auxiliary therapies for cancers have been reported. For example, cheng-Xiong Wei et al developed injectable composite hydrogels with chitosan/hyaluronic acid/sodium beta-glycerophosphate as matrix and carbon particles as photothermal agents. The tumor inhibition rate of the injectable composite hydrogel to a Balb/c nude mice bone and sarcoma model under the irradiation of near infrared laser (808 nm) reaches 98.4%, and the evaluation of bone regeneration of an SD rat skull defect model shows that the composite hydrogel can promote the formation of new bones, the ratio of the bone volume to the total volume is 76.2% after 8 weeks, and the in-situ magnetic hydrogel is designed in sharp contrast .(Cheng Xiong-Wei,Jin Xin,Wu Cheng-Wei,et al.Injectable composite hydrogel based on carbon particles for photothermal therapy of bone tumor and bone regeneration[J].Journal of Materials Science&Technology,2022,11864-72.)XuYan with 23.9% of a control group, and the like, and the gel is composed of a triblock polymer matrix (NDP) and graphene oxide nano-sheets with the surfaces decorated with ferric oxide nano-particles (Fe 3O4 @rGO, marked as FG), and the hydrogel (NDP-FG) not only has an efficient operation blood stopping effect, but also can prevent tumor recurrence, and the stable vascular embolism performance also shows that the NDP-FG hydrogel has good application prospect .(Xu Yan,Sun Tian-Ci,Song Yong-Hong,et al.In situ Thermal-Responsive Magnetic Hydrogel for Multidisciplinary Therapy of Hepatocellular Carcinoma[J].Nano Letters,2022,22(6):2251-2260.) in treating liver cancer through arterial embolism, but the materials of the hydrogel are complex, so that the application of the hydrogel in the aspect of tumor treatment is limited.
Ultrasonic waves are mechanical waves with extremely short wavelength, and have unique physical effects, noninvasive performance and safety, so that the ultrasonic waves have wide application in the treatment of diseases such as stones, joints and the like, and besides, the ultrasonic power therapy (SDT) taking the ultrasonic waves as a main initiating means is also brand-new in terms of cancer treatment, and is hopeful to become a safe and noninvasive novel cancer treatment means. Polylysine is co-assembled with Pluronic F127 as in Min Sun et al and crosslinked by Genipin to form a stable nanogel structure. Subsequently, ICAM-1 antibodies were grafted onto nanogels (designated GenPLPFT) for active targeting of tumors. After in vitro ultrasonic treatment, F127 is peeled off from GenPLPFT, the nano gel is induced to expand, the stability of the nano gel is reduced, and the drug release is accelerated so as to treat cancer (Min Sun,Yue Tao,Wang Congyu,et al.Ultrasound-Responsive Peptide Nanogels to Balance Conflicting Requirements for Deep Tumor Penetration and Prolonged Blood Circulation[J].ACS Nano,2022,16(6):9183-9194.)., but the ultrasonic sensitive hydrogel is complex to prepare, has a large number of microspheres in structure, is easily excreted from the body by the metabolism of the body and loses the treatment capacity, and in addition, the chemotherapeutic drugs loaded in the microspheres have potential risks for the health of patients. Therefore, designing an ultrasound-induced non-drug cancer treatment strategy with simple material preparation and difficult loss has great significance in the field of cancer treatment.
Disclosure of Invention
Aiming at the technical problems existing at present, the invention designs an in-situ antibacterial anticancer hydrogel triggered by ultrasonic waves and thermal effects thereof based on the characteristics of ultrasonic deep treatment and noninvasive treatment, wherein the in-situ antibacterial anticancer hydrogel consists of sulfhydryl sodium alginate (SA-SH), arginine-modified sodium alginate (SA-Arg), modified titanium dioxide nano-particles (TiO 2@MnO2, TMN) and beta-sodium glycerophosphate (beta-GP). After ultrasonic treatment, the in-situ antibacterial and anticancer hydrogel can generate sol-gel conversion and generate chemical substances such as ROS, NO, O 2 and the like, the chemical substances have broad-spectrum antibacterial property, and can excite cell immunoreaction activity, promote cancer cell apoptosis and improve TME (transition metal oxide) to generate synergistic antibacterial and anticancer effects while killing bacteria in wounds, and the ultrasonic sensitive hydrogel can provide a simple and efficient treatment strategy for ultrasonic therapy of cancers and has great significance in the field of cancer treatment.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
A preparation method of acoustic-thermal double-response hydrogel comprises the steps of grafting cysteine and arginine onto Sodium Alginate (SA) by utilizing condensation reaction of carboxyl and amino, and preparing sulfhydryl sodium alginate (SA-SH) and arginine-modified sodium alginate (SA-Arg); adding a certain amount of KMnO 4 solution into the aminated nano TiO 2 aqueous solution under an ultrasonic state to obtain TiO 2@MnO2; SA-SH and SA-Arg are dissolved in deionized water together, a certain amount of TiO 2@MnO2 is added to prepare a hydrogel precursor solution, a certain amount of beta-GP solution is added, and the acoustic-thermal double-response hydrogel can be obtained after ultrasonic treatment.
The preparation method of the acoustic-thermal double-response hydrogel specifically comprises the following steps:
(1) Dissolving sodium alginate in deionized water, adding NHS and EDC, activating at 25deg.C for 30min, adding cysteine, reacting at room temperature for 12 hr, dialyzing the obtained reactant, and freeze drying to obtain SA-SH; dissolving sodium alginate in deionized water, adding NHS and EDC, activating at 25deg.C for 30min, adding arginine, reacting at room temperature for 12 hr, dialyzing the obtained reactant, and freeze drying to obtain SA-Arg;
(2) Mixing and dispersing TiO 2 and APTES into an alkaline solution, reacting for 12 hours at 5 ℃, carrying out suction filtration after the reaction is finished, washing filter residues with deionized water and absolute ethyl alcohol in sequence, and carrying out vacuum drying to obtain aminated TiO 2 nano particles; dispersing the aminated TiO 2 nano-particles into KMnO 4 solution, performing ultrasonic treatment for 2 hours, and vacuum drying the obtained reactant to obtain TiO 2@MnO2;
(3) Mixing SA-SH and SA-Arg, dissolving in deionized water, and adding a TiO 2@MnO2 solution to obtain a hydrogel precursor solution; and adding beta-GP solution into the hydrogel precursor solution, and performing ultrasonic treatment for 10-30 min to obtain the acoustic-thermal double-response hydrogel.
In the step (1), sodium alginate of SA-SH is prepared: NHS: EDC: the molar ratio of cysteine is 1:1:1:1, a step of; preparation of sodium alginate of SA-Arg: NHS: EDC: arginine in a molar ratio of 1:1:1:1.
In the step (2), the mass ratio of TiO 2 to APTES is 100:1.
In the step (2), the alkaline solution is a 0.01M NaOH solution.
In the step (2), the concentration of the KMnO 4 solution is 10mg/mL.
In the step (3), SA-SH in the hydrogel precursor solution: sA-Arg: the mass ratio of TiO 2@MnO2 is 30:30:1.
In the step (3), the hydrogel precursor solution: the volume ratio of the beta-GP solution is 3.2:3.
In the step (3), the concentration of the beta-GP solution is 58 weight percent.
The acoustic-thermal double-response hydrogel prepared by the preparation method is provided.
The application of the acoustic-thermal double-response hydrogel in preparing medicaments with the effects of resisting bacteria, promoting wound healing and treating cancers.
The invention has the remarkable advantages that:
(1) The method adopts the hydrogel precursor solution with injectability and adopts ultrasound and the thermal effect thereof as a gelling means, thereby improving the safety, convenience and depth of treatment.
(2) After ultrasonic treatment, the hydrogel generates substances such as ROS, NO, O 2 and the like to improve TME and promote cancer cell apoptosis, and has synergistic anticancer effect.
(3) The-SH and-S-S-in the hydrogel have reversible denaturation, can continuously consume H 2O2 and GSH, and accelerate cancer cell death.
(4) The ultrasonic energy improves the permeability of cell membranes, so that small molecular substances can enter cancer cells more easily, and the cancer treatment effect is improved.
Drawings
FIG. 1 is a schematic representation of the sol-gel transition of hydrogels under the influence of sonothermal and their use in cancer therapy.
FIG. 2 is a reaction equation for SA-SH and SA-Arg.
Fig. 3 is an X-ray photoelectron spectrum (XPS) of TiO 2@MnO2.
Fig. 4 is an oxygen production capacity map of TiO 2@MnO2.
Fig. 5 is a plot of ROS production of TiO 2@MnO2 under sonication.
Fig. 6 is a digital image of the hydrogel before and after gelling.
Fig. 7 is an infrared thermal imaging picture of hydrogel ultrasound.
FIG. 8 is an infrared spectrum of a hydrogel.
FIG. 9 is a graph of the antimicrobial properties of hydrogels under different conditions.
Detailed Description
The invention discloses a hydrogel material with acoustic-thermal dual responsiveness, which is prepared from the following materials: sodium alginate, cysteine, arginine, tiO 2, a silane coupling agent KH550 (APTES), KMnO4, beta sodium glycerophosphate (beta-GP) and deionized water, wherein the sol-gel transition of the hydrogel material under the action of sound and heat and the application of the hydrogel material in cancer treatment are schematically shown in figure 1.
The following examples are illustrative of the invention and are not intended to limit the scope of the invention.
Example 1:
Step1: 1g of sodium alginate was added to 100mL of deionized water, and after complete dissolution, a sodium alginate solution was obtained, to which a certain amount of NHS and EDC were added to activate carboxyl groups (molar ratio of each substance is SA: NHS: edc=1:1:1), under the following conditions: activating at 25deg.C for 30min, adding 0.605g cysteine, reacting at 25deg.C for 12 hr, dialyzing in deionized water with dialysis bag with molecular weight cutoff of 8000-14000 for 3d, and lyophilizing at-26deg.C under vacuum condition of 0.09MPa for 2d to obtain SA-SH; 1g of sodium alginate was added to 100mL of deionized water, and after complete dissolution, a sodium alginate solution was obtained, to which a certain amount of NHS and EDC were added to activate carboxyl groups (molar ratio of each substance is SA: NHS: edc=1:1:1), under the following conditions: activating at 25deg.C for 30min, adding 0.870g arginine, reacting at 25deg.C for 12 hr, dialyzing in deionized water with dialysis bag with molecular weight cutoff of 8000-14000 for 3d, and lyophilizing at-26deg.C under vacuum condition of 0.09MPa for 2d to obtain SA-Arg; wherein the reaction equations involved are shown in FIG. 2.
Step 2: 100mg of TiO 2 and 1mg of APTES are mixed and dispersed into 100mL of NaOH solution with the concentration of 0.01M, the mixture is reacted for 12 hours at the temperature of 25 ℃, a 200-micrometer filter membrane is adopted for suction filtration after the reaction is finished, filter residues are sequentially filtered and washed for 3 times by deionized water and absolute ethyl alcohol respectively in vacuum, and the mixture is dried for 6 hours at the temperature of 50 ℃ in a vacuum drying box, so that the aminated TiO 2 nano particles are obtained; 60mg of aminated TiO 2 nano particles are dispersed into 100mL of KMnO 4 solution with the concentration of 10mg/mL, the solution is subjected to ultrasonic treatment at the frequency of 1.5MHz and the power of 100W for 2 hours at the temperature of 25 ℃, and the solution is dried at the temperature of 50 ℃ for 3 hours under the vacuum of 0.086MPa to obtain TiO 2@MnO2, and the TiO 2@MnO2 is dispersed into deionized water for standby.
Step 3: mixing and dissolving 0.06g of SA-SH and 0.06g of SA-Arg into 3mL of deionized water, and adding 0.2mL of 10mg/mL of TiO 2@MnO2 solution into the mixture to obtain a hydrogel precursor solution; 3mL of 58wt% beta-GP solution is added into 3.2mL of hydrogel precursor solution, and ultrasonic treatment is carried out for 10min at 25 ℃ with power of 1.5MHz and 100W, so that the acoustic-thermal double-response hydrogel (a hydrogel sample of TiO 2@MnO2) is obtained.
FIG. 3 is an X-ray photoelectron spectrum of TiO 2@MnO2. As can be seen, the main peaks of O1s, mn 2p and Ti 2p appear on the TiO 2@MnO2 sample, indicating the presence of Mn. The main O1 peak at 529.40eV corresponds to the lattice oxygen of the Ti-O bond. Mn 2p XPS spectrum has two peaks at 641.67eV and 653.78eV, corresponding to Mn 2p 3/2 and Mn 2p 1/2, respectively. As can be seen from the calculation of the two peak areas of Mn 2p, the ratio of Mn 3+/Mn4+ was about 0.6, indicating the simultaneous presence of MnO 2 and Mn 2O3 in the sample. In the Ti 2p region, the Ti 2p 2/2 and Ti 2p 2/3 main peak positions of TiO 2@MnO2 occur at 458.83eV and 464.50eV, respectively. The above results indicate successful synthesis of TiO2@MnO 2.
Fig. 4 is an oxygen production capacity map of TiO 2@MnO2. As can be seen, tiO 2@MnO2 has oxygen production characteristics that are positively correlated with the concentration of the reactant compared to pure TiO 2, whereas pure TiO 2 produces little oxygen, indicating the successful loading of MnO 2 on TiO 2 from the side.
Fig. 5 is a plot of ROS production of TiO 2@MnO2 under sonication. DPBF is a substance with sensitivity to ROS, and ultraviolet absorption peaks around 400nm are commonly used for representing ROS. After sonication, the ROS produced by TiO 2@MnO2 react with DPBF, resulting in a decrease in absorbance at 400nm, which is in line with design expectations.
Fig. 6 is a digital image of the hydrogel before and after gelling. After ultrasonic treatment, the hydrogel solution can undergo sol-gel transition within 10 min.
Fig. 7 is an infrared thermal imaging picture of hydrogel ultrasound. The temperature before ultrasonic treatment is 25 ℃, and after ultrasonic treatment, the temperature of the hydrogel is increased to about 35.8 ℃, which shows that the hydrogel has certain ultrasonic temperature sensitivity.
FIG. 8 is an infrared spectrum of a hydrogel. As compared with pure SA, SA-SH showed two more peaks of 1700cm -1 and 2500cm -1, representing an amide bond and a thiol group, respectively, indicating successful grafting of cysteines. After Gel formation, the 2500cm -1 peak in SA-Gel disappeared and the surface sulfhydryl groups reacted to form disulfide bonds.
Example 2:
Placing the prepared bacillus subtilis in a culture solution, sealing with a sealing film, and culturing in a bacteria incubator (37 ℃) for 24 hours; placing a hydrogel sample (marked as SA-gel+TMN2) added with 2mg of TiO 2@MnO2 in an ultra-clean bench for sterilization for 30min for later use; taking out the cultured bacterial liquid in an ultra-clean workbench, and measuring the OD value of each bacterial liquid by using an enzyme-labeled instrument. To each glass tube, 9mL of sterile culture solution was added, and each of the solutions was diluted to an appropriate multiple by 10-fold dilution according to the OD value of the solution. Four holes are selected from a 24-hole plate, and a proper amount of diluted bacterial liquid is added and is respectively marked as 1,2,3 and 4. Wherein, the hole No. 1 is a blank control group, the hole No. 2 is a blank ultrasonic control group, the hole No. 3 is a SA-gel+TMN2 group, the hole No. 4 is a SA-gel+TMN2 ultrasonic group, and the ultrasonic time of the holes No. 2 and No. 4 is 10min (1.5 MHz, 100W power, 25 ℃). After the ultrasonic treatment, 50 mu L of bacterial liquid is taken from each hole and placed on a clean bacterial culture medium, and after the bacterial liquid is cultured for 12 hours at 37 ℃, the bacterial liquid is taken out for observing the antibacterial effect, and the antibacterial performance is shown in figure 9. As can be seen from the graph, the colony count of the blank ultrasonic group was hardly changed from that of the blank group, indicating that the mere ultrasonic treatment did not have antibacterial property. In addition, the colony count of the SA-gel+TMN2 ultrasonic group is smaller than that of the SA-gel+TMN2 ultrasonic group, the blank ultrasonic group and the blank ultrasonic group, which shows that the antibacterial performance of the SA-gel+TMN2 after ultrasonic treatment is enhanced, and the design expectations are met. In conclusion, the SA-gel+TMN2 after ultrasonic treatment shows good antibacterial property and has potential of application in antibacterial aspect.
The foregoing description of the preferred embodiments of the present invention is not intended to limit the scope of the invention, and all other embodiments obtained without inventive effort by a person of ordinary skill in the art after reading the present invention are within the scope of the invention.
Claims (9)
1. A preparation method of the acoustic-thermal double-response hydrogel is characterized by comprising the following steps: the method comprises the following steps:
(1) Dissolving sodium alginate in deionized water, adding NHS and EDC, activating at 25deg.C for 30min, adding cysteine, reacting at room temperature for 12 hr, dialyzing the obtained reactant, and freeze drying to obtain SA-SH; dissolving sodium alginate in deionized water, adding NHS and EDC, activating at 25deg.C for 30min, adding arginine, reacting at room temperature for 12 hr, dialyzing the obtained reactant, and freeze drying to obtain SA-Arg;
(2) Mixing and dispersing TiO 2 and APTES into an alkaline solution, reacting for 12 hours at 25 ℃, carrying out suction filtration after the reaction is finished, washing filter residues with deionized water and absolute ethyl alcohol in sequence, and carrying out vacuum drying to obtain aminated TiO 2 nano particles; dispersing the aminated TiO 2 nano-particles into KMnO 4 solution, performing ultrasonic treatment for 2 hours, and vacuum drying the obtained reactant to obtain TiO 2@MnO2;
(3) Mixing SA-SH and SA-Arg, dissolving in deionized water, and adding a TiO 2@MnO2 solution to obtain a hydrogel precursor solution; adding a beta-GP solution into the hydrogel precursor solution, and performing ultrasonic treatment for 10-30 min to obtain the acoustic-thermal double-response hydrogel;
in the step (2), the alkaline solution is a 0.01M NaOH solution.
2. The method for preparing the acoustic-thermal dual-response hydrogel according to claim 1, wherein: in the step (1), sodium alginate of SA-SH is prepared: NHS: EDC: the molar ratio of cysteine is 1:1:1:1, a step of; preparation of sodium alginate of SA-Arg: NHS: EDC: arginine in a molar ratio of 1:1:1:1.
3. The method for preparing the acoustic-thermal dual-response hydrogel according to claim 1, wherein: in the step (2), the mass ratio of TiO 2 to APTES is 100:1.
4. The method for preparing the acoustic-thermal dual-response hydrogel according to claim 1, wherein: in the step (2), the concentration of the KMnO 4 solution is 10mg/mL.
5. The method for preparing the acoustic-thermal dual-response hydrogel according to claim 1, wherein: in the step (3), SA-SH in the hydrogel precursor solution: sA-Arg: the mass ratio of TiO 2@MnO2 is 30:30:1.
6. The method for preparing the acoustic-thermal dual-response hydrogel according to claim 1, wherein: in the step (3), the hydrogel precursor solution: the volume ratio of the beta-GP solution is 3.2:3.
7. The method for preparing the acoustic-thermal dual-response hydrogel according to claim 1, wherein: in the step (3), the concentration of the beta-GP solution is 58 weight percent.
8. An acoustic-thermal dual response hydrogel made by the method of claim 1.
9. The use of the acoustic-thermal dual-response hydrogel of claim 8 in the preparation of a medicament having antibacterial, wound healing promoting and cancer treatment effects.
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