CN116023681A - 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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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-response hydrogel mainly comprises sulfhydryl sodium alginate (SA-SH), arginine-modified sodium alginate (SA-Arg), modified titanium dioxide nano-particles (TiO) 2 @MnO 2 ) Beta-sodium glycerophosphate (beta-GP). Upon sonication, the hydrogel undergoes a sol-gel transition and produces ROS, NO and O 2 The chemical substances can excite the immunoreactivity of wound or tumor immune cells, promote the apoptosis of the wound or cancer cells and improve the tumor microenvironment, and produce 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-XionWei 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 on a Balb/c nude mice osteosarcoma model under the irradiation of near infrared laser (808 nm) reaches 98.4%, and the evaluation of bone regeneration on 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 ratio is in clear contrast with 23.9% of a control group. (ChengXiong-Wei, jinxin, wuCheng-Wei, et al, injectabalecomposite hydrogelbasedoncoumarticles for photothermalthapeutic ofbonet oridandbonegeneration [ J ]].JournalofMaterialsScience&Technology,2022,11864-72.) XuYan et al designed an in situ magnetic hydrogel composed of a triblock polymer matrix (NDP) and surface decorated with iron oxide nanoparticles (Fe 3 O 4 The hydrogel (NDP-FG) not only has high-efficiency 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 in treating liver cancer through arterial embolism. (Xu Yan, sunTian-Ci, songYong-Hong, et al Instituthermal-ResponsiveMagneticHydrogelfor MultidisciplinaryTherapyofHepatocellularCarcinoma [ J)]Nanoletters,2022,22 (6): 2251-2260.) but these hydrogels are complex materials and difficult to implement in therapeutic approachesThus limiting its use in tumor therapy.
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. After co-assembly of polylysine with PluronicF127 as in MinSun et al, stable nanogel structures are formed by Genipin cross-linking. Subsequently, ICAM-1 antibodies were grafted onto nanogels (designated GenPLPFT) for active targeting of tumors. After in vitro sonication, F127 was peeled from GenPLPFT, inducing nanogel swelling, decreasing its stability, and accelerating drug release to treat cancer (MinSun, yueTao, wangCongyu, et al ultrasonic bond-Responsive PeptideNanogelstoBalanceConflictingRequirementsforDeepTumorPenetrationandProlonged BloodCirculation [ J ] ACSNano,2022,16 (6): 9183-9194.). However, the ultrasound sensitive hydrogel has complex preparation and most of structures, is easily excreted by the body to lose the therapeutic capability, 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 which is 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 is prepared from sulfhydryl sodium alginate (SA-SH), arginine-modified sodium alginate (SA-Arg), modified titanium dioxide nano particles (TiO) 2 @MnO 2 TMN) and sodium beta-glycerophosphate (beta-GP). Upon injection into the Tumor Microenvironment (TME), the in situ antimicrobial anticancer hydrogel undergoes a sol-gel transition and generates ROS, NO and O after sonication 2 And chemical substances with broad-spectrum antibacterial property, and can kill bacteria in woundThe ultrasonic sensitive hydrogel can provide a simple and efficient treatment strategy for ultrasonic therapy of cancer, 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 method for preparing acoustic-thermal dual-response hydrogel comprises condensing carboxyl and amino to obtain cysteine and arginin
Acid grafting to Sodium Alginate (SA) to prepare sulfhydryl sodium alginate (SA-SH) and arginine-modified sodium alginate (SA-Arg); adding a certain amount of KMnO4 solution into the aminated nano TiO2 water solution under an ultrasonic state to obtain TiO2@MnO2; SA-SH and SA-Arg are dissolved in deionized water together, a certain amount of TiO2@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 is 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) TiO is mixed with 2 Mixing with APTES, dispersing in alkaline solution, reacting at 5deg.C for 12 hr, filtering, washing the residue with deionized water and absolute ethanol, and vacuum drying to obtain amino TiO 2 A nanoparticle; aminated TiO 2 Nanoparticle dispersion to KMnO 4 Ultrasonic treatment is carried out for 2 hours in the solution, and the obtained reactant is dried in vacuum to obtain TiO 2 @MnO 2 ；
(3) Mixing SA-SH and SA-Arg, dissolving in deionized water, adding TiO 2 @MnO 2 Obtaining a hydrogel precursor solution; addition of beta-GP to hydrogel precursor solutionAnd carrying out ultrasonic treatment on the solution 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), tiO 2 And APTES with a mass ratio of 100:1.
in the step (2), the alkaline solution is a 0.01M NaOH solution.
In the step (2), KMnO 4 The concentration of the solution was 10mg/mL.
In the step (3), SA-SH in the hydrogel precursor solution: sA-Arg: tiO (titanium dioxide) 2 @MnO 2 The mass ratio of (2) 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) The hydrogel generates ROS, NO and O after ultrasonic treatment 2 Such substances improve TME and pro-cancer apoptosis, producing synergistic anticancer effects.
(3) the-SH and-S-S-in the hydrogel have reversible denaturation and can continuously consume H 2 O 2 And GSH, 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 TiO 2 @MnO 2 X-ray photoelectron spectroscopy (XPS).
FIG. 4 is TiO 2 @MnO 2 Is used for generating oxygen energy.
FIG. 5 is TiO under ultrasonic treatment 2 @MnO 2 ROS production profile of (c).
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 and TiO 2 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:
step 1: 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: 100mgTiO 2 Mixing with 1mg APTES, dispersing into 100mL NaOH solution with concentration of 0.01M, reacting at 25deg.C for 12 hr, vacuum filtering with 200 μm filter membrane, vacuum filtering and washing the filter residue with deionized water and absolute ethanol respectively for 3 times, and drying at 50deg.C in vacuum drying oven for 6 hr to obtain aminated TiO 2 A nanoparticle; 60mg of aminated TiO 2 Nanoparticle dispersion to 100mL of KMnO 10mg/mL 4 The TiO is obtained after the solution is dried for 3 hours at 50 ℃ under the vacuum of 0.086MPa under the conditions of 1.5MHz frequency, 100W power and 25 ℃ ultrasonic treatment for 2 hours 2 @MnO 2 Dispersing in deionized water for standby.
Step 3: 0.06gSA-SH and 0.06gSA-Arg were mixed and dissolved in 3mL of deionized water, to which 0.2mL of 10mg/mL TiO was added 2 @MnO 2 Obtaining 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, thus obtaining the acoustic-thermal double-response hydrogel (TiO) 2 @MnO 2 Is a hydrogel sample).
FIG. 3 is TiO 2 @MnO 2 X-ray photoelectron spectroscopy of (c). As can be seen from the figure, in TiO 2 @MnO 2 The main peaks of O1s, mn2p and Ti2p appear on the sample, indicating the presence of Mn. The main O1 peak at 529.40eV corresponds to the lattice oxygen of the Ti-O bond. Mn2pXPS spectrum has two peaks at 641.67eV and 653.78eV, corresponding to Mn2p respectively 3/2 And Mn2p 1/2 . As can be seen from the calculation of the two peak areas of Mn2p, mn 3+ /Mn 4+ About 0.6, indicating the presence of MnO in the sample 2 And Mn of 2 O 3 . In the Ti2p region, tiO 2 @MnO 2 Is Ti2p of (2) 2/2 And Ti2p 2/3 Main peak position divisionAppear at 458.83eV and 464.50eV, respectively. The above results indicate that TiO2@MnO 2 Is a successful synthesis of (a).
FIG. 4 is TiO 2 @MnO 2 Is used for generating oxygen energy. From the figure, it can be seen that with pure TiO 2 In comparison with TiO 2 @MnO 2 Has oxygen-generating property positively correlated with reactant concentration, while pure TiO 2 Almost no oxygen is generated, and the MnO is shown from the side 2 In TiO 2 Is a successful load of (a).
FIG. 5 is TiO under ultrasonic treatment 2 @MnO 2 ROS production profile of (c). DPBF is a substance with sensitivity to ROS, and ultraviolet absorption peaks around 400nm are commonly used for representing ROS. After ultrasonic treatment, tiO 2 @MnO 2 The ROS produced will react with DPBF, resulting in a decrease in absorbance at 400nm, which results are consistent 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. SA-SH is 1700cm more than pure SA -1 And 2500cm -1 The two peaks, representing an amide bond and a thiol group, respectively, indicate successful grafting of cysteine. After gelling, 2500cm in SA-Gel -1 The surface sulfhydryl groups react 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; will add 2mgTiO 2 @MnO 2 Placing the hydrogel sample (marked as SA-gel+TMN2) in an ultra-clean workbench 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. 9mL of sterile culture solution was added to each glass tube, and each of the solutions was diluted by 10-fold dilution according to the OD value of the solutionTo the appropriate multiple. 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 (10)
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) TiO is mixed with 2 Mixing with APTES, dispersing in alkaline solution, reacting at 25deg.C for 12 hr, filtering, washing the residue with deionized water and absolute ethanol, and vacuum drying to obtain amino TiO 2 A nanoparticle; aminated TiO 2 Nanoparticle dispersion to KMnO 4 Ultrasonic treatment is carried out for 2 hours in the solution, and the obtained reactant is dried in vacuum to obtain TiO 2 @MnO 2 ；
(3) Mixing SA-SH and SA-Arg, dissolving in deionized water, adding TiO 2 @MnO 2 Obtaining 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.
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), tiO 2 And APTES with a mass ratio of 100:1.
4. the method for preparing the acoustic-thermal dual-response hydrogel according to claim 1, wherein: in the step (2), the alkaline solution is a 0.01M NaOH solution.
5. The method for preparing the acoustic-thermal dual-response hydrogel according to claim 1, wherein: in the step (2), KMnO 4 The concentration of the solution was 10mg/mL.
6. 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: tiO (titanium dioxide) 2 @MnO 2 The mass ratio of (2) is 30:30:1.
7. 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.
8. 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.
9. An acoustic-thermal dual response hydrogel made by the method of claim 1.
10. Use of the acoustic-thermal dual-response hydrogel of claim 1 in the preparation of a medicament having antibacterial, wound healing promoting and cancer treatment effects.
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