CN113521297A - Bionic nano material and preparation method and application thereof - Google Patents
Bionic nano material and preparation method and application thereof Download PDFInfo
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- CN113521297A CN113521297A CN202110796115.6A CN202110796115A CN113521297A CN 113521297 A CN113521297 A CN 113521297A CN 202110796115 A CN202110796115 A CN 202110796115A CN 113521297 A CN113521297 A CN 113521297A
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- polyacrylic acid
- chlorin
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- cerium dioxide
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- OYINILBBZAQBEV-UWJYYQICSA-N (17s,18s)-18-(2-carboxyethyl)-20-(carboxymethyl)-12-ethenyl-7-ethyl-3,8,13,17-tetramethyl-17,18,22,23-tetrahydroporphyrin-2-carboxylic acid Chemical compound N1C2=C(C)C(C=C)=C1C=C(N1)C(C)=C(CC)C1=CC(C(C)=C1C(O)=O)=NC1=C(CC(O)=O)C([C@@H](CCC(O)=O)[C@@H]1C)=NC1=C2 OYINILBBZAQBEV-UWJYYQICSA-N 0.000 claims abstract description 81
- CETPSERCERDGAM-UHFFFAOYSA-N ceric oxide Chemical compound O=[Ce]=O CETPSERCERDGAM-UHFFFAOYSA-N 0.000 claims abstract description 79
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
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- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
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Abstract
A bionic nanometer material and its preparation method and application are provided. The invention relates to a bionic nano material which comprises cerium dioxide, polyacrylic acid, chlorin e6, cinobufagin and a bionic membrane, wherein the polyacrylic acid is coated on the surface of the cerium dioxide to synthesize the nano material, the cinobufagin and chlorin e6 are respectively loaded on the surface of the nano material through physical adsorption and chemical bond combination to obtain a nano composite material, and the bionic membrane is coated on the outer layer of the nano composite material to obtain the bionic nano material. The bionic nano material has better stability, dispersibility and safety, has long duration of an oxygen generating strategy, can still keep effective photodynamic killing effect in an anoxic environment, is beneficial to reducing the side effect of chemotherapy drugs and enhancing the tumor enrichment efficiency of the chemotherapy drugs, and is applied to the treatment of combining photodynamic therapy with chemotherapy for resisting tumors.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a bionic nano material and a preparation method and application thereof.
Background
Chemotherapy is one of the most widely used tumor treatments at present, however, the systemic distribution and lack of targeting ability of chemotherapeutic drugs also result in damage to healthy cells. With the development of nanotechnology in medical applications, the dilemma of combination therapy is brought about by the combination of various treatment modes to reduce the dosage of chemotherapeutic drugs or by improving drug targeting strategies through drug delivery systems. The combination of photodynamic/chemotherapeutic approaches has developed a number of excellent therapeutic strategies due to their good regioselectivity, minimal invasiveness, and low toxicity. However, photodynamic therapy as an oxygen-dependent treatment is in most cases not compatible with the hypoxic environment inside the tumor, and photosensitizers that enter the cells often do not find sufficient oxygen to convert, resulting in a reduction in the therapeutic effect. To overcome this problem, oxygen carrier strategies were developed to provide additional oxygen, but photodynamic therapy is a long-term treatment process with a single burst of oxygen with poor oxygen availability and sustainability. Therefore, there is still a need to develop a sustainable oxygen production strategy to address the current challenges.
Cerium dioxide is a rare earth metal oxide with a fluorite structure, and the specific external electronic structure and oxygen vacancy of the cerium oxide cause the coexistence of two cerium ions (Ce3+/Ce4+) with different valence states on the surface, wherein the content of the surface Ce3+ is the catalytic core of peroxidase-like enzyme. Therefore, the unique structure enables cerium dioxide to have endogenous peroxidase-like activity, and the peroxidase-like activity of the cerium dioxide can be utilized to actively decompose excessive H in a tumor microenvironment2O2Oxygen is generated to overcome the tumor hypoxia. The oxygen production mode which can be continuously catalyzed and does not consume the oxygen is expected to develop a nano enzyme active preparation with strong persistence and high stability for treating tumors, however, the material toxicity and the surface modification of the cerium dioxideThe biological application of the material is limited by the properties of weak capacity, and the synthesis method of most cerium dioxide needs extremely high calcination temperature and causes difficulty in large-scale production, so that a cerium dioxide nano enzyme preparation which is safer, more reliable and easier to synthesize needs to be developed.
Disclosure of Invention
Aiming at the problems, the invention provides a bionic nano material which has self oxygen generation capacity, can load photosensitizer and chemotherapeutic drug, has high biological safety and small particle size, also provides a preparation method of the nano bionic material which has simple process, no need of high temperature, short time consumption and easy scale production, and correspondingly provides an application of the bionic nano material in preparing an anti-tumor photodynamic therapy combined chemotherapy carrier, wherein the bionic nano material is a polyacrylic acid modified cerium dioxide nano material which is loaded with dihydroporphin e6 and cinobufagin.
The invention provides a bionic nano material which comprises cerium dioxide, polyacrylic acid, chlorin e6, cinobufagin and a bionic membrane, wherein the polyacrylic acid is coated on the surface of the cerium dioxide to synthesize the nano material, the cinobufagin and chlorin e6 are respectively loaded on the surface of the nano material through physical adsorption and chemical bond combination to obtain the nano composite material, and the bionic membrane is coated on the outer layer of the nano composite material to obtain the bionic nano material.
Preferably, the particle size of the bionic nano material is 10nm-20 nm.
The invention provides a preparation method of the bionic nano material, which comprises the following steps:
s1, decomposing cerium carbonate by nitric acid to obtain cerium ions, uniformly dispersing the cerium ions and polyacrylic acid in double distilled water, dropwise adding ammonia water and stirring, wherein the ammonia water is slowly dropwise added, centrifuging to remove insoluble precipitates, and then performing ultrasonic dispersion to obtain polyacrylic acid modified cerium dioxide, namely obtaining the nano material;
s2, stirring and mixing chlorin e6, 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS), adding polyacrylic acid modified cerium dioxide prepared in the step S1, continuing stirring, and centrifugally dispersing the obtained solution to obtain polyacrylic acid modified cerium dioxide loaded with chlorin e 6;
s3, adding cinobufagin into polyacrylic acid modified cerium dioxide loaded with chlorin e6, mixing and stirring, and performing centrifugal dispersion to obtain polyacrylic acid modified cerium dioxide loaded with chlorin e6 and cinobufagin in a co-loading manner, so as to obtain the nano composite material;
s4, ultrasonically crushing the collected erythrocyte membranes and cancer cell membranes, and stirring and reacting in PBS to obtain a bionic membrane;
s5, co-sonicating polyacrylic acid modified cerium dioxide co-loaded with chlorin e6 and cinobufagin and a bionic membrane, stirring in a constant-temperature water bath, and centrifugally dispersing to obtain the polyacrylic acid modified cerium dioxide bionic nano material co-loaded with chlorin e6 and cinobufagin, so that the bionic nano material is obtained.
Preferably, in the step S1, the ratio of the polyacrylic acid to the cerium carbonate is 1: 2.3-3, the concentration of the ammonia water is 20% -30%, the stirring speed is 500-700 rpm, the stirring time is 12-16 h, the centrifugal rotation speed is 3500-4500 rpm, the centrifugal time is 5-10 min, the co-centrifugal water washing is performed for 5-7 times, the ultrasonic power is 80-100W, and the ultrasonic time is 10-15 min.
Preferably, the ratio of polyacrylic acid modified ceria, chlorin e6, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) in step S2 is 0.05: 0.5-1: 6-12: 12-24, the stirring speed is 500-700 rpm, the stirring time of the chlorin e6 after EDC and NHS are added is 2-6 h, the stirring time of the chlorin e6 after polyacrylic acid modified cerium dioxide is added is 6-24 h, the centrifugal rotation speed is 10000-12000 rpm, and the centrifugal time is 10-15 min.
Preferably, in the step S3, the ratio of the cinobufagin to the polyacrylic acid modified cerium dioxide loaded with chlorin e6 is 0.5-1: 10, the stirring speed is 500-700 rpm, the stirring time is 4-6 h, the centrifugal rotation speed is 10000-12000 rpm, and the centrifugal time is 10-15 min.
Preferably, the ratio of the erythrocyte membrane to the cancer cell membrane in step S4 is 2: 1-2, the ultrasonic power is 80-100W, the ultrasonic time is 2-5 min, the ultrasonic temperature is 0-4 ℃, the stirring speed is 500-700 rpm, and the stirring time is 2-3 h.
Preferably, in step S5, the ratio of the polyacrylic acid modified cerium dioxide co-loaded with chlorin e6 and cinobufagin to the biomimetic membrane is 1: 5-10, the ultrasonic power is 80-100W, the ultrasonic time is 2-5 min, the stirring speed of the water bath is 500-700 rpm, the temperature of the water bath is 35-37 ℃, the stirring time is 2-4 hours, and the centrifugal speed is 8000-1000 rpm.
The invention provides application of a bionic nano material in preparation of a combined chemotherapy carrier for anti-tumor photodynamic therapy.
Compared with the prior art, the invention has the following beneficial effects:
1. the polyacrylic acid coating of the polyacrylic acid modified cerium dioxide bionic nano material co-loaded with chlorin e6 and cinobufagin improves the water solubility and difficult modification of cerium dioxide, and the bionic coating improves the biological safety of the cerium dioxide.
2. The bionic nano material is prepared by taking polyacrylic acid-coated cerium dioxide as a core carrier, and the polyacrylic acid coating can be used as a carrier substrate to load chlorin e6 through chemical bonds of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS), so that the chlorin e6 is difficult to leak from the surface of the material, the systemic phototoxicity of the material is reduced, and meanwhile, cinobufagin can be loaded through physical adsorption, and the loading mode can be used for controllably releasing chemotherapeutic drugs through regulating the bonding strength through pH value, and reducing the damage of the chemotherapeutic drugs to healthy cells. The camouflage of the bionic membrane can avoid the recognition of macrophages, and meanwhile, the bionic membrane is actively targeted to tumor tissues through the homotypic targeting principle, so that the targeting property and the in vivo retention time of cerium dioxide are improved, the circulation time of the bionic nanometer material is prolonged, the side effect of chemotherapeutic drugs is favorably reduced, and the tumor enrichment efficiency of the bionic nanometer material is enhanced.
3. The bionic nano material is prepared by the structural design that the chlorin e6 and cinobufagin are loaded on the ceric oxide wrapped by polyacrylic acid, and can be widely applied to photodynamic therapy with weakened effect caused by tumor hypoxia microenvironment. The bionic nano material utilizes the self oxygen production capacity of cerium dioxide and the active oxygen conversion capacity of chlorin e6 to design a cascade reaction anti-tumor strategy of oxygen production, oxygen consumption and active oxygen production. Compared with the traditional oxygen carrier strategy, the method has stronger sustainability and higher oxygen utilization rate. The bionic nano material also has a photoresponse and pH response mechanism, can realize the controllable release of active oxygen and chemotherapeutic drugs, activates chlorin e6 to generate active oxygen under the promotion of laser, can still keep effective photodynamic killing effect under an anoxic environment, actively releases the drugs to reduce the toxic and side effects of the chemotherapeutic drugs and the photosensitizer under a low pH value, and the extremely small particle size of the bionic nano material is also beneficial to increasing the surface activity of cerium dioxide and the tissue permeability of the bionic nano material.
4. The raw material selection and the structural sequence design of the bionic nano material supplement each other, so that the bionic nano material has better stability, dispersibility and safety, can generate active oxygen to cause apoptosis under the irradiation of laser, can provide extra oxygen for the consumption of the active oxygen during the production, can be applied to the tumor treatment in an extreme anoxic environment, and can achieve a multi-hand treatment strategy by combining oxygen, photodynamic and chemotherapy.
5. The preparation method of the polyacrylic acid modified cerium dioxide bionic nano material loaded with the chlorin e6 and the cinobufagin is simple to operate, does not need high temperature, is short in time consumption, and is easy for large-scale production and application.
Drawings
FIG. 1 is a transmission electron microscope image of polyacrylic acid modified cerium dioxide biomimetic nanomaterial loaded with chlorin e6 and cinobufagin in example 1 of the present invention;
FIG. 2 is a graph of the ultraviolet absorption spectra of the cerium dioxide, chlorin e6, polyacrylic acid modified cerium dioxide co-loaded with chlorin e6 and cinobufagin and polyacrylic acid modified cerium dioxide biomimetic nanomaterial co-loaded with chlorin e6 and cinobufagin in example 1 of the present invention;
FIG. 3 shows that exogenous H is added to polyacrylic acid modified cerium dioxide biomimetic nanomaterial of co-supported chlorin e6 and cinobufagin in example 1 of the present invention2O2The attached figure at the lower right corner of the later oxygen production curve is a picture of an oxygen production object;
FIG. 4 shows the consumption H of polyacrylic acid modified cerium dioxide biomimetic nano-materials with chlorin e6 and cinobufagin co-loaded in example 1 of the present invention2O2The rate of (d);
FIG. 5 is the immune evasion imaging of polyacrylic acid modified cerium dioxide co-loaded with chlorin e6 and cinobufagin and polyacrylic acid modified cerium dioxide biomimetic nanomaterial co-loaded with chlorin e6 and cinobufagin in example 1 of the present invention, wherein the gray fluorescence represents the nanocomposite material (CPCC)/nano biomimetic material (CPCCM) entering macrophages;
FIG. 6 is a biodistribution quantification chart of free chlorin e6, polyacrylic acid modified cerium dioxide co-loaded with chlorin e6 and cinobufagin and polyacrylic acid modified cerium dioxide bionic nano-material co-loaded with chlorin e6 and cinobufagin in example 1 of the present invention;
FIG. 7 is a live-dead dye image of free chlorin e6, polyacrylic acid modified cerium dioxide co-loaded with chlorin e6 and cinobufagin, and polyacrylic acid modified cerium dioxide biomimetic nanomaterial co-loaded with chlorin e6 and cinobufagin in example 1 of the present invention (gray fluorescence represents labeled dead cells);
FIG. 8 is the tumor volume change of breast cancer mice treated with free chlorin e6 and cinobufagin, polyacrylic acid modified cerium dioxide co-loaded with chlorin e6 and cinobufagin, and polyacrylic acid modified cerium dioxide bio-nanomaterial co-loaded with chlorin e6 and cinobufagin in example 1 of the present invention;
FIG. 9 shows the change of tumor fluorescence intensity (black circles indicate fluorescence range) of breast cancer mice treated with free chlorin e6 and cinobufagin, polyacrylic acid modified cerium dioxide co-loaded with chlorin e6 and cinobufagin, and polyacrylic acid modified cerium dioxide biomimetic nanomaterial co-loaded with chlorin e6 and cinobufagin according to example 1 of the present invention.
Detailed Description
The present invention will be described in detail with reference to FIGS. 1 to 9, wherein illustrative examples and descriptions of the present invention are provided to explain the present invention, but not to limit the present invention, and in the following examples, unless otherwise specified, raw materials and instruments used are commercially available, and the concentration unit M is mol/L, DMSO is dimethyl sulfoxide, and PBS is phosphate buffered saline.
Example 1
The bionic nano material comprises cerium dioxide, polyacrylic acid, chlorin e6, cinobufagin and a bionic membrane, wherein the polyacrylic acid is coated on the surface of the cerium dioxide to synthesize the nano material, the cinobufagin and chlorin e6 are respectively loaded on the surface of the nano material through physical adsorption and chemical bond combination to obtain the nano composite material, the bionic membrane is coated on the outer layer of the nano composite material to obtain the bionic nano material, and the particle size of the bionic nano material is 10nm-20 nm.
The invention provides a preparation method of the bionic nano material, which comprises the following steps:
s1, uniformly dispersing 1M cerium ions (obtained by decomposing 2.3g of cerium carbonate by using concentrated nitric acid in the method) and 1g of polyacrylic acid in double distilled water, slowly dropwise adding 40ml of 30% ammonia water, stirring at 600rpm of a stirrer until the solution becomes light yellow, and continuously stirring for 12 hours until the solution becomes dark brown. Centrifuging for 10min at 4000rpm of a centrifuge to remove insoluble precipitate, continuously centrifuging and washing for 5 times under the condition, and performing ultrasonic treatment for 15min at 80-100W to obtain polyacrylic acid modified cerium dioxide, namely obtaining a nano material (marked as CP);
s2, dissolving 1mg chlorin e6 in 1ml DMSO, adding 12mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 24mg of N-hydroxysuccinimide (NHS) and stirring at 600rpm of a stirrer for 4h, dropping the mixture after the reaction into 1mg/ml polyacrylic acid modified cerium dioxide and continuing stirring for 24 h. Centrifuging for 15min at 12000rpm by using a centrifuge to obtain polyacrylic acid modified cerium dioxide loaded with chlorin e 6;
s3, adding 100ug/ml cinobufagin into the obtained polyacrylic acid modified cerium dioxide loaded with chlorin e6, stirring for 4h at 600rpm of a stirrer, and centrifuging for 15min at 12000rpm of a centrifuge to obtain polyacrylic acid modified cerium dioxide loaded with chlorin e6 and cinobufagin, so as to obtain a nano composite material (recorded as CPCC);
s4, carrying out ultrasonic treatment on the collected erythrocyte membranes and cancer cell membranes on ice for 5min at the speed of 80-100W, and breaking the large membrane structure through PBS 1: 1 mixing the two membrane solutions, and stirring for 4 hours at the temperature of 37 ℃ and the rpm of a stirrer 600 to obtain a bionic membrane;
s5, mixing the prepared polyacrylic acid modified cerium dioxide and bionic membrane 1: 10 is mixed with 80W ultrasonic for 2min, then the mixture is stirred for 4h in water bath at the water bath temperature of 37 ℃ and the stirring machine at 600rpm, and then the mixture is centrifugally dispersed by a centrifugal machine at 8000rpm to obtain the polyacrylic acid modified cerium dioxide bionic nano material with co-loaded chlorin e6 and cinobufagin, namely the bionic nano material (recorded as CPCCM).
As shown in fig. 1, transmission electron microscopy imaging analysis was performed on polyacrylic acid modified Ceria (CP), codoporphine e6 and cinobufagin based polyacrylic acid modified ceria biomimetic nanomaterial (CPCCM) prepared in this example, and the result showed that uniformly dispersed spherical ceria was successfully prepared, and the particle size was 15nm ± 5, and the biomimetic membrane was successfully coated on the surface of codoporphine e6 and cinobufagin based polyacrylic acid modified ceria.
The polyacrylic acid modified cerium dioxide (CP), chlorin e6(Ce6), polyacrylic acid modified cerium dioxide (CPCC) co-loaded with chlorin e6 and cinobufagin, and polyacrylic acid modified cerium dioxide biomimetic nanomaterial (CPCCM) co-loaded with chlorin e6 and cinobufagin, which are prepared in this example 1, were analyzed by an ultraviolet spectrophotometer to obtain an ultraviolet absorption spectrum graph as shown in fig. 2, from which it can be seen that the CPCCM shows characteristic absorption peaks of Ce ions, chlorin e6 and hybrid membrane (M).
As shown in figures 3 and 4 of the drawings,in vitro peroxidase activity evaluation was performed on the polyacrylic acid-modified cerium dioxide biomimetic nanomaterial (CPCCM) co-loaded with chlorin e6 and cinobufagin prepared in example 1, and as a result, exogenous H was found on the surface2O2Oxygen rapidly increased within 10min after addition of (c), and significant steam drum generation was observed in the bottom right image. Meanwhile, hydrogen peroxide is quickly decomposed after the bionic nano material is added, and the polyacrylic acid modified cerium dioxide bionic nano material co-loaded with chlorin e6 and cinobufagin can catalyze H2O2The decomposition of (a) produces a large amount of oxygen.
Example 2
The application of the polyacrylic acid modified cerium dioxide bionic nano material co-loaded with the chlorin e6 and the cinobufagin in immune evasion and tumor targeting adopts the polyacrylic acid modified cerium dioxide bionic nano material co-loaded with the chlorin e6 and the cinobufagin prepared in example 1.
Incubating polyacrylic acid modified cerium dioxide (CPCC) co-loaded with chlorin e6 and cinobufagin and polyacrylic acid modified cerium dioxide bionic nano-material (CPCCM) co-loaded with chlorin e6 and cinobufagin with macrophages to observe the uptake degree of the polyacrylic acid modified cerium dioxide bionic nano-material (CPCCM), wherein gray fluorescence represents the nano-composite material (CPCC)/nano-bionic material (CPCCM) entering the macrophages, and the result is shown in figure 5, the nano-composite material (CPCC) which is not wrapped by the bionic membrane is identified and phagocytized by the macrophages when the concentration reaches more than 100 mu g/ml, and the nano-composite material (CPCCM) which is wrapped by the bionic membrane is not phagocytized in the concentration range, which indicates that the modification of the bionic membrane can effectively escape the identification of an immune system. The in vivo targeting experiment of FIG. 6 shows (CCeO in the figure)2Is CPCC, CCeO2M is CPCCM), the fluorescence intensity of Free chlorin e6(Free Ce6) at a Tumor part (Tumor) is obviously lower than that of a nano composite material (CPCC) after tail vein injection for 48 hours, and the nano composite material (CPCCM) wrapped by a bionic membrane has stronger fluorescence, thereby further improving the enrichment amount of the Tumor and prolonging the retention time in the Tumor.
Example 3
The invention relates to an application of polyacrylic acid modified cerium dioxide bionic nano material co-loaded with chlorin e6 and cinobufagin in resisting breast cancer cells in vitro, which adopts the polyacrylic acid modified cerium dioxide bionic nano material co-loaded with chlorin e6 and cinobufagin prepared in example 1.
The killing effect of laser activated/shut-off chlorin e6(Ce6), polyacrylic acid modified cerium dioxide (CPCC) co-loaded with chlorin e6 and cinobufagin and polyacrylic acid modified cerium dioxide bionic nano-material (CPCCM) co-loaded with chlorin e6 and cinobufagin on breast cancer cells in an anoxic environment is evaluated by a live-dead staining method (gray light spots in the figure are marked dead cells). As shown in fig. 7, chlorin e6 could not exert normal photodynamic killing effect under laser irradiation due to the influence of oxygen deficient environment, and the fluorescence intensity was weak. The drug active release fluorescence of the CPCC is increased when the CPCC is not irradiated by laser, and the fluorescence is weaker than that of the CPCC due to the lower drug release rate of the film when the CPCCM is not irradiated by the laser. Under laser irradiation, the membrane structure of the CPCCM is disintegrated to increase the drug release, and the catalytic oxygen production effect of the cerium dioxide improves the tumor anoxic environment, so that the CPCCM and the CPCC can achieve high-strength killing effect under laser irradiation.
Example 4
The invention relates to an application of polyacrylic acid modified cerium dioxide bionic nano material co-loaded with chlorin e6 and cinobufagin in resisting breast cancer cells in vivo, which adopts the polyacrylic acid modified cerium dioxide bionic nano material co-loaded with chlorin e6 and cinobufagin prepared in example 1.
As shown in fig. 8 and 9, breast cancer transplantation tumor mice were treated with 100 μ L of polyacrylic acid-modified cerium oxide (CPCC) co-loaded with chlorin e6 and cinobufagin and polyacrylic acid-modified cerium oxide biomimetic nanomaterial (CPCCM) co-loaded with chlorin e6 and cinobufagin and free chlorin e6 and cinobufagin (CC + L), wherein L represents laser, at a concentration of 2 mg/ml. Compared with a control group, the volume of the tumor of the mouse treated by the CPCCM + L is reduced and kept unchanged on the 6 th day, which indicates that the tumor growth is inhibited, and the fluorescence intensity of the CPCCM + L group is reduced to the lower detection limit through a fluorescence image (the fluorescence is the biological fluorescence of tumor cells, namely the black circle mark) after the treatment of the mouse is finished, which indicates that the CPCCM + L can play a better role in treating the breast cancer with the tumor.
The technical solutions provided by the embodiments of the present invention are described in detail above, and the principles and embodiments of the present invention are explained herein by using specific examples, and the descriptions of the embodiments are only used to help understanding the principles of the embodiments of the present invention; meanwhile, for a person skilled in the art, according to the embodiments of the present invention, there may be variations in the specific implementation manners and application ranges, and in summary, the content of the present description should not be construed as a limitation to the present invention.
Claims (9)
1. A bionic nano material is characterized in that: the bionic nano material comprises cerium dioxide, polyacrylic acid, chlorin e6, cinobufagin and a bionic membrane, wherein the polyacrylic acid is coated on the surface of the cerium dioxide to synthesize the nano material, the cinobufagin and chlorin e6 are respectively loaded on the surface of the nano material through physical adsorption and chemical bond combination to obtain the nano composite material, and the bionic membrane is coated on the outer layer of the nano composite material to obtain the bionic nano material.
2. The biomimetic nanomaterial according to claim 1, wherein: the particle size of the bionic nano material is 10nm-20 nm.
3. The preparation method of the bionic nano material according to any one of claims 1-2, characterized by comprising the following steps:
s1, decomposing cerium carbonate by nitric acid to obtain cerium ions, uniformly dispersing the cerium ions and polyacrylic acid in double distilled water, dropwise adding ammonia water, stirring, centrifuging to remove insoluble precipitates, and performing ultrasonic dispersion to obtain polyacrylic acid modified cerium dioxide, namely obtaining the nano material;
s2, stirring and mixing chlorin e6, 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS), adding polyacrylic acid modified cerium dioxide prepared in the step S1, continuing stirring, and centrifugally dispersing the obtained solution to obtain polyacrylic acid modified cerium dioxide loaded with chlorin e 6;
s3, adding cinobufagin into polyacrylic acid modified cerium dioxide loaded with chlorin e6, mixing and stirring, and performing centrifugal dispersion to obtain polyacrylic acid modified cerium dioxide loaded with chlorin e6 and cinobufagin in a co-loading manner, so as to obtain the nano composite material;
s4, ultrasonically crushing the collected erythrocyte membranes and cancer cell membranes, and stirring and reacting in PBS to obtain a bionic membrane;
s5, co-sonicating polyacrylic acid modified cerium dioxide co-loaded with chlorin e6 and cinobufagin and a bionic membrane, stirring in a constant-temperature water bath, and centrifugally dispersing to obtain the polyacrylic acid modified cerium dioxide bionic nano material co-loaded with chlorin e6 and cinobufagin, so that the bionic nano material is obtained.
4. The method for preparing the biomimetic nano material according to claim 3, characterized in that: in the step S1, the ratio of polyacrylic acid to cerium carbonate is 1: 2.3-3, the concentration of ammonia water is 20% -30%, the stirring speed is 500 rpm-700 rpm, the stirring time is 12-16 h, the centrifugal speed is 3500 rpm-4500 rpm, the centrifugal time is 5-10 min, the total centrifugal washing is performed for 5-7 times, the ultrasonic power is 80W-100W, and the ultrasonic time is 10-15 min.
5. The method for preparing the biomimetic nano material according to claim 3, characterized in that: the ratio of polyacrylic acid modified ceria, chlorin e6, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) in step S2 was 0.05: 0.5-1: 6-12: 12-24, the stirring speed is 500-700 rpm, the stirring time of the chlorin e6 after EDC and NHS are added is 2-6 h, the stirring time of the chlorin e6 after polyacrylic acid modified cerium dioxide is added is 6-24 h, the centrifugal rotation speed is 10000-12000 rpm, and the centrifugal time is 10-15 min.
6. The method for preparing the biomimetic nano material according to claim 3, characterized in that: the ratio of the cinobufagin to the polyacrylic acid modified cerium dioxide loaded with chlorin e6 in the step S3 is 0.5-1: 10, the stirring speed is 500-700 rpm, the stirring time is 4-6 h, the centrifugal rotation speed is 10000-12000 rpm, and the centrifugal time is 10-15 min.
7. The method for preparing the biomimetic nano material according to claim 3, characterized in that: the ratio of the erythrocyte membrane to the cancer cell membrane in the step S4 is 2: 1-2, the ultrasonic power is 80-100W, the ultrasonic time is 2-5 min, the ultrasonic temperature is 0-4 ℃, the stirring speed is 500-700 rpm, and the stirring time is 2-3 h.
8. The method for preparing the biomimetic nano material according to claim 3, characterized in that: the ratio of polyacrylic acid modified cerium dioxide and bionic membrane which are co-loaded with chlorin e6 and cinobufagin in the step S5 is 1: 5-10, the ultrasonic power is 80-100W, the ultrasonic time is 2-5 min, the stirring speed of the water bath is 500-700 rpm, the temperature of the water bath is 35-37 ℃, the stirring time is 2-4 hours, and the centrifugal speed is 8000-1000 rpm.
9. Use of a biomimetic nanomaterial according to any one of claims 1-2 or a biomimetic nanomaterial prepared by the preparation method according to any one of claims 3-8 in preparation of a carrier for combined chemotherapy of anti-tumor photodynamic therapy.
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