CN114655993A - Nano-copper ferrite, preparation method and application thereof - Google Patents

Nano-copper ferrite, preparation method and application thereof Download PDF

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CN114655993A
CN114655993A CN202210306090.1A CN202210306090A CN114655993A CN 114655993 A CN114655993 A CN 114655993A CN 202210306090 A CN202210306090 A CN 202210306090A CN 114655993 A CN114655993 A CN 114655993A
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copper
nano
oleate
iron
mixing
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张桂龙
李庆东
田梗
魏鹏飞
杨春华
姜文国
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Binzhou Medical College
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Abstract

The invention provides a nano-copper ferrite, a preparation method and application thereof, relating to the technical field of biomedical materials, wherein the method comprises the following steps: mixing copper oleate and iron oleate into 1-octadecene to obtain a mixture, adding oleic acid and sodium oleate into the mixture, and sequentially heating and precipitating to obtain copper-iron nanoparticles; mixing the copper-iron nanoparticlesAfter dispersion with NOBF4Sequentially mixing, removing impurities and centrifuging the DMF solution, and taking a precipitate obtained by centrifuging to obtain the nano copper ferrite; the method can solve the technical problem that the existing iron-based nano material has low performance of catalyzing Fenton reaction in physiological neutral and weakly acidic tumor environments so that the growth of cancer cells cannot be effectively inhibited.

Description

Nano-copper ferrite, preparation method and application thereof
Technical Field
The invention relates to the technical field of biomedical materials, in particular to a nano-copper ferrite, a preparation method and application thereof.
Background
Chemotherapy is still the mainstay of current cancer therapy. However, in the course of chemotherapy, the systemic administration mode often causes problems of nonspecific biodistribution of the drug, low bioavailability of the drug, systemic toxicity and the like. In recent years, with the advent of nanotechnology, the application of nanomaterials in the medical field brings new hopes to tumor patients. In the research of nanomedicine, chemodynamic therapy (CDT) is an emerging highly effective cancer treatment strategy, the therapeutic mechanism of which is via the introduction of hydrogen peroxide (H) into tumor cells2O2) Conversion to cytotoxic hydroxyl radical (. OH) accelerated apoptosis of tumor cells. In addition, due to H in the tumor tissue2O2Over-expressed characteristics, H in normal tissues2O2The content is extremely low, so that the CDT therapy has the advantages of tumor treatment specificity and low invasiveness.
In the research of a plurality of CDT therapies, the iron-based nano material as a CDT agent is widely applied to the diagnosis and treatment of tumors, mainly because the iron-based nano material has higher biological safety and the function of magnetic resonance imaging, and is beneficial to realizing the integration of tumor diagnosis and treatment based on the magnetic resonance imaging. The iron-based nano material has higher specific surface area, can be used as a nano drug carrier, and after entering tumor tissues, the structure of the iron-based nano material collapses due to the weak acidity of the tumor microenvironment, so that the anti-cancer drug is released, and the accurate treatment of the tumor is favorably realized. In addition, the iron-based nano material can release Fe in a tumor microenvironment2+Ions, obviously improve Fe in tumor tissues2+The content of ions. These free Fe2+Ions can rapidly generate Fenton reaction (Fe)2++H2O2→Fe3++OH-+ OH.), H that overexpresses in cancer cells2O2The high-oxidative OH is catalyzed to generate oxidative damage to lipid, protein, DNA and the like, so that the synergistic treatment of CDT and chemical drugs is realized. However, the present research shows that Fe2+The ion has low performance of catalyzing Fenton reaction under physiological neutral and weak acid tumor environment, and is not enough to effectively inhibit the growth of cancer cells.
Disclosure of Invention
The invention aims to provide a nano copper ferrite which can solve the technical problem that the existing iron-based nano material has low performance of catalyzing Fenton reaction in physiological neutral and weak acid tumor environments so that the growth of cancer cells cannot be effectively inhibited.
The second purpose of the invention is to provide a preparation method of the nano-copper ferrite, which is simple to prepare and has higher efficiency.
The third purpose of the invention is to provide the application of the nano-copper ferrite prepared by the preparation method of the nano-copper ferrite in preparing a tumor drug treatment system.
The technical problem to be solved by the invention is realized by adopting the following technical scheme.
In a first aspect, the present application provides a nano-copper ferrite having a chemical formula of CuxFe3- xO4And X is the molar ratio of copper to the nano-copper ferrite. The nano copper ferrite is beneficial to realizing the aim of multi-mode synergetic tumor treatment such as chemotherapy, chemodynamic therapy, photothermal therapy and the like, avoids the problems of drug resistance, side effect and the like generated by single chemotherapy drug treatment, and lays a material foundation for realizing efficient and safe diagnosis and treatment integration of tumor patients.
In a second aspect, the application provides a preparation method of a nano-copper ferrite, comprising the following steps: mixing copper oleate and ferric oleate in 1-octadecene to obtain mixture, adding oleic acid and ferric oleate into the mixtureSequentially heating and precipitating sodium oleate to obtain copper-iron nanoparticles; dispersing copper and iron nanoparticles and NOBF4Sequentially mixing, removing impurities and centrifuging the DMF solution, and taking a precipitate obtained by centrifugation to obtain the nano copper ferrite. The method comprises the steps of heating and decomposing a mixed solution of copper oleate and iron oleate in a high-boiling-point organic solvent by a high-temperature decomposition method, and preparing nanoparticles with high catalytic performance, high photothermal performance and high imaging performance by changing the proportion of the copper oleate to the iron oleate. Compared with the traditional iron-based nano material, the nano particles have better Fenton catalytic performance, and the Fenton catalytic capability and the photo-thermal conversion capability of the nano particles are obviously superior to those of Fe3O4And (3) nanoparticles. In addition, the nano copper ferrite has good biocompatibility. Has no obvious toxicity to normal cells and has the capability of selectively killing tumor cells. The in vivo anti-tumor result also proves that the tumor of the mouse is obviously inhibited after the LFCCD treatment, and the weight and blood routine of the mouse have no obvious difference compared with the contrast group, so the nano copper ferrite is beneficial to realizing the aim of multi-mode synergetic tumor treatment such as chemotherapy, chemodynamic treatment, photothermal treatment and the like, avoids the problems of drug resistance, side effect and the like generated by single chemotherapy drug treatment, and lays a material foundation for realizing efficient and safe diagnosis and treatment integration of tumor patients.
In a third aspect, the application also provides an application of the nano-copper ferrite prepared by the preparation method of the nano-copper ferrite in preparing a tumor drug treatment system. The nano copper ferrite and the chemotherapeutic drugs are assembled into a nano cluster through the liposome to prepare the intelligent nano treatment system.
Compared with the prior art, the invention has at least the following advantages or beneficial effects:
the invention provides a preparation method of nano-copper ferrite, which comprises the steps of heating and decomposing a mixed solution of copper oleate and iron oleate in a high-boiling-point organic solvent by a high-temperature decomposition method, and preparing nano-particles with high catalytic performance, high photo-thermal performance and high imaging performance by changing the proportion of the copper oleate to the iron oleate. The nano-particles have the advantages of being compared with the traditional iron-based nano-materialsBetter Fenton catalytic performance, and the Fenton catalytic capability and the photothermal conversion capability of the catalyst are obviously superior to those of Fe3O4And (3) nanoparticles. In addition, the nano copper ferrite has good biocompatibility. Has no obvious toxicity to normal cells and has the capability of selectively killing tumor cells. The in vivo anti-tumor result also proves that the tumor of the mouse is obviously inhibited after the LFCCD treatment, and the weight and blood routine of the mouse have no obvious difference compared with the contrast group, so the nano copper ferrite is beneficial to realizing the aim of multi-mode synergetic tumor treatment such as chemotherapy, chemodynamic treatment, photothermal treatment and the like, avoids the problems of drug resistance, side effect and the like generated by single chemotherapy drug treatment, and lays a material foundation for realizing efficient and safe diagnosis and treatment integration of tumor patients.
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In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1(a) different CuxFe3-xO4TEM pictures of (X is 0.066, 0.106, 0.119, 0.126, 0.190, 0, respectively); (b) cu (copper)xFe3-xO4Temperature profile under 650nm laser irradiation; (c) cuxFe3-xO4Treated TMB uv-vis absorption spectrum; (d) cuxFe3-xO4Relaxation rate r of2A value;
FIG. 2(a) TEM image of LFCCD; (b) the change of the particle size before and after the LFCCD is treated under the weak acidic condition; (c) TEM picture of LFCCD after weak acid treatment;
FIG. 3(a) different concentrations of CuXFe3-xO4(x ═ 0.119) change in cell survival rate following 24h treatment of THLE-3 and 293T cells; (b) survival rates after CT26 cells after 24 hours treatment with different samples and different concentrations; (c) different samples andsurvival rate of CT26 cells after 48 hours of treatment at different concentrations;
FIG. 4(a) the change in relative tumor volume in mice from different treatment groups; (b) changes in body weight of mice during treatment with different treatment methods; (c) conventional blood analysis data of mice 24h after intravenous injection of PBS (control), Cam/Dox or LFCCD;
FIG. 5(a) CuxFe3-xO4Or cross-sectional and coronal T2-weighted MR images of tumor-bearing mice before and after LFCCD injection; (b) tumor and kidney MRI signal to noise ratio changes (Δ SNR) in mice.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail below with reference to specific examples.
In a first aspect, the present application provides a nano-copper ferrite having a chemical formula of CuxFe3-xO4Wherein X is the molar ratio of copper to the nano-copper ferrite.
In a second aspect, the application provides a preparation method of a nano-copper ferrite, which is characterized by comprising the following steps: mixing copper oleate and iron oleate into 1-octadecene to obtain a mixture, adding oleic acid and sodium oleate into the mixture, and sequentially heating and precipitating to obtain copper-iron nanoparticles; dispersing copper and iron nanoparticles and NOBF4Sequentially mixing, removing impurities and centrifuging the DMF solution, and taking the precipitate obtained by centrifugation to obtain the nano copper ferrite. The method comprises the steps of heating and decomposing a mixed solution of copper oleate and iron oleate in a high-boiling-point organic solvent by a high-temperature decomposition method, and preparing the catalyst with high catalytic performance, high photo-thermal performance and high formation by changing the proportion of the copper oleate to the iron oleateLike the nanoparticles of the properties. Compared with the traditional iron-based nano material, the nano particles have better Fenton catalytic performance, and the Fenton catalytic capability and the photo-thermal conversion capability of the nano particles are obviously superior to those of Fe3O4And (3) nanoparticles. In addition, the nano copper ferrite has good biocompatibility. Has no obvious toxicity to normal cells and has the capability of selectively killing tumor cells. The in vivo anti-tumor result also proves that the tumor of the mouse is obviously inhibited after the LFCCD treatment, and the weight and blood routine of the mouse have no obvious difference compared with the contrast group, so the nano copper ferrite is beneficial to realizing the aim of multi-mode synergetic tumor treatment such as chemotherapy, chemodynamic treatment, photothermal treatment and the like, avoids the problems of drug resistance, side effect and the like generated by single chemotherapy drug treatment, and lays a material foundation for realizing efficient and safe diagnosis and treatment integration of tumor patients.
The preparation of the copper oleate and the iron oleate comprises the following steps: mixing ferric chloride, copper chloride and sodium oleate, adding a mixed solution of ethanol, n-hexane and water, heating to 70 ℃, refluxing for 2-4 hours to obtain a mixed solution, separating an oil phase and a water phase of the mixed solution, and cleaning the oil phase to obtain a mixture of iron oleate and copper oleate. The purity of the iron oleate and the copper oleate prepared by the method is high, and the subsequent preparation of the same iron alloy is convenient.
The mixture, oleic acid and sodium oleate are heated for 0.5-1 hour at the temperature of 280-320 ℃. The heating temperature and the heating time can ensure the stability of the copper oleate and the iron oleate, and the yield of the prepared copper oleate and the prepared iron oleate is higher.
The heating of the mixture, oleic acid and sodium oleate also comprises the step of introducing inert gas, wherein the inert gas comprises nitrogen. The inert gas is used for protecting the reaction of the waste gas and other impurity gases such as oxygen in the air during heating to generate byproducts.
The copper-iron nanoparticles and NOBF4In a volume ratio of 1: (1-2), NOBF4The concentration of the DMF solution of (1) is 0.01-0.05 mol/L. The proportion interval can ensure that the copper and iron nano particles are completely dispersed in the copper and iron nano particles.
The impurity removal comprises the following steps: mixing copper-iron nanoparticles with NOBF4And mixing the DMF solution, shaking until the nano particles are transferred from the n-hexane layer to the DMF layer, removing the n-hexane layer, and then adding DMSA to remove impurities, thus finishing mixing. The nano particles are completely dispersed in the DMF layer by transferring the DMF layer, so that the n-hexane layer is conveniently removed, and the n-hexane layer is prevented from participating in a subsequent reaction system.
In a third aspect, the application also provides an application of the nano-copper ferrite prepared by the preparation method of the nano-copper ferrite in preparing a tumor drug treatment system.
The preparation method of the tumor drug treatment system comprises the following steps of mixing nano copper ferrite with a hydrogenated soybean phospholipid chloroform solution, a DSPE-PEG2000 chloroform solution, a cholesterol chloroform solution and a camptothecin chloroform solution, evaporating chloroform to obtain a film, adding an adriamycin hydrochloride aqueous solution and deionized water into the film, performing ultrasonic hydration for 25-35min to obtain a drug crude product, centrifuging the drug crude product, and taking a precipitate to obtain the tumor drug treatment system. The liposome is copper-doped ultra-small ferroferric oxide nanoparticles (Cu)xFe3-xO4) Based on the nano particles and the anti-cancer drugs (camptothecin and adriamycin), the nano particles and the anti-cancer drugs are assembled into an intelligent nano diagnosis and treatment platform through the liposome. Cu (copper)xFe3-xO4Endows the nano platform with good photothermal effect, chemodynamic therapeutic effect and magnetic resonance imaging effect. The liposome is used as a carrier, has excellent tumor microenvironment response capability, and provides guarantee for the safety of the nano platform. Whereas camptothecin, doxorubicin, is used in chemotherapy.
The mole ratio of the hydrogenated soybean phospholipid in the hydrogenated soybean phospholipid chloroform solution, the DSPE-PEG2000 in the DSPE-PEG2000 chloroform solution and the cholesterol in the cholesterol chloroform solution is (80-90): (1-1.5): (8-12). The proportion interval can provide guarantee for the safety of the copper-iron nano material.
The above chloroform solution of hydrogenated soybean phospholipid, chloroform solution of DSPE-PEG2000, chloroform solution of cholesterol and adriamycin hydrochloride have concentration of 8-12 mg/mL. The concentration interval can provide a proper dispersion environment for the nano-copper ferrite, and the treatment effect of camptothecin, adriamycin and the like can be maintained at a high level.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
Synthesis of copper oleate/iron oleate mixture: 10mmol of ferric chloride (FeCl) is added into a three-neck flask3) And 1mmol of copper chloride (CuCl)2) And 32mmol of sodium oleate, followed by addition of a mixed solution of 60mL of ethanol, 18mL of n-hexane and 6mL, and then heating the flask to 70 ℃ for reflux for 3 hours. After the reaction was cooled to room temperature, the oil phase and the water phase were separated, the oil phase was washed three times with deionized water and then placed in an oven overnight.
CuxFe3-xO4The synthesis of (2): dispersing dried iron oleate and copper oleate in 40mL of 1-octadecene, adding 4mmol of oleic acid and 1.5mmol of sodium oleate, and gradually heating to 300 ℃ under the protection of nitrogen and maintaining for 0.5 h. Cooling to room temperature, and adding ethanol to precipitate the obtained iron-copper nano material. After washing with ethanol for three times, the mixture was dispersed in n-hexane for further use.
CuxFe3-xO4Surface ligand exchange: 5mL of nanoparticles dispersed in n-Hexane (5mg) and 5mL of NOBF4(0.01M) of DMF solution, shaking for 5min until the nanoparticles were transferred from the n-hexane layer to the DMF layer, discarding the n-hexane layer, and adding DMSA0.1g. Shaking the shaking table for 0.5h, adding 10mL of water, and centrifuging for 10 min. Washing the precipitate with ethanol for 2 times, and re-dispersing in water to obtain CuxFe3-xO4(X＝0.066)。
Example 2
Synthesis of copper oleate iron oleate mixture: 9mmol of ferric chloride (FeCl) is added into a three-neck flask3) And 2mmol of copper chloride (CuCl)2) And 31mmol of sodium oleate, followed by addition of a mixed solution of 60mL of ethanol, 18mL of n-hexane and 6mL, and then heating the flask to 70 ℃ for reflux for 3 hours. After the reaction was cooled to room temperature, the oil phase and the water phase were separated, the oil phase was washed three times with deionized water and then placed in an oven overnight.
And (3) synthesis of nano copper ferrite: dispersing dried iron oleate and copper oleate in 40mL of 1-octadecene, adding 4mmol of oleic acid and 2mmol of sodium oleate, and gradually heating to 300 ℃ under the protection of nitrogen and maintaining for 0.5 hour. And cooling to room temperature, and adding ethanol to precipitate the obtained copper-iron nano material. After washing with ethanol for three times, the mixture was dispersed in n-hexane for further use.
And (3) exchanging the nano copper ferrite ligand: 5mL of nanoparticles dispersed in n-Hexane (6mg) and 5mL of NOBF4(0.02M) in DMF, shaking for 6min until the nanoparticles were transferred from the n-hexane layer to the DMF layer, discarding the n-hexane layer, and adding DMSA0.15g. After shaking for 0.5h on a shaker, 10mL of water was added and centrifuged for 10 min. Washing the precipitate with ethanol twice, and dispersing in water again to obtain CuxFe3-xO4(X＝0.106)。
Example 3
Synthesis of copper oleate iron oleate mixture: a three-neck flask is added with 8mmol of ferric chloride (FeCl)3) And 3mmol of copper chloride (CuCl)2) And 30mmol of sodium oleate, followed by addition of a mixed solution of 60mL of ethanol, 18mL of n-hexane and 6mL, and then heating the flask to 70 ℃ for reflux for 4 hours. After the reaction was cooled to room temperature, the oil phase and the water phase were separated, the oil phase was washed with deionized water 3 times and then placed in an oven overnight.
CuxFe3-xO4(X ═ 0.119) synthesis of nanoparticles: dispersing dried iron oleate and copper oleate in 40mL of 1-octadecene, adding 5mmol of oleic acid and 2.5mmol of sodium oleate, reacting under the protection of nitrogen, gradually heating to 300 ℃, and maintaining for 1 h. And cooling to room temperature, and adding ethanol to precipitate the obtained copper-iron nano material. After washing with ethanol for three times, the mixture was dispersed in n-hexane for further use.
CuxFe3-xO4(X ═ 0.119) nanoparticle ligand exchange: 5mL of nanoparticles dispersed in n-hexane (7mg) and 5mL of NOBF4(0.03M) in DMF, shaking for 7min until the nanoparticles were transferred from the n-hexane layer to the DMF layer, discarding the n-hexane layer, and adding 0.2g of DMSA. After shaking the shaker for 1h, 10mL of water was added and centrifuged for 10 min. Washing the precipitate with ethanol twice, and dispersing in water again to obtain CuxFe3-xO4(X＝0.119)。
Example 4
Synthesis of copper oleate iron oleate mixture: 7mmol of ferric chloride (FeCl) is added into a three-neck flask3) And 4mmol of copper chloride (CuCl)2) And 29mmol of sodium oleate, followed by addition of a mixed solution of 60mL of ethanol, 18mL of n-hexane and 6mL, and then heating the flask to 70 ℃ for reflux for 4 hours. After the reaction was cooled to room temperature, the oil phase and the water phase were separated, the oil phase was washed with deionized water 3 times and then placed in an oven overnight.
CuxFe3-xO4Synthesis of (X ═ 0.129): dispersing dried iron oleate and copper oleate in 40mL of 1-octadecene, adding 5mmol of oleic acid and 3mmol of sodium oleate, reacting under the protection of nitrogen, gradually heating to 300 ℃, and maintaining for 1 h. Cooling to room temperature, and adding ethanol to precipitate the FeCu nanometer material. After washing with ethanol for three times, the mixture was dispersed in n-hexane for further use.
CuxFe3-xO4(X ═ 0.129) surface-bound ligand exchange: 5mL of nanoparticles dispersed in n-hexane (8mg) and 5mL of NOBF4(0.04M) in DMF, shaking for 8min until the nanoparticles were transferred from the n-hexane layer to the DMF layer, discarding the n-hexane layer, and adding 0.3g of DMSA. After shaking for 1h in a shaker, 10mL of water was added and centrifuged for 10 min. Washing the precipitate with ethanol twice, and dispersing in water again to obtain CuxFe3-xO4(X＝0.129)。
Example 5
Synthesis of copper oleate iron oleate mixture: 6mmol of ferric chloride (FeCl) is added into a three-neck flask3) And 5mmol of copper chloride (CuCl)2) And 28mmol of sodium oleate, followed by the addition of a mixed solution of 60mL of ethanol, 18mL of n-hexane and 6mL, and then the flask was heated to 70 ℃ under reflux for 4 hours. After the reaction was cooled to room temperature, the oil phase and the water phase were separated, the oil phase was washed with deionized water 3 times and then placed in an oven overnight.
CuxFe3-xO4Synthesis of (X ═ 0.190): dispersing dried iron oleate and copper oleate in 40mL of 1-octadecene, adding 5mmol of oleic acid and 3mmol of sodium oleate, reacting under the protection of nitrogen, gradually heating to 300 ℃, and maintaining for 30 min.Cooling to room temperature, and adding ethanol to precipitate the FeCu nanometer material. After washing with ethanol for three times, the mixture was dispersed in n-hexane for further use.
CuxFe3-xO4(X ═ 0.190) surface-bound ligand exchange: 5mL of nanoparticles dispersed in n-hexane (9mg) and 5mL of NOBF4(0.04M) in DMF, shaking for 8min until the nanoparticles were transferred from the n-hexane layer to the DMF layer, discarding the n-hexane layer, and adding 0.3g of DMSA. After shaking for 1h in a shaker, 10mL of water was added and centrifuged for 10 min. Washing the precipitate with ethanol twice, and dispersing in water again to obtain CuxFe3-xO4(X＝0.190)。
Example 6
Hydrogenated Soybean Phospholipid (HSPC), cholesterol, DSPE-PEG2000 were dissolved in chloroform to prepare 10mg/mL solutions. Camptothecin (Cam) and doxorubicin hydrochloride (Dox) were formulated as 10mg/mL solutions in chloroform and deionized water, respectively.
2.5131mL of HSPC chloroform solution, 150 μ L of cholesterol chloroform solution and 533.1 μ L of DSPE-PEG2000 chloroform solution are respectively taken, so that the molar ratio of the HSPC, the cholesterol and the DSPE-PEG2000 is 85:10: 1. In addition, Cu is addedxFe3-xO45mg, 2mL of Cam chloroform solution, after mixing well, the chloroform was evaporated using a rotary evaporator until a uniform thin film was formed in the flask. (X is 0.119)
Adding 2mL of doxorubicin hydrochloride aqueous solution and 3mL of deionized water, and carrying out ultrasonic hydration for 30 min. The obtained nano-drug was centrifuged at 150000 Xg and 4 ℃ for 2 h. Separating supernatant, re-dispersing the precipitate in 5mL of water, and storing at 4 deg.C to obtain the tumor drug therapy system.
Test example 1
And (3) measuring the contents of iron and copper elements by adopting an inductively coupled plasma mass spectrometry (ICP-MS). Nano copper ferrite is expressed as CuxFe3-xO4Then the above five CuxFe3-xO4The X values of (A) are 0.066, 0.106, 0.119, 0.129 and 0.190 respectively. The Transmission Electron Microscope (TEM) imaging result shows that CuxFe3-xO4The nano-crystals have similar size range within 10-20 nm, and the appearance thereof gradually increases with the increase of the copper doping ratioGradually changing from spherical to square and then to irregular. CuxFe3-xO4The nano crystal is more pure Fe after being irradiated by 650nm laser for 10 minutes3O4Has better photo-thermal effect. CuxFe3-xO4The temperature of the nano-crystal can be increased by 13-18 ℃, and pure Fe3O4The temperature of (a) increases only by about 4 deg.c. The results show that the doping of copper obviously improves Fe3O4The photothermal properties of (1). Then, we evaluated Cu by 3,3', 5,5' -Tetramethylbenzidine (TMB) assayxFe3-xO4The ability of the nanocrystals to catalyze fenton-type reactions. TMB was oxidized by OH to form TMB-ox (blue) with an absorbance maximum of 652 nm. The results show that CuxFe3-xO4The Fenton catalytic capability of the nanocrystalline is obviously superior to that of the traditional Fe3O4. This verifies our idea that simple iron-based nanomaterials can significantly improve catalytic performance by doping with copper. Cu was then evaluated using a 7.0T magnetic resonance scannerxFe3- xO4T of2The effect is enhanced. Through 1/T2The ratio of the concentration of iron ions to the concentration of CuxFe3-xO4Transverse relaxation rate (r)2). It can be observed that Cu is compared with the other groupsxFe3-xO4(x-0.119) at 320.71mM-1s-1A (r)2Highest value, indicating CuxFe3-xO4(x ═ 0.119) has the strongest T2MRI contrast capability.
As shown above, CuxFe3-xO4(x ═ 0.119) may be a better contrast agent with good catalytic and photothermal properties, and can be used for subsequent experimental exploration.
Test example 2
As can be seen from the TEM image, the morphology of the LFCCD nano-particles is spherical nanoclusters, the size of the LFCCD nano-particles is 100nm, and the LFCCD nano-particles have excellent monodispersity. In addition, the uv-vis absorption spectrum of LFCCD showed typical peaks for Dox and Cam, indicating that Dox and Cam have been successfully loaded into magnetic nanoliposomes. To determine whether LFCCD could be released in the tumor microenvironmentChemoradiotherapy medicine and ultra-small CuxFe3-xO4(x ═ 0.119) nanocrystals, we treated LFCCD nanoparticles mimicking a weakly acidic tumor microenvironment (pH 4.5). As shown, after treatment, the nanocluster structure of the LFCCD begins to collapse and break into many tiny nanocrystals, and at the same time, the hydrodynamic size of the LFCCD is significantly reduced, indicating that the LFCCD has a strong response capability to the tumor microenvironment.
Test example 3
1.1 in vitro safety assessment
The biological safety of nanoliposomes is an important consideration in evaluating their potential for clinical application. The results show that the magnetic nano-liposome has lower cytotoxicity to THLE-3 and 293T cells, and the survival rate is over 70 percent in the concentration range of 0-160mg/mL, which indicates that the ultra-small LFCCD nano-liposome has lower toxicity to normal cells.
1.2 evaluation of antitumor efficacy in vitro
5 Control groups, respectively Control (without any treatment), Cam/Dox (mixed solution of camptothecin and doxorubicin), LFCC (unloaded doxorubicin), LFCCD + Laser (plus 650nm Laser irradiation treatment), were set to evaluate the viability of CT26 cells treated in different groups. With increasing concentration, the survival rate of CT26 cells cultured by different treatments decreased. More importantly, LFCCDs showed higher cytotoxicity than Cam/Dox and LFCC groups due to the synergistic effect of iron death and chemotherapy. In addition, LFCCD + Laser has a stronger inhibitory effect on cell viability than LFCCD, since an increase in temperature when using Laser light not only burns tumor cells but also promotes iron death.
Test example 4
1.1 evaluation of antitumor efficacy in vivo
To further evaluate the anti-tumor capacity of LFCCD in vivo, BALB/c mice carrying CT26 were constructed by injection of CT26 cells, followed by injection of Cam, Cam/Dox, LFCC, LFCCD and LFCCD + L via tail vein. Tumor growth may be partially inhibited after Cam treatment. However, LFCC has a greater ability to inhibit tumor growth than free Cam, suggesting that iron death is effective in promoting LFCC anti-cancer activity. Notably, Cam and Dox injection in combination also effectively inhibited tumor growth, indicating the advantages of Cam and Dox combination therapy. The antitumor ability of the LFCCD group further confirms this result. More importantly, the LFCCD + L group showed the strongest anticancer activity, suggesting that the use of laser could further inhibit tumor growth.
1.2 in vivo safety assessment
As a new therapeutic drug, in addition to the curative effect, the safety, pharmacokinetics and biodistribution of the drug also need to be evaluated systematically in vivo, and whether the developed preparation has potential clinical application value or not. The body weights of the different groups of mice were monitored during the treatment, and there was no significant difference in the body weights of the groups of mice.
However, in the results of conventional blood analysis, white blood cells increased significantly and red blood cells decreased significantly after Cam/Dox treatment of mice. These results indicate that Cam/Dox has severe hematologic toxicity. In addition, the conventional blood indexes of the LFCCD after treatment have no obvious change, which shows that the LFCCD can reduce the toxicity of Cam and Dox and has good blood biocompatibility. As can be seen from the analysis, the LFCCD has good tissue biosafety and blood biocompatibility, and has potential clinical application potential in the aspect of cancer treatment.
Test example 5
Evaluation of in-vivo magnetic resonance imaging Performance
Injecting BALB/c mouse with tumor with CuxFe3-xO4Or LFCCD at a dose of 2mg/kg by T using a 7.0T MRI scanner2WI observed the tumor area before and after treatment. In the cross section shown in FIG. 5, CuxFe3-xO4The tumor area of the treated mice did not change significantly (white circles) but the LFCCD gradually darkened, especially over 120 minutes. Cu injectionxFe3-xO4Coronal plane T of mouse2Weighted imaging only appeared slightly dark 30min after injection, with no significant change at other time points. This may be due to ultra small CuxFe3-xO4Nanocrystals were rapidly metabolized within 30 minutes of tail vein injection. We note that LFCCD processingTumor tissue of mice showed the darkest MR images at 120 minutes of tail vein injection, consistent with the cross-sectional results. These results indicate that LFCCD compares CuxFe3-xO4The nano-crystal is accumulated in the tumor more effectively, thereby realizing accurate diagnosis of the tumor. Typically, particles larger than 10nm are excreted outside the body via the liver metabolic pathway. While particles smaller than 10nm are metabolized via the renal pathway. Notably, we found that at T2In the weighted cross-sectional images, the kidneys (gray circles) of LFCCD treated mice appeared visibly black at 120 minutes, and the mouse kidneys in the coronal plane appeared darkest at 150 minutes, which means that a large number of LFCCDs were passing through the renal metabolic pathway. This is because LFCCDs are efficiently degraded in cancer cells and are broken into a large number of ultra-small particles, which are excreted outside the body through the renal route. This result further demonstrates that LFCCDs have a strong ability to respond to the tumor microenvironment and are biodegradable. In contrast, Cu was injectedxFe3-xO4Posterior, axial and coronal positions T2The kidney area on the weighted images darkened rapidly at 30min and then gradually recovered with increasing time, indicating ultra-small CuxFe3-xO4Nanocrystals are readily metabolized by the kidneys. In conclusion, the LFCCD can be effectively accumulated in the tumor, is degraded and metabolized through a renal pathway, and shows good tumor MRI diagnostic capability and biodegradability.
In summary, the embodiment of the present invention provides a preparation method and an application of a nano copper ferrite:
the embodiment of the invention provides a preparation method of nano-copper ferrite, which comprises the steps of heating and decomposing a mixed solution of copper oleate and iron oleate in a high-boiling-point organic solvent by a high-temperature decomposition method, and changing the proportion of the copper oleate to the iron oleate to prepare nano-particles with high catalytic performance, high photothermal performance and high imaging performance. Compared with the traditional iron-based nano material, the nano particles have better Fenton catalytic performance, and the Fenton catalytic capability and the photo-thermal conversion capability of the nano particles are obviously superior to those of Fe3O4And (3) nanoparticles. In addition, the nano-copper ferrite has good performanceIs disclosed. Has no obvious toxicity to normal cells and has the capability of selectively killing tumor cells. The in vivo anti-tumor result also proves that the tumor of the mouse is obviously inhibited after the LFCCD treatment, and the weight and blood routine of the mouse have no obvious difference compared with the contrast group, so the nano copper ferrite is beneficial to realizing the aim of multi-mode synergetic tumor treatment such as chemotherapy, chemodynamic treatment, photothermal treatment and the like, avoids the problems of drug resistance, side effect and the like generated by single chemotherapy drug treatment, and lays a material foundation for realizing efficient and safe diagnosis and treatment integration of tumor patients.
The copper-iron alloy has good biocompatibility and high Fenton catalytic performance; the preparation process is simple, the cost is relatively cheap, and the production is easy; the raw materials are environment-friendly and have no chemical pollution.
The embodiments described above are some, but not all embodiments of the invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Claims (10)

1. A nano-copper ferrite is characterized in that the chemical formula of the nano-copper ferrite is CuxFe3-xO4And X is the molar ratio of copper to the nano-copper ferrite.
2. The preparation method of the nano-copper ferrite as claimed in claim 1, comprising the steps of: mixing copper oleate and iron oleate together in 1-octadecene to obtain a mixture, adding oleic acid and sodium oleate into the mixture, and sequentially heating and precipitating to obtain copper-iron nanoparticles;
dispersing the copper-iron nano particles and NOBF4Sequentially mixing, removing impurities and centrifuging the DMF solution, and taking the precipitate obtained by centrifugation to obtain the nano copper ferrite.
3. The method of preparing nano-copper ferrite according to claim 2, wherein the preparation of copper oleate and iron oleate comprises the steps of: mixing ferric chloride, copper chloride and sodium oleate, adding a mixed solution of ethanol, n-hexane and water, heating to 70 ℃, refluxing for 2-4 hours to obtain a mixed solution, separating an oil phase and a water phase of the mixed solution, and cleaning the oil phase to obtain a mixture of the ferric oleate and the copper oleate.
4. The method for preparing nano-copper ferrite according to claim 2, wherein the heating time of the mixture, the oleic acid and the sodium oleate is 0.5-1 hour, and the heating temperature is 280-320 ℃.
5. The method for preparing nano-copper ferrite according to claim 4, wherein the step of introducing an inert gas is further included when the mixture, the oleic acid and the sodium oleate are heated, and the inert gas includes nitrogen.
6. The method of claim 2, wherein the copper-iron nanoparticles and the NOBF are formed by mixing the copper-iron nanoparticles with the NOBF4In a volume ratio of 1: (1-2) the NOBF4The concentration of the DMF solution of (1) is 0.01-0.05 mol/L.
7. The method for preparing nano-copper ferrite according to claim 2, wherein the impurity removal comprises the following steps: contacting the copper-iron nanoparticles with the NOBF4Mixing the DMF solution, shaking until the nano particles are transferred from the n-hexane layer to the DMF layer, discarding the n-hexane layer, and adding DMSA to remove impurities to complete mixing.
8. Use of the nano-copper ferrite prepared by the method of any one of claims 1 to 6 in the preparation of a system for the treatment of tumor drugs.
9. The application of claim 8, which comprises the following steps of mixing the nano copper ferrite with a hydrogenated soybean lecithin chloroform solution, a DSPE-PEG2000 chloroform solution, a cholesterol chloroform solution and a camptothecin chloroform solution, evaporating chloroform to obtain a film, adding an adriamycin hydrochloride aqueous solution and deionized water into the film, performing ultrasonic hydration for 25-35min to obtain a crude drug, centrifuging the crude drug, and taking a precipitate to obtain the tumor drug treatment system.
10. The use according to claim 9, wherein the molar ratio of hydrogenated soy phospholipids in the hydrogenated soy phospholipids chloroform solution, DSPE-PEG2000 in the DSPE-PEG2000 chloroform solution and cholesterol in the cholesterol chloroform solution is (80-90): (1-1.5): (8-12), the concentrations of the hydrogenated soybean phospholipid chloroform solution, the DSPE-PEG2000 chloroform solution, the cholesterol chloroform solution and the doxorubicin hydrochloride aqueous solution are all 8-12 mg/mL.
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