CN114533936A - Thermal response magnetic hydrogel, preparation method and application thereof - Google Patents

Thermal response magnetic hydrogel, preparation method and application thereof Download PDF

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CN114533936A
CN114533936A CN202210172715.XA CN202210172715A CN114533936A CN 114533936 A CN114533936 A CN 114533936A CN 202210172715 A CN202210172715 A CN 202210172715A CN 114533936 A CN114533936 A CN 114533936A
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thermal response
hydrogel
temperature
magnetic hydrogel
magnetic
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CN114533936B (en
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陆杨
何涛
闫旭
孙天赐
宋永红
曹葆强
徐运军
胡金龙
彭伟
骆广义
李敏
陈�胜
方蔚伟
董良
宣守虎
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Hefei University of Technology
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Abstract

The invention relates to the technical field of magnetic materials, in particular to a thermal response magnetic hydrogel, a preparation method and application thereof. The magnetic thermal response hydrogel overcomes the defects of single function, insufficient mechanical property and easy fragmentation in blood vessels of the existing hydrogel embolization agent, can realize in-situ gelatinization in blood vessels by means of the temperature of an organism and show stable intravascular embolization performance, and realizes magnetic thermal response magnetic hydrogel-mediated liver cancer interventional embolization combined magnetic thermotherapy; meanwhile, the magnetic thermal response hydrogel has soft tissue adhesion performance, can be used for local magnetic thermal recurrence prevention treatment after liver cancer operation, is simple in preparation method, mild in preparation conditions and high in biological safety, and can be used as a clinical medical hydrogel material.

Description

Thermal response magnetic hydrogel, preparation method and application thereof
Technical Field
The invention relates to the technical field of magnetic materials, in particular to a thermal response magnetic hydrogel, a preparation method and application thereof.
Background
Primary liver cancer (HCC) is one of the common digestive system malignancies worldwide, surgical resection is the first-line scheme for early liver cancer treatment, and the surgical resection liver cancer treatment scheme faces 2 important problems:
(1) the primary liver cancer is hidden, has no specific symptoms in the early stage, and most patients belong to the middle and late stage of the course of the disease when the diagnosis is confirmed. Transarterial embolization chemotherapy (TACE) is the first-line treatment regimen for middle and advanced liver cancer. TACE is administered with iodized oil mixed with chemotherapeutic drug doxorubicin (Iodide @ DOX) and doxorubicin eluting microspheres (DEBDOX) as embolic agent to effectively treat HCC. Iodide @ DOX is a strong-mobility liquid embolic agent, and blood is cleared quickly and cannot be embolized for a long time. The DEBDOX solid particles have larger embolus size and are difficult to embolise the small HCC feeding vessel ends; (2) high postoperative recurrence rate is another difficulty faced by the surgical resection of liver cancer treatment regimens. The recurrence rate within 5 years after liver cancer resection is as high as 60-70%, and the death rate of patients with recurrence is nearly as high as 100%. Systemic radiotherapy and chemotherapy can play a certain role in preventing the recurrence of tumor after surgical resection, but the harm of systemic toxicity caused by radiotherapy and chemotherapy to patients cannot be ignored. The new target drugs and immune drugs are on the market, and bring new hopes and choices for the postoperative treatment of liver cancer patients. However, whether the liver cancer patients can benefit from the traditional Chinese medicine composition also needs further clinical case accumulation, and the extremely high medication cost can not be borne by most common patients.
The shear-thinning hydrogel has the potential of being developed into a novel embolic agent and a nano material local delivery carrier by virtue of excellent injectability, mechanical controllability and drug loading function. The hydrogel embolic agent has been reported to have the defects of weak mechanical property and single function.The hydrogel has weak mechanical strength and can not bear the physiological pressure in the artery, the hydrogel is easy to be cracked, the gel fragments swim to the blood vessels of normal tissues to form ectopic embolism, the single embolism chemotherapy can not obtain the optimal curative effect, and the radiofrequency ablation is required to be combined,125I invasive adjuvant therapy such as radiotherapy. These treatments are prone to radiation damage or penetrating bleeding from normal liver tissue. In addition, the liver is soft in texture and rich in blood supply, has dual blood supply of a portal vein system and a hepatic artery system, and has the problem of massive bleeding of incisal wound during liver cancer surgical resection. Excessive bleeding can cause the surface of the incisal wound to be slippery, and the hydrogel is required to have strong soft tissue adhesion capacity. Most of the reported current hydrogel materials for tumor margin treatment cannot meet the requirement of high adhesion, and are difficult to be really applied to clinical hepatoma resection treatment.
Magnetic energy is converted into heat energy by a magnetic material under a high-frequency Alternating Magnetic Field (AMF), so that the temperature of tissues at a tumor part is increased (above 42 ℃), and the aim of inducing cancer cell apoptosis is fulfilled. The magnetic induction thermotherapy becomes a research hotspot in the current tumor treatment field by virtue of the advantages of no tissue penetration depth, higher tumor thermal injury efficiency, almost no systemic toxicity, minimal invasion and the like, and is considered as a new liver cancer treatment method with huge clinical application potential.
In view of the above-mentioned drawbacks, the inventors of the present invention have finally obtained the present invention through a long period of research and practice.
Disclosure of Invention
The invention aims to solve the problem that the existing hydrogel material cannot simultaneously take the interventional embolization treatment of liver cancer and the postoperative recurrence prevention treatment into consideration due to single function, weak mechanical property and insufficient adhesion property, and provides a thermal response magnetic hydrogel, a preparation method and application thereof.
In order to achieve the aim, the invention discloses a preparation method of a thermal response magnetic hydrogel, which comprises the following steps:
s1: dissolving polyethylene glycol and triethylamine in dichloromethane, and introducing argon for protection to obtain a mixed solution;
s2: dissolving 4-cyano-4- (phenylcarbonylthio) pentanoic acid-succinimide ester in dichloromethane, dropwise adding the dichloromethane into the mixed solution, stirring at room temperature for 10-24 hours, settling the obtained product in diethyl ether, and performing vacuum drying to obtain a macromolecular chain transfer agent;
s3: dissolving the macromolecular chain transfer agent obtained in the step S2 in dioxane, adding a temperature-sensitive monomer, acrylic acid-N-succinimide ester and a free radical initiator, fully dissolving, introducing argon for protection, reacting for 24-48 h at 50-90 ℃ after three freeze-thaw cycles, settling the obtained product in ether for three times, and performing vacuum drying to obtain a temperature-sensitive polymer;
s4: dissolving the temperature-sensitive polymer obtained in the step S3 in dichloromethane, then adding triethylamine and micromolecules with adhesive functional groups, fully dissolving, introducing argon for protection, reacting at room temperature for 12-48 h, settling the obtained product in diethyl ether twice, and drying in vacuum to obtain a temperature-sensitive copolymer;
s5: adding a two-dimensional nano sheet into distilled water, performing ultrasonic uniform dispersion, adding polystyrene sodium sulfate and hydrazine hydrate, reacting for 24-48 h at 100 ℃, performing suction filtration and freeze drying on the obtained product to obtain a two-dimensional nano sheet-polystyrene sodium sulfate compound, adding the two-dimensional nano sheet-polystyrene sodium sulfate compound and ferric acetylacetonate into tetraethylene glycol, performing ultrasonic uniform dispersion, introducing argon protection, heating the solution to 270-300 ℃ in a gradient manner, and centrifuging and removing supernatant after the reaction is finished to obtain an iron-carrying nano sheet aqueous solution;
s6: and (4) dissolving the temperature-sensitive copolymer obtained in the step S4 in the iron-carrying nanosheet aqueous solution obtained in the step S5 to obtain the thermal response magnetic hydrogel.
The amounts of the polyethylene glycol, the triethylamine and the dichloromethane in the step S1 are respectively 1-20 g, 1-10 g and 20-200 mL.
The amounts of 4-cyano-4- (phenylcarbonylthio) pentanoic acid-succinimidyl ester and dichloromethane in the step S2 are 1-10 g and 5-20 mL, respectively.
In the step S3, the amounts of the macromolecular chain transfer agent, dioxane, a temperature-sensitive monomer, acrylic acid-N-succinimidyl ester and a free radical initiator are respectively 0.1-1 g, 5-20 mL, 2-20 g, 1-10 g and 0.1-1 g, the temperature-sensitive monomer is any one of N-isopropyl acrylamide, N-diethyl-2-acrylamide, N-N-propyl acrylamide and polyethylene glycol methacrylate, and the free radical initiator is any one of azobisisobutyronitrile, dimethyl azobisisobutyrate and benzoyl peroxide.
In the step S4, the amounts of the temperature-sensitive polymer, the dichloromethane, the triethylamine and the micromolecules with adhesive functional groups are respectively 0.1-2 g, 10-40 mL, 0.1-2 g and 1-20 g, and the micromolecules with adhesive functional groups are dopamine hydrochloride or gallic acid.
In the step S5, the amounts of the two-dimensional nano sheet, the distilled water, the polystyrene sodium sulfate, the hydrazine hydrate, the two-dimensional nano sheet-polystyrene sodium sulfate compound, the ferric acetylacetonate and the tetraethylene glycol are respectively 100-500 mg, 100-500 mL, 1-10 g, 100-500 μ L, 50-200 mg, 10-20 g and 50-200 mL, and the two-dimensional nano sheet is any one of graphene oxide, mica and montmorillonite.
The step S5 lyophilization temperature was-60 ℃.
The gradient temperature increase rate in the step S5 is set to 5 ℃/min.
The invention also discloses the thermal response magnetic hydrogel prepared by the preparation method and application of the thermal response magnetic hydrogel in auxiliary liver cancer resection and postoperative recurrence prevention equipment.
The thermal response magnetic hydrogel comprises two materials of a temperature-sensitive copolymer and an iron-loaded nanosheet. The temperature-sensitive copolymer endows a hydrogel system with thermal gelling performance and tissue adhesion, and the iron-loaded nanosheet provides the thermal response magnetic hydrogel with magnetocaloric performance. The two materials are compounded to prepare the novel thermal response magnetic hydrogel with excellent magnetic thermal property, stable mechanical property and tissue adhesion, and the thermal response magnetic hydrogel-mediated liver cancer interventional embolism combined magnetic thermal therapy and postoperative magnetic thermal recurrence prevention treatment are realized.
The thermal response magnetic hydrogel disclosed by the invention has excellent magnetocaloric property, stable mechanical property and good tissue adhesion.
The application of the thermal response magnetic hydrogel is applied to interventional embolization treatment combined magnetic thermotherapy of primary or metastatic liver cancer which cannot be resected by an operation or small liver cancer which a patient does not want to be operated due to various reasons, and postoperative recurrence prevention treatment of resectable primary or metastatic liver cancer.
Compared with the prior art, the invention has the beneficial effects that:
1. the thermal response magnetic hydrogel provided by the invention has the advantages of excellent magnetic thermal property, stable mechanical property and tissue adhesion. The magnetic thermal response hydrogel overcomes the defects of single function, insufficient mechanical property and easy fragmentation in blood vessels of the existing hydrogel embolization agent, can realize in-situ gelatinization in blood vessels by means of the temperature of an organism and show stable intravascular embolization performance, and realizes magnetic thermal response magnetic hydrogel-mediated liver cancer interventional embolization combined magnetic thermotherapy; meanwhile, the magnetic-thermal anti-recurrence plaster has soft tissue adhesion performance and can be used for local magnetic-thermal anti-recurrence treatment after liver cancer operation;
2. the thermal response magnetic hydrogel provided by the invention has the advantages of simple preparation method, mild preparation conditions, high biological safety and no pollution, is a material with high safety, and can be used as a clinical medical hydrogel material;
3. the thermal response magnetic hydrogel provided by the invention has the advantages of stable structure, strong practicability and higher clinical and market application potentials.
Drawings
FIG. 1 is a graph showing (a) an XRD pattern, (b) an infrared spectrum, (c) storage modulus, loss modulus as a function of temperature, (d) a cross-sectional scanning electron micrograph (SEM, Zeiss Supra 40, Germany), (e) a scanning electron micrograph (EDS, X-Max, Oxford), (f) a magnetocaloric temperature rise curve, (g) photographs of an adherent pigskin, a metal sheet and glass, and (h) adhesion strength to the pigskin, the metal sheet and the glass, of a thermally responsive magnetic hydrogel prepared in example 1 of the present invention;
FIG. 2 is a graph of the thermo-responsive magnetic hydrogel prepared in example 1 of the present invention and a control group showing (a) a hemostatic process of rat liver, (b) an observation and comparison of a blood loss amount of rat liver, (c) a statistical comparison of a blood loss amount of rat liver, and (d-e) a scan after contacting with red blood cells;
FIG. 3 is a graph showing the effect of the thermal response magnetic hydrogel prepared in example 1 of the present invention on a control group (a) after tumor-treated mice for 14 days, (b-c) a thermal heating infrared thermogram and a temperature variation curve of the treated mice, (d) a tumor recurrence rate curve of the treated mice for 14 days, and (e) a comparison graph of the tumor mass and the tumor volume of the treated mice for 14 days;
FIG. 4 is a photograph of the thermoresponsive magnetic hydrogel prepared in example 1 of the present invention (a) showing the peripheral artery before and after embolization of rabbit ear and IR thermograph, (b) a graph showing the oxyhemoglobin saturation of rabbit ear and the temperature change of embolized region, and (c) a photograph showing the artery supplying blood to rabbit VX2 liver tumor;
FIG. 5 is a graph of the thermal response magnetic hydrogel prepared in example 1 of the present invention showing (a) a model process of liver tumor treated by minimally invasive laparoscopic surgery VX2, (b) a photograph of liver after magnetocaloric treatment, (c-d) a pathological section of tumor and a comparison of tumor necrosis factor.
Detailed Description
The above and further features and advantages of the present invention are described in more detail below with reference to the accompanying drawings.
Example 1
This example performs the preparation of a thermoresponsive magnetic hydrogel as follows:
step 1: dissolving 1.5g of polyethylene glycol (Mw ═ 4000) and 1g of triethylamine in 20mL of dichloromethane, introducing argon for protection, dissolving 1.5g of 4-cyano-4- (phenylcarbonylthio) pentanoic acid-succinimidyl ester in 10mL of dichloromethane, dropwise adding the solution into the solution through a dropping funnel, stirring the solution at room temperature for 24 hours, settling the obtained product in diethyl ether for three times, and drying in vacuum to obtain the macromolecular chain transfer agent;
step 2: dissolving 0.1g of the macromolecular chain transfer agent obtained in the step 1 in 5mL of 1, 4-dioxane, putting the obtained solution into a polymerization bottle, adding 5g N-isopropyl acrylamide, 2g of acrylic acid-N-succinimidyl ester and 0.1g of azobisisobutyronitrile, fully dissolving, introducing argon for protection, reacting for 24 hours at 78 ℃ after three freeze-thaw cycles, settling the obtained product in diethyl ether for three times, and performing vacuum drying to obtain a temperature-sensitive polymer;
and step 3: dissolving 1g of the temperature-sensitive polymer obtained in the step 2 in 10mL of dichloromethane, then adding 0.5g of triethylamine and 2g of dopamine with hydrochloric acid, fully dissolving, introducing argon for protection, reacting at room temperature for 16 hours, settling the obtained product in diethyl ether twice, and drying in vacuum to obtain a temperature-sensitive copolymer (named as NDP);
and 4, step 4: adding 100mg of graphene oxide into 100mL of distilled water, carrying out ultrasonic uniform dispersion, adding 2g of polystyrene sodium sulfate and 100 mu L of hydrazine hydrate, reacting at 100 ℃ for 24 hours, and carrying out suction filtration and freeze-drying (the freeze-drying temperature is-60 ℃) on the obtained product to obtain the graphene-polystyrene sodium sulfate compound. 100mg of graphene-polystyrene sodium sulfate compound and 10g of iron acetylacetonate are added into 50mL of tetraethylene glycol, the mixture is uniformly dispersed by ultrasonic, argon is introduced for protection, and the solution is subjected to gradient temperature rise to 270 ℃ (the temperature rise rate is set to be 5 ℃/min). Centrifuging and removing supernatant after the reaction is finished to obtain an iron-loaded graphene aqueous solution (named FG);
and 5: and (3) dissolving the temperature-sensitive copolymer obtained in the step (3) in an iron-loaded graphene aqueous solution (the concentration of the iron-loaded graphene is 10-100 mg/mL), so as to obtain the thermal response magnetic hydrogel (named NDP-FG).
In the step 5, the mass ratio of the copolymer to the iron-loaded graphene aqueous solution is 1: 4.
To compare the magnetocaloric properties of the thermoresponsive magnetic hydrogels, a control hydrogel was prepared as follows: and (3) dissolving the copolymer obtained in the step (3) in a deionized water solution (the mass ratio of the copolymer to the deionized water is 1:4), so as to obtain the hydrogel (named NDP) of the control group.
FIG. 1(a) is an XRD (X ray diffraction) pattern of the thermo-responsive magnetic hydrogel (NDP-FG) prepared in this example and the iron-loaded graphene (FG), and it can be seen that NDP-FG has three stronger diffraction peaks in the directions of 38 °, 57 ° and 62 °, which is in contrast to Fe3O4The (311), (511) and (440) crystal plane diffraction peak heights of the nanoparticles are consistent (JCPDS No. 19-0629); FIG. 1(b) is an infrared spectrum of NDP-FG and NDP, and it can be seen that the NDP-FG hydrogel has a wavelength of 585cm-1And 1750cm-1The peak appears due to the formation of Fe-O bonds and carboxyl groups carried by FG nanoplates, demonstrating the successful preparation of thermo-responsive magnetic hydrogel (NDP-FG). Fig. 1(d-e) is a scanning electron microscope image and a scanning electron microscope energy spectrum of a cross section of the thermal response magnetic hydrogel, and it can be seen that the thermal response magnetic hydrogel is of a pore structure, contains three characteristic elements of carbon, oxygen and iron, and the iron element is uniformly distributed in the original solution of the thermal response magnetic hydrogel.
Fig. 1(c) is a graph showing the change of storage modulus and loss modulus of the thermal response magnetic hydrogel along with the change of temperature, and it can be seen that: with the increase of the temperature, the NDP-FG shows obvious phase transition behavior at about 15 ℃, the right solution state is converted into a gel state, and with the further increase of the temperature, the gel state is kept all the time, and sensitive thermal responsiveness is shown.
Fig. 1(f) is a graph showing the magnetocaloric temperature rise of the thermoresponsive magnetic hydrogel and the control hydrogel in an Alternating Magnetic Field (AMF), and it can be seen that the temperature of NDF-FG rises from 20 ℃ to 49 ℃ within 10 minutes, while no temperature rise is observed in the NDP material, indicating that the thermoresponsive magnetic hydrogel has a good magnetocaloric temperature rise effect.
Fig. 1(g-h) is a photograph and a graph of adhesion strength of a thermal response magnetic hydrogel to pigskin, metal sheets and glass, and it can be seen that the thermal response magnetic hydrogel has good adhesion to organic/inorganic materials, which provides favorable conditions for application of the thermal response magnetic hydrogel in clinical liver hemostasis.
In order to test the liver hemostatic performance of the thermal response magnetic hydrogel, an adult male SD rat is anesthetized, the abdomen is exposed, hairs on the abdomen are cut by a surgical scissors until the skin is exposed, the skin is opened layer by using the surgical scissors after the sterilization treatment, the liver of the rat is exposed, a wound is scratched on the surface of the liver by using a scalpel lightly, the thermal response magnetic hydrogel is injected to a bleeding part immediately after blood flows out of the wound, and shooting and recording are carried out. In addition, this example designs NDP hydrogel hemostasis, clinical gelatin sponge (Gelfoam) hemostasis, and no treatment of wound (Control) as a Control group. As shown in FIGS. 2(a-c), the thermo-responsive magnetic hydrogel was superior to the control in both the speed of hemostasis and the reduction of bleeding volume. FIG. 2(d-e) is a scanning picture of NDP-FG hydrogel and NDP hydrogel after contact with erythrocytes, and it can be seen that NDP-FG after contact with erythrocytes causes the pseudopodia of erythrocytes to stretch outwards and cross-link with each other, promoting the aggregation between erythrocytes, thereby accelerating the blood coagulation process, and indicating that the thermo-responsive magnetic hydrogel has good liver hemostasis performance.
In order to test the magnetic thermal killing effect of the thermal response magnetic hydrogel on the tumor and the tumor recurrence inhibition capacity, 30 hip-back tumors with the volume of about 100mm are selected3The tumor-bearing mice of (1) were subjected to the experiment. After anesthetizing the mice, the skin of the tumor site of the mice was incised, and the tumor mass was peeled off and removed, and then NDP-FG hydrogel (200 μ L) was injected at the tumor excision site of 20 of the mice. As an experimental control group, phosphate buffered saline (PBS, 200 μ L) was injected at the tumor excision sites of the remaining 10 mice, and then the skin of all the tumor excision sites of the mice was sutured. 10 mice injected with NDP-FG hydrogel and PBS were treated under an Alternating Magnetic Field (AMF) for 15 minutes, all mice were cultured under the same environment for 14 days, and the tumor recurrence of the mice was observed and recorded. On day 14, mice that remained alive were sacrificed, tumors were removed, and the weight of the tumors was recorded and photographed. As shown in FIG. 3(a), the tumors of the mice in the NDP + AMF group did not recur after 14 days, and the tumors of the mice in the other two groups apparently recurred. As shown in FIG. 3(b-c), the temperature of the thermal response magnetic hydrogel at the tumor excision site of the mouse can be raised to over 45 ℃, and the residual tumor tissue can be effectively killed. As shown in fig. 3(d), the tumor recurrence rate of the mice treated with the thermal response magnetic hydrogel was only 20% after 14 days, and the tumor recurrence rate of the other two groups of mice reached 100%. As shown in fig. 3(e), the mass and volume of the tumor relapsed after 14 days in the mice treated with the thermal response magnetic hydrogel are much lower than those in the other two groups, indicating that the thermal response magnetic hydrogel has good effect of killing tumor by magnetic heat and the ability of inhibiting tumor recurrence.
To test the effect of thermal response magnetic hydrogel arterial embolization, this example designed rabbit ear-margin arterial embolization experiments as follows: NDP-FG hydrogel (0.2mL) was injected into the marginal artery of the anesthetized rabbit, and the embolized rabbit ear was photographed and recorded at the set time points (0 day, 1 day, 3 days, 7 days), and the embolized rabbit ear was subjected to blood oxygen concentration and temperature measurement using a portable oximeter (Yuwell. China) and an infrared thermal imager (Fluke-Ti 400). FIG. 4(a) is a photograph and an infrared thermograph of the rabbit before and after embolization of the ear-marginal artery, and it can be seen that the rabbit ear embolization part is significantly reduced in temperature and ulcerated 7 days after embolization. Fig. 4(b) is a graph showing the blood oxygen concentration and temperature variation curve of the ear artery of the rabbit for embolization, and it can be seen that the temperature and blood oxygen concentration in the embolized region are far lower than the normal parameter range, indicating that the thermal response magnetic hydrogel has a better embolization effect on the ear artery of the rabbit.
In order to further test the embolization effect of the thermal response magnetic hydrogel on primary liver cancer arterial blood vessels, the arterial embolization experiment of new zealand white rabbit liver cancer tumor was designed as follows: after a new zealand white rabbit with VX2 tumor growing in the liver was anesthetized, the femoral artery was isolated using a sterile surgical instrument, an interventional microcatheter was introduced into the VX2 tumor-bearing artery site with the aid of a subtraction angiography (DSA), an NDP-FG solution (0.1mL) was injected into the VX2 tumor-bearing artery site through the microcatheter, and the embolization effect was observed. Fig. 4(c) is a photograph of an artery for embolization of a artery supplying blood to a liver tumor of rabbit VX2 with a thermo-responsive magnetic hydrogel, and it can be seen that NDP-FG hydrogel can be clearly observed in the artery supplying blood to the tumor, and secondary angiography shows that the tumor site cannot be imaged because the contrast agent cannot reach. In addition, non-target arteries experience reflux of contrast due to changes in blood flow (deviation from the embolization region). These results confirmed that the blood supply vessels around the tumor were completely blocked by the hydrogel, indicating that the thermoresponsive magnetic hydrogel has the potential to treat liver cancer via arterial embolization.
In order to test the anti-recurrence effect of the thermal response magnetic hydrogel after primary liver cancer resection, the experiment of thermotherapy for resection of new zealand white rabbit liver cancer tumor was designed as follows: as shown in fig. 5(a), a new zealand white rabbit having VX2 tumor growing in the liver was anesthetized and then the tumor was excised under laparoscopic guidance, and then NDP-FG hydrogel was applied to the tumor-excised area and subjected to magnetic heat treatment after completion of the excision surgery. As shown in fig. 5(b), the liver was removed 15 days after the treatment, and no recurrence of tumor was observed. FIG. 5(c-d) is a comparison graph of H & E section, fluorescent staining section (TNF alpha) and TNF alpha quantitative analysis of tissue staining in the untreated liver cancer region and the liver cancer resection region after treatment, and the results show that no obvious normal liver cancer cells are found in the liver cancer resection region after treatment and more positive expression of TNF alpha (tumor necrosis factor) is shown compared with the untreated liver cancer. The results prove that the thermal response magnetic hydrogel can obviously inhibit the recurrence of the liver cancer after resection under the alternating magnetic field.
Example 2
The thermal response magnetic hydrogel for multi-modal treatment of liver cancer is prepared by the following steps:
step 1: 10g of polyethylene glycol (Mw 4000) and 5g of triethylamine are dissolved in 100mL of dichloromethane, and argon is introduced into the solution to protect the solution. Dissolving 4 g of 4-cyano-4- (phenylcarbonylthio) pentanoic acid-succinimidyl ester in 10mL of dichloromethane, dropwise adding the solution into the solution through a dropping funnel, stirring the solution at room temperature for 12 hours, settling the obtained product in diethyl ether for three times, and obtaining a macromolecular chain transfer agent after vacuum drying;
step 2: dissolving 0.2g of the macromolecular chain transfer agent obtained in the step 1 in 5mL of 1, 4-dioxane, putting the obtained solution into a polymerization bottle, adding 10g N-N-propyl acrylamide, 50g of acrylic acid-N-succinimidyl ester, 0.1g of benzoyl peroxide and the like, fully dissolving, introducing argon for protection, reacting for 24 hours at 78 ℃ after three freeze-thaw cycles, settling the obtained product in ether for three times, and performing vacuum drying to obtain a temperature-sensitive polymer;
and step 3: dissolving 5g of the temperature-sensitive polymer obtained in the step 2 in 30mL of dichloromethane, then adding 1g of triethylamine, 10g of gallic acid and the like, fully dissolving, introducing argon for protection, reacting at room temperature for 12 hours, settling the obtained product in diethyl ether twice, and drying in vacuum to obtain a temperature-sensitive copolymer;
and 4, step 4: adding 200mg of mica into 200mL of distilled water, uniformly dispersing by ultrasonic wave, adding 10g of polystyrene sodium sulfate and 500 mu L of hydrazine hydrate, reacting for 24 hours at 100 ℃, and performing suction filtration and freeze drying (the freeze drying temperature is-60 ℃) on the obtained product to obtain the mica-polystyrene sodium sulfate compound. 200mg of mica-polystyrene sodium sulfate compound and 20g of iron acetylacetonate are added into 200mL of tetraethylene glycol, the mixture is uniformly dispersed by ultrasonic, argon is introduced for protection, and the solution is heated to 270 ℃ in a gradient manner (the heating rate is set to be 5 ℃/min). Centrifuging and removing supernatant after the reaction is finished to obtain an iron-carrying mica sheet aqueous solution;
and 5: and (3) dissolving the temperature-sensitive copolymer obtained in the step (3) in an iron-carrying mica sheet aqueous solution (the concentration of the iron-carrying mica sheet is 100mg/mL), so as to obtain the thermal response magnetic hydrogel.
In the step 5, the mass ratio of the copolymer to the iron-carrying mica sheet aqueous solution is 1: 6.
X-ray diffraction (Philips X' Pert PRO SUPER X-ray diffraction) and scanning electron microscopy (EDS, X-Max, Oxford) prove that the thermal response magnetic hydrogel prepared in the embodiment contains three characteristic elements of carbon, oxygen and iron. The modulus test proves that the thermal response magnetic hydrogel prepared by the embodiment has good temperature response. The magnetocaloric temperature rise test proves that the thermal response magnetic hydrogel prepared by the embodiment has good magnetocaloric temperature rise effect. An adhesion experiment and a rat liver hemostasis experiment prove that the thermal response magnetic hydrogel prepared by the embodiment has good tissue adhesion and liver hemostasis effect. The mouse tumor resection experiment proves that the thermal response magnetic hydrogel prepared by the embodiment has good tumor killing and tumor recurrence inhibiting capabilities. Artery embolism experiments of liver cancer tumors of New Zealand rabbits prove that the thermal response magnetic hydrogel prepared by the embodiment has the potential of treating liver cancer by artery embolism.
Example 3
This example prepares a thermoresponsive magnetic hydrogel by the following steps:
step 1: 1.5g of polyethylene glycol (Mw 4000) and 1g of triethylamine were dissolved in 20mL of dichloromethane, and argon gas was introduced. Dissolving 4-cyano-4- (phenylcarbonylthio) pentanoic acid-succinimidyl ester in 10mL of dichloromethane, dropwise adding the solution into the solution through a dropping funnel, stirring the solution at room temperature for 24 hours, settling the obtained product in diethyl ether for three times, and drying in vacuum to obtain a macromolecular chain transfer agent;
step 2: dissolving 0.1g of the macromolecular chain transfer agent obtained in the step 1 in 5mL of 1, 4-dioxane, putting the obtained solution into a polymerization bottle, adding 5g N-isopropyl acrylamide, 2g of acrylic acid-N-succinimidyl ester and 0.1g of azobisisobutyronitrile, fully dissolving, introducing argon for protection, reacting for 48 hours at 40 ℃ after three freeze-thaw cycles, settling the obtained product in ether once, and performing vacuum drying to obtain a thermosensitive polymer;
and step 3: dissolving 5g of the temperature-sensitive polymer obtained in the step 2 in 20mL of dichloromethane, then adding 2g of triethylamine, 10g of gallic acid and the like, fully dissolving, introducing argon for protection, reacting at room temperature for 36 hours, settling the obtained product in diethyl ether twice, and drying in vacuum to obtain a temperature-sensitive copolymer;
and 4, step 4: and (3) dissolving the temperature-sensitive copolymer obtained in the step (3) in a deionized water solution to obtain a temperature-sensitive copolymer solution.
In step 4, the mass ratio of the copolymer to the deionized water is 1: 4.
The temperature sensitivity test proves that the temperature sensitivity copolymer solution prepared by the embodiment can not be converted into a gel state when the temperature is raised to 20 ℃, and the temperature is further raised and still kept in a solution state, which indicates that the polymerization efficiency is low when the synthesis temperature of the temperature sensitivity polymer is lower than 50-90 ℃, and the temperature sensitivity polymer can not be effectively synthesized.
Example 4
This example prepares a thermoresponsive magnetic hydrogel by the following steps:
step 1: 5g of polyethylene glycol (Mw 4000) and 5g of triethylamine were dissolved in 100mL of dichloromethane, and argon gas was introduced. Dissolving 4 g of cyano-4- (phenylcarbonylthio) pentanoic acid-succinimidyl ester in 10mL of dichloromethane, dropwise adding the solution into the solution through a dropping funnel, stirring the solution at room temperature for 24 hours, settling the obtained product in diethyl ether for three times, and vacuum-drying to obtain a macromolecular chain transfer agent;
step 2: dissolving 0.5g of the macromolecular chain transfer agent obtained in the step 1 in 20mL of 1, 4-dioxane, putting the obtained solution into a polymerization bottle, adding 10g N, N-diethyl-2-acrylamide, 5g of acrylic acid-N-succinimidyl ester and 0.2g of dimethyl azodiisobutyrate, fully dissolving, introducing argon for protection, reacting at 60 ℃ for 24 hours after three freeze-thaw cycles, settling the obtained product in diethyl ether for three times, and performing vacuum drying to obtain a temperature-sensitive polymer;
and step 3: dissolving 1g of the temperature-sensitive polymer obtained in the step 2 in 20mL of dichloromethane, then adding 0.2g of triethylamine and 10g of dopamine hydrochloride, fully dissolving, introducing argon for protection, reacting at room temperature for 24 hours, settling the obtained product in diethyl ether twice, and drying in vacuum to obtain a temperature-sensitive copolymer;
and 4, step 4: 10g of iron acetylacetonate is added into 100mL of tetraethylene glycol, the mixture is uniformly dispersed by ultrasonic, argon is introduced for protection, and the solution is heated to 270 ℃ in a gradient manner (the heating rate is set to be 5 ℃/min). Centrifuging and removing supernatant after the reaction is finished to obtain an iron oxide nanoparticle aqueous solution;
and 5: and (3) dissolving the temperature-sensitive copolymer obtained in the step (3) in an iron oxide nanoparticle aqueous solution (with the concentration of 20mg/mL) to obtain the thermal response magnetic hydrogel.
In step 5, the mass ratio of the copolymer to the iron oxide nanoparticles is 1: 5.
The observation of the gel morphology proves that the iron nanoparticles in the thermal response magnetic hydrogel prepared in the embodiment are not uniformly dispersed, and the magnetocaloric temperature rise test proves that the temperature rise effect of the thermal response magnetic hydrogel prepared in the embodiment under the alternating magnetic field is not obvious.
The foregoing is merely a preferred embodiment of the invention, which is intended to be illustrative and not limiting. It will be understood by those skilled in the art that various changes, modifications and equivalents may be made therein without departing from the spirit and scope of the invention as defined in the appended claims.

Claims (8)

1. The preparation method of the thermal response magnetic hydrogel is characterized by comprising the following steps of:
s1: dissolving polyethylene glycol and triethylamine in dichloromethane, and introducing argon for protection to obtain a mixed solution;
s2: dissolving 4-cyano-4- (phenylcarbonylthio) pentanoic acid-succinimide ester in dichloromethane, dropwise adding the dichloromethane into the mixed solution, stirring at room temperature for 10-24 hours, settling the obtained product in diethyl ether, and performing vacuum drying to obtain a macromolecular chain transfer agent;
s3: dissolving the macromolecular chain transfer agent obtained in the step S2 in dioxane, adding a temperature-sensitive monomer, acrylic acid-N-succinimide ester and a free radical initiator, fully dissolving, introducing argon for protection, reacting for 24-48 h at 50-90 ℃ after three freeze-thaw cycles, settling the obtained product in ether for three times, and performing vacuum drying to obtain a temperature-sensitive polymer;
s4: dissolving the temperature-sensitive polymer obtained in the step S3 in dichloromethane, then adding triethylamine and micromolecules with adhesive functional groups, fully dissolving, introducing argon for protection, reacting at room temperature for 12-48 h, settling the obtained product in diethyl ether twice, and drying in vacuum to obtain a temperature-sensitive copolymer;
s5: adding a two-dimensional nano sheet into distilled water, performing ultrasonic uniform dispersion, adding sodium polystyrene sulfate and hydrazine hydrate, reacting for 24-48 h at 100 ℃, performing suction filtration and freeze drying on the obtained product to obtain a two-dimensional nano sheet-sodium polystyrene sulfate compound, adding the two-dimensional nano sheet-sodium polystyrene sulfate compound and ferric acetylacetonate into tetraethylene glycol, performing ultrasonic uniform dispersion, introducing argon protection, heating the solution to 270-300 ℃ in a gradient manner, performing centrifugation after the reaction is finished, and removing a supernatant to obtain an iron-loaded nano sheet aqueous solution;
s6: and (4) dissolving the temperature-sensitive copolymer obtained in the step S4 in the iron-carrying nanosheet aqueous solution obtained in the step S5 to obtain the thermal response magnetic hydrogel.
2. The method for preparing a thermal response magnetic hydrogel according to claim 1, wherein the amounts of polyethylene glycol, triethylamine and dichloromethane in step S1 are 1-20 g, 1-10 g and 20-200 mL, respectively.
3. The method for preparing a thermally responsive magnetic hydrogel according to claim 1, wherein the amounts of 4-cyano-4- (phenylcarbonylthio) pentanoic acid-succinimidyl ester and dichloromethane in step S2 are 1-10 g and 5-20 mL, respectively.
4. The method for preparing a thermal response magnetic hydrogel according to claim 1, wherein in step S3, the macromolecular chain transfer agent, dioxane, temperature sensitive monomer, acrylic acid-N-succinimide ester, and free radical initiator are respectively used in an amount of 0.1-1 g, 5-20 mL, 2-20 g, 1-10 g, and 0.1-1 g, the temperature sensitive monomer is any one of N-isopropylacrylamide, N-diethyl-2-acrylamide, N-propylacrylamide, and polyethylene glycol methacrylate, and the free radical initiator is any one of azobisisobutyronitrile, dimethyl azobisisobutyrate, and benzoyl peroxide.
5. The method for preparing a thermal response magnetic hydrogel according to claim 1, wherein the amounts of the thermo-sensitive polymer, dichloromethane, triethylamine, and the small molecule with an adhesive functional group in step S4 are 0.1-2 g, 10-40 mL, 0.1-2 g, and 1-20 g, respectively, and the small molecule with an adhesive functional group is dopamine hydrochloride or gallic acid.
6. The method for preparing a thermal response magnetic hydrogel according to claim 1, wherein in step S5, the amounts of the two-dimensional nanosheets, distilled water, sodium polystyrene sulfate, hydrazine hydrate, two-dimensional nanosheet-sodium polystyrene sulfate composite, ferric acetylacetonate, and tetraethylene glycol are 100-500 mg, 100-500 mL, 1-10 g, 100-500 μ L, 50-200 mg, 10-20 g, and 50-200 mL, respectively, and the two-dimensional nanosheets are any one of graphene oxide, mica, and montmorillonite.
7. A thermally responsive magnetic hydrogel produced by the production method according to any one of claims 1 to 6.
8. Use of the thermally responsive magnetic hydrogel of claim 7 in an assisted hepatoma resection and postoperative anti-recurrence device.
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