CN113750233B - Nanocomposite and preparation method and application thereof - Google Patents
Nanocomposite and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of medicine, and particularly relates to a nanocomposite and a preparation method and application thereof. The nanocomposite provided by the invention comprises: an inorganic nanomaterial and BSA molecules modified on the surface of the inorganic nanomaterial; the inorganic nanomaterial includes: two-dimensional structure Ti 3 C 2 Nanoplatelets and are loaded on the two-dimensional structure Ti 3 C 2 Positively charged CuO on nanoplatelet surface 2 Nano dots. The invention is based on the principle of positive and negative charges and has a two-dimensional structure Ti 3 C 2 CuO is loaded on the surface of the nano-sheet 2 By means of CuO 2 Self-feeding H specifically in tumor microenvironment 2 O 2 The triggered Fenton reaction and exogenous ultrasonic stimulation realize efficient generation of ROS and cooperatively promote the tumor treatment effect. The nanocomposite provided by the invention is suitable for the sound power and chemical power synergistic treatment and high-efficiency treatment of tumors, particularly gliomas, and has important significance for the development of clinical tumor treatment and the progress of nano-ultrasonic medicine.
Description
Technical Field
The invention belongs to the field of medicine, and particularly relates to a nanocomposite and a preparation method and application thereof.
Background
In 1989, yumita et al stimulated the photosensitizers commonly used in photodynamic with ultrasound: hematoporphyrin and its derivatives have also been found to produce ROS that cause significant cytotoxicity, resulting in apoptosis/necrosis of cancer cells. Such a kind ofThe new approach to tumor treatment is called sonodynamic therapy (sonodynamic therapy, SDT). Reactive Oxygen Species (ROS) are chemically reactive molecules, including singlet oxygen 1 O 2 ) Superoxide radical (O) 2 · - ) Hydroxyl radical (. OH) and peroxide (O) 2 - ) Plays an important role in the cell life cycle. At lower concentrations, ROS can act as a key signaling molecule within cells to regulate cell growth, proliferation, and differentiation. However, abnormal production of ROS in cells will lead to oxidative damage of lipids, proteins or and DNA. Normally, cells are able to balance this oxidative damage to protect the cells from death. Excessive ROS can damage cell membranes, inhibit mitochondrial function, damage DNA to cause gene mutation, cause energy metabolism disorder, calcium overload and the like, cause irreversible oxidative damage to cells and cause apoptosis and programmed necrosis. Therefore, the selective breakthrough of the threshold value of ROS balance in tumor cells can effectively induce the death of tumor cells. SDT is a reactive oxygen related tumor treatment that converts ambient oxygen into cytotoxic ROS by low frequency ultrasound (exogenous stimulus) irradiation activation Sonosensitizers; is a representative method for treating cancers by utilizing ROS, has great potential of anti-tumor treatment, has lower toxic and side effects, and is not easy to generate drug resistance. Compared with the traditional radiotherapy and chemotherapy, the SDT has the advantages of non-invasiveness, non-radioactivity, high selectivity and the like. Compared with optical treatment (photodynamic/photothermal treatment), the sonodynamic has excellent tissue penetrating power, and the penetration depth can reach tens of centimeters, so that the sonodynamic can be used for treating deep tumors.
The organic sound sensitizers reported at present are porphyrin derivatives such as hematoporphyrin, protoporphyrin, phthalocyanine and the like and fat-soluble small molecules. The organic sound-sensitive agent has small molecules and low water solubility, is easy to be rapidly metabolized in vivo, has short blood circulation time, can not form effective enrichment at tumor sites, and can not achieve ideal sound power effect. And is also a photosensitizer, which is easy to generate phototoxicity and skin toxicity and has low bioavailability. The advent of nanobiotechnology has provided a new approach to the loading and transport of organic sonosensitizer molecules. By utilizing the novel carrier to carry the sound sensitive agent in a targeted way, the enrichment and accumulation of the sound sensitive agent in tumors can be effectively improved. Therefore, the development of sound-sensitive agents with higher efficiency, better stability and better biological safety for the efficient treatment of the SDT of tumors is needed in clinic.
At present, the key point of research is to develop a novel and efficient sound-sensitive agent so as to improve the effect of sound power treatment. Compared with the organic sound-sensitive agent, the inorganic sound-sensitive agent titanium oxide (TiO 2 ) Nanoparticles are highly stable and biosafety sonosensitizers that have evolved in recent years. As a typical semiconductor nanomaterial, titanium oxide nanoparticles can realize electrons under ultrasonic excitation (e - ) And cavity (h) + ) Thereby generating ROS to kill tumor cells. Research has found that TiO is utilized 2 The effect of the nano particles on the acoustic dynamic treatment of deep tissue tumors is less than that of TiO 2 The treatment group of the nano sound sensitive agent is improved by 15 times. But TiO 2 There are also drawbacks to be improved such as wide band gap, easy recombination of electrons and holes, etc., resulting in a decrease in ROS production efficiency.
Disclosure of Invention
In view of the above, the invention aims to provide a nanocomposite, a preparation method and application thereof, when the nanocomposite is used as a sound sensitizer, the nanocomposite can realize efficient generation of ROS, and the nanocomposite can carry out sound power treatment on tumors and chemical power cooperative treatment at the same time, so that the treatment effect is better and thorough, and the tumor recurrence caused by residual tumors is effectively avoided.
The present invention provides a nanocomposite material comprising: an inorganic nanomaterial and BSA molecules modified on the surface of the inorganic nanomaterial;
the inorganic nanomaterial includes: two-dimensional structure Ti 3 C 2 Nanoplatelets and are loaded on the two-dimensional structure Ti 3 C 2 Positively charged CuO on nanoplatelet surface 2 Nano dots.
The invention provides a preparation method of the nanocomposite, which comprises the following steps:
to a two-dimensional structure Ti 3 C 2 Nanosheets, positively charged CuO 2 Mixing the nano-dots with bovine serum albumin, and carrying out solid-liquid separation to obtain the nano-composite material.
Preferably, the two-dimensional structure Ti 3 C 2 The nano-sheet is prepared by the following steps:
ti is mixed with 3 AlC 2 Sequentially carrying out hydrofluoric acid etching treatment and tetrapropylammonium hydroxide intercalation treatment on the powder to obtain a two-dimensional structure Ti 3 C 2 A nano-sheet.
Preferably, the Ti is 3 AlC 2 The powder is prepared according to the following steps:
mixing titanium powder, aluminum powder and graphite powder, and pressing to obtain Ti 3 AlC 2 A biscuit;
subjecting the Ti to 3 AlC 2 Sintering the biscuit in the atmosphere of protective gas to obtain Ti 3 AlC 2 A bulk material;
for the Ti 3 AlC 2 Grinding the bulk material to obtain Ti 3 AlC 2 And (3) powder.
Preferably, the specific steps of sequentially performing the hydrofluoric acid etching treatment and the tetrapropylammonium hydroxide intercalation treatment include:
i) Ti is mixed with 3 AlC 2 Mixing the powder with HF water solution, and carrying out solid-liquid separation to obtain Ti after hydrofluoric acid etching treatment 3 C 2 A material;
ii) Ti to be subjected to hydrofluoric acid etching treatment 3 C 2 Mixing the material with tetrapropylammonium hydroxide, and carrying out solid-liquid separation to obtain the two-dimensional structure Ti 3 C 2 A nano-sheet.
Preferably, in step i), the aqueous HF solution has a concentration of 30 to 50 wt.%; the Ti is 3 AlC 2 The ratio of powder to aqueous HF solution was 10g: (40-100) mL.
Preferably, in step i), the temperature of the mixing is 15-35 ℃; the rotational speed of the mixing is 400-1000 rpm; the mixing time is 1-5 days.
Preferably, in step ii), the catalyst is prepared as Ti 3 AlC 2 The Ti of the powder gauge which is subjected to the hydrofluoric acid etching treatment 3 C 2 The ratio of the material to tetrapropylammonium hydroxide used was 10g: (40-100) mL.
Preferably, in step ii), the temperature of the mixing is 15-35 ℃; the rotational speed of the mixing is 400-1000 rpm; the mixing time is 1-5 days.
Preferably, the positively charged CuO 2 The nano-dots are prepared according to the following steps:
mixing soluble salt of copper, polyvinylpyrrolidone and hydrogen peroxide in alkaline aqueous solution for reaction, and ultrafiltering to obtain CuO with positive charge 2 Nano dots.
Preferably, the two-dimensional structure Ti 3 C 2 Nanosheets, positively charged CuO 2 The molar ratio of nanodots to bovine serum albumin is 1: (1-5): (1-5).
The invention also provides application of the nanocomposite in preparation of tumor sound power and chemical power cooperative treatment drugs.
Compared with the prior art, the invention provides a nanocomposite and a preparation method and application thereof. The nanocomposite provided by the invention comprises: an inorganic nanomaterial and BSA molecules modified on the surface of the inorganic nanomaterial; the inorganic nanomaterial includes: two-dimensional structure Ti 3 C 2 Nanoplatelets and are loaded on the two-dimensional structure Ti 3 C 2 Positively charged CuO on nanoplatelet surface 2 Nano dots. The invention is based on the principle of positive and negative charges and has a two-dimensional structure Ti 3 C 2 CuO is loaded on the surface of the nano-sheet 2 By means of CuO 2 Self-supplied H specific in tumor microenvironment (tumor microenvironment, TME) 2 O 2 The triggered Fenton reaction and exogenous ultrasonic stimulation realize efficient generation of ROS, and cooperatively promote the tumor treatment effect, and more specifically: 1) The invention adopts a two-dimensional structure Ti 3 C 2 The nano-sheet replaces the traditional TiO 2 Acoustic sensitizer, two-dimensional structure Ti 3 C 2 The nano-sheet has large specific surface area and can be used as a medicine or a function through Van der Waals forceThe nano material provides storage and anchoring sites, and has high stability, good biosafety and potential for clinical application; and Ti is 3 C 2 H capable of being bound by tumor region while participating in treatment 2 O 2 In situ oxidation to Ti 3 C 2 /TiO 2 The presence of carbon (C) favors TiO 2 The separation of electrons and holes excited by ultrasound improves the ROS production efficiency, thereby enhancing the effect of SDT. 2) By means of CuO 2 CuO has the characteristic of tumor microenvironment response 2 Can generate Cu in the slightly acidic environment of tumor focus area when participating in treatment 2+ And H 2 O 2 Thereby in situ elevating intratumoral H 2 O 2 Is enhanced by H 2 O 2 Cu and Cu 2+ The chemical kinetics treatment (chemodynamic therapy, CDT) of hydroxyl free radicals is generated for Fenton reaction of reactants, so that apoptosis of tumor cells is caused, and the tumor treatment effect is further improved. In addition, the size, the morphology and the performance of the material are further adjusted by modifying BSA molecules on the surface of the material, so that the BSA material has good dispersibility and high stability in aqueous solution and physiological environment. The nanocomposite (Ti) 3 C 2 /CuO 2 BSA) is suitable for the sonodynamic and chemodynamic synergistic and efficient treatment of tumors, in particular gliomas, and has important significance for the development of clinical tumor treatment and the progress of nano-ultrasound medicine.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required to be used in the embodiments or the description of the prior art will be briefly described below, and it is obvious that the drawings in the following description are only embodiments of the present invention, and that other drawings can be obtained according to the provided drawings without inventive effort for a person skilled in the art.
FIG. 1 is a multilayer structure Ti as provided in embodiment 1 of the invention 3 C 2 SEM electron microscopy of (a);
FIG. 2 is a diagram of Ti as provided in example 1 of the present invention 3 C 2 TEM electron microscope image of the nano-sheet;
FIG. 3 is a diagram of Ti as provided in example 1 of the present invention 3 C 2 /CuO 2 TEM electron microscopy of nanoparticles prepared at a molar ratio of 1:2:2;
FIG. 4 shows Ti as provided in example 1 of the present invention 3 C 2 /CuO 2 TEM electron microscope image of nanoparticles prepared with a molar ratio of 1:1:2;
FIG. 5 is a diagram of Ti as provided in example 1 of the present invention 3 C 2 /CuO 2 TEM electron microscopy of nanoparticles prepared at a molar ratio of 1:3:2;
FIG. 6 is a diagram of Ti as provided in example 1 of the present invention 3 C 2 /CuO 2 HADDF-STEM map of BSA nanoparticles;
FIG. 7 is a diagram of Ti as provided in example 1 of the present invention 3 C 2 /CuO 2 -energy scattering mapping graph of BSA nanoparticles;
FIG. 8 is a diagram of Ti as provided in example 1 of the present invention 3 C 2 /CuO 2 Atomic force microscopy of BSA nanoparticles;
FIG. 9 shows the measurement of Ti by an atomic force microscope according to example 1 of the present invention 3 C 2 /CuO 2 -thickness profile of BSA nanoparticles;
FIG. 10 is a DLS map provided in example 1 of the present invention;
FIG. 11 is a bar graph of different material concentrations versus U87 glioma cytotoxicity provided by an embodiment of the invention;
FIG. 12 is a graph of body weight of mice with different concentration material groups provided in an embodiment of the present invention;
FIG. 13 is a graph of HE staining of the major organs of mice with different concentration material groups provided by the examples of the present invention;
FIG. 14 is a real image of different groups of tumors provided by an embodiment of the present invention;
FIG. 15 is a graph of relative tumor volume versus time for different groups provided by an embodiment of the present invention;
FIG. 16 is a graph of HE and immunofluorescence staining of different groups of tumor tissue provided by the examples of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The present invention provides a nanocomposite material comprising: an inorganic nanomaterial and BSA molecules modified on the surface of the inorganic nanomaterial;
the inorganic nanomaterial includes: two-dimensional structure Ti 3 C 2 Nanoplatelets and are loaded on the two-dimensional structure Ti 3 C 2 Positively charged CuO on nanoplatelet surface 2 Nano dots.
The invention also provides a preparation method of the nanocomposite, which comprises the following steps:
to a two-dimensional structure Ti 3 C 2 Nanosheets, positively charged CuO 2 Mixing the nano dots with Bovine Serum Albumin (BSA), and carrying out solid-liquid separation to obtain the nano composite material.
In the preparation method provided by the invention, the two-dimensional structure Ti 3 C 2 The nano-sheets are preferably prepared according to the following steps:
ti is mixed with 3 AlC 2 Sequentially carrying out hydrofluoric acid etching treatment and tetrapropylammonium hydroxide intercalation treatment on the powder to obtain a two-dimensional structure Ti 3 C 2 A nanosheet; wherein the purpose of the etching treatment is to remove Ti 3 AlC 2 The purpose of the intercalation treatment is to convert the material into ultrathin two-dimensional nano-sheets.
The two-dimensional structure Ti provided by the invention 3 C 2 In the nano-sheet preparation step, the Ti 3 AlC 2 The particle size of the powder is preferably 50 to 800nm, and may be specifically 50nm, 100nm, 150nm, 200nm, 250nm, 300nm, 350nm, 400nm, 450nm, 500nm, 550nm, 600nm, 650nm, 700nm, 750nm or 800nm; the Ti is 3 AlC 2 The powder is preferably prepared according to the following steps:
mixing titanium powder, aluminum powder and graphite powder, and pressing to obtain Ti 3 AlC 2 A biscuit;
subjecting the Ti to 3 AlC 2 Sintering the biscuit in the atmosphere of protective gas to obtain Ti 3 AlC 2 A bulk material;
for the Ti 3 AlC 2 Grinding the bulk material to obtain Ti 3 AlC 2 And (3) powder.
The Ti is provided in the invention 3 AlC 2 In the powder preparation step, the particle size of the titanium powder is preferably 200 to 400 mesh, more preferably 325 mesh; the particle size of the aluminum powder is preferably 200 to 400 meshes, more preferably 325 meshes; the particle size of the graphite powder is preferably 200-400 mesh, more preferably 300 mesh; the molar ratio of the titanium powder in terms of Ti atoms, the aluminum powder in terms of Al atoms, and the graphite powder in terms of C atoms is preferably 2:1:1; the mixing mode is preferably ball milling; the mixing time is preferably 5 to 20 hours, more preferably 10 hours; the pressing pressure is preferably 5 to 20MPa, more preferably 10MPa; the shielding gas includes, but is not limited to, argon; the sintering temperature is preferably 1200-1800 ℃, more preferably 1500 ℃; the sintering time is preferably 1 to 3 hours, more preferably 2 hours.
The two-dimensional structure Ti provided by the invention 3 C 2 In the preparation step of the nanosheet, the specific steps of sequentially performing the hydrofluoric acid etching treatment and the tetrapropylammonium hydroxide intercalation treatment preferably include:
i) Ti is mixed with 3 AlC 2 Mixing the powder with HF water solution, and carrying out solid-liquid separation to obtain Ti after hydrofluoric acid etching treatment 3 C 2 A material;
ii) Ti to be subjected to hydrofluoric acid etching treatment 3 C 2 Mixing the material with tetrapropylammonium hydroxide (TPAOH), and performing solid-liquid separation to obtain the two-dimensional structure Ti 3 C 2 A nano-sheet.
In the above treatment step provided by the present invention, in step i), the concentration of the aqueous HF solution is preferably 30. Mu.m50wt%, more preferably 40wt%; the Ti is 3 AlC 2 The ratio of powder to aqueous HF solution is preferably 10g: (40-100) mL, more preferably 10g:60mL; the temperature of the mixing is preferably 15-35 ℃, more preferably 25 ℃ (room temperature); the rotational speed of the mixing is preferably 400 to 1000rpm, more preferably 600rpm; the mixing time is preferably 1 to 5 days, more preferably 3 days.
In the above-mentioned treatment step provided by the present invention, in the step i), the solid-liquid separation is preferably centrifugal separation, and the rotational speed of the centrifugal separation is preferably 10000 to 15000rpm, more preferably 13000rpm; after solid-liquid separation, ti which is subjected to hydrofluoric acid etching treatment is obtained 3 C 2 The material is washed, preferably by water and ethanol.
In the above-mentioned treatment step provided by the present invention, in step ii), the composition is prepared by 3 AlC 2 The Ti of the powder gauge which is subjected to the hydrofluoric acid etching treatment 3 C 2 The ratio of material to tetrapropylammonium hydroxide is preferably 10g: (40-100) mL, more preferably 10g:60mL; the temperature of the mixing is preferably 15-35 ℃, more preferably 25 ℃ (room temperature); the rotational speed of the mixing is preferably 400 to 1000rpm, more preferably 600rpm; the mixing time is preferably 1 to 5 days, more preferably 3 days.
In the above-mentioned treatment step provided by the present invention, in the step ii), the solid-liquid separation is preferably centrifugal separation, and the rotational speed of the centrifugal separation is preferably 10000 to 15000rpm, more preferably 13000rpm; after solid-liquid separation, the obtained two-dimensional structure Ti 3 C 2 The nanoplatelets are washed to remove residual tetrapropylammonium hydroxide, preferably in a manner of water washing and ethanol washing, and the number of times of washing is preferably repeated 3 times.
In the preparation method provided by the invention, the CuO with positive charge 2 The nanodots are preferably prepared according to the following steps:
mixing soluble salt of copper, polyvinylpyrrolidone (PVP) and hydrogen peroxide in alkaline aqueous solution for reaction, and ultrafiltering to obtain CuO with positive charge 2 Nano dots.
The positively charged CuO provided in the invention 2 In the nanodot preparation step, the soluble salt of copper is preferably copper chloride (CuCl) 2 ) The method comprises the steps of carrying out a first treatment on the surface of the The viscosity average molecular weight (Mv) of the polyvinylpyrrolidone is preferably 5000-20000, and can be 5000, 10000, 15000 or 20000; the alkalinity is preferably provided by an alkali metal hydroxide, preferably sodium hydroxide. In the present invention, the specific process of the mixing reaction is preferably: mixing copper salt aqueous solution, polyvinylpyrrolidone, alkali metal hydroxide aqueous solution and hydrogen peroxide for reaction; wherein the concentration of the copper salt aqueous solution is preferably 0.005-0.02 mol/L, more preferably 0.01mol/L; the concentration of the alkali metal hydroxide aqueous solution is preferably 0.01 to 0.05mol/L, more preferably 0.02mol/L; the concentration of the hydrogen peroxide is preferably 10-50 wt%, more preferably 30wt%; the dosage ratio of the copper salt aqueous solution, the polyvinylpyrrolidone, the alkali metal hydroxide aqueous solution and the hydrogen peroxide is preferably (1-10) mL: (0.1-1) g: (1-10) mL: 100. Mu.L, more preferably 5mL:0.5g:5mL: 100. Mu.L. In the present invention, the temperature of the mixing reaction is preferably 15 to 35 ℃, more preferably 25 ℃ (room temperature); the rotational speed of the mixing is preferably 400 to 1000rpm, more preferably 600rpm; the mixing time is preferably 10 to 60 minutes, more preferably 30 minutes.
The positively charged CuO provided in the invention 2 In the nano-dot preparation step, the molecular weight cut-off of an ultrafiltration tube used for ultrafiltration is preferably 10000-50000, more preferably 30000; the rotation speed of the ultrafiltration is preferably 3000-6000 rpm, more preferably 4500rpm; the number of times of ultrafiltration is preferably 1 to 5 times, more preferably 3 times; the total consumption of the ultrafiltration is preferably 20 to 60 minutes, more preferably 40 minutes. After the ultrafiltration is completed, the resulting positively charged CuO is preferably 2 The nanodots are redispersed in water and dialyzed to remove residual polyvinylpyrrolidone.
In the preparation method provided by the invention, the molecular weight of the bovine serum albumin is preferably 50-100 kDa, more preferably 66kDa; the bovine serum albumin is preferably provided by Macklin (Macklin).
In the present invention provideIn the preparation method, the two-dimensional structure Ti 3 C 2 Nanoplatelets and positively charged CuO 2 The molar ratio of nanodots is preferably 1: (1-5), specifically 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5, most preferably 1:2; the two-dimensional structure Ti 3 C 2 The molar ratio of the nano-sheet to the bovine serum albumin is preferably 1: (1-5), specifically 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5, most preferably 1:2.
In the preparation method provided by the invention, the two-dimensional structure Ti 3 C 2 Nanosheets, positively charged CuO 2 The rotation speed of mixing the nanodots with the bovine serum albumin is preferably 300-1000 rpm, more preferably 600rpm; the mixing time is preferably 2 to 6 hours, more preferably 4 hours.
In the preparation method provided by the invention, the two-dimensional structure Ti 3 C 2 Nanosheets, positively charged CuO 2 The mode of carrying out solid-liquid separation after the mixing of the nanodots and the bovine serum albumin is preferably centrifugal separation, the rotating speed of the centrifugal separation is preferably 10000-15000 rpm, more preferably 13000rpm, and the time of the centrifugal separation is preferably 5-30 min, more preferably 10min; after solid-liquid separation, the nanocomposite (Ti 3 C 2 /CuO 2 -BSA), the washing lotion of which is preferably Phosphate Buffered Saline (PBS).
In the preparation method provided by the invention, after the nanocomposite is prepared, the nanocomposite is preferably dispersed in a physiological saline solution and stored in a refrigerating manner.
The technical proposal provided by the invention is based on the principle of positive and negative charges and has a two-dimensional structure Ti 3 C 2 CuO is loaded on the surface of the nano-sheet 2 By means of CuO 2 Self-supplied H specific in tumor microenvironment (tumor microenvironment, TME) 2 O 2 The triggered Fenton reaction and exogenous ultrasonic stimulation realize efficient generation of ROS, and cooperatively promote the tumor treatment effect, and more specifically: 1) The invention adopts a two-dimensional structure Ti 3 C 2 The nano-sheet replaces the traditional TiO 2 Acoustic sensitizer, two-dimensional structure Ti 3 C 2 The nano-sheet has large specific surface area, can provide storage and anchoring sites for medicines or functional nano-materials through Van der Waals force, and has high stability, good biosafety and potential for clinical application; and Ti is 3 C 2 H capable of being bound by tumor region while participating in treatment 2 O 2 In situ oxidation to Ti 3 C 2 /TiO 2 The presence of carbon (C) favors TiO 2 The separation of electrons and holes excited by ultrasound improves the ROS production efficiency, thereby enhancing the effect of SDT. 2) By means of CuO 2 CuO has the characteristic of tumor microenvironment response 2 Can generate Cu in the slightly acidic environment of tumor focus area when participating in treatment 2+ And H 2 O 2 Thereby in situ elevating intratumoral H 2 O 2 Is enhanced by H 2 O 2 Cu and Cu 2+ The chemical kinetics treatment (chemodynamic therapy, CDT) of hydroxyl free radicals is generated for Fenton reaction of reactants, so that apoptosis of tumor cells is caused, and the tumor treatment effect is further improved. In addition, the size, the morphology and the performance of the material are further adjusted by modifying BSA molecules on the surface of the material, so that the BSA material has good dispersibility and high stability in aqueous solution and physiological environment. The nanocomposite (Ti) 3 C 2 /CuO 2 BSA) is suitable for the sonodynamic and chemodynamic synergistic and efficient treatment of tumors, in particular gliomas, and has important significance for the development of clinical tumor treatment and the progress of nano-ultrasound medicine.
For clarity, the following examples are provided in detail.
Example 1
1) Ultra-thin two-dimensional structure Ti 3 C 2 Preparation of nanosheets:
preparing ultrathin two-dimensional structure Ti by adopting hydrofluoric acid (HF) etching and a liquid phase stripping method of cation intercalation agent (TPAOH) intercalation 3 C 2 The specific process of the nano sheet is as follows: mixing titanium powder (Ti, 325 mesh), aluminum powder (Al, 325 mesh) and graphite powder (graphite, 300 mesh) in a molar ratio of 2:1:1, ball milling for 10h, and under the pressure of 10MPaPressed into cylindrical Ti 3 AlC 2 A biscuit; heating the biscuit to 1500 ℃ in a high-temperature sintering furnace under the protection of argon (Ar) for sintering, keeping the temperature for two hours, and cooling the furnace to room temperature (25 ℃) to obtain MAX-phase ceramic block material (Ti) 3 AlC 2 ) The method comprises the steps of carrying out a first treatment on the surface of the Pulverizing Ti with mortar and pestle 3 AlC 2 The ceramic block is obtained as powder with the particle size of 300-500 nm, 10g of the powder is magnetically stirred in 60mL of HF aqueous solution (concentration 40 wt%) at room temperature for 3 days at 600rpm; then, the precipitate was collected by centrifugation (centrifugation at 13000 rpm), and washed 3 times with water and ethanol; subsequently, the precipitate was dispersed in 60mL of TPAOH (tetrapropylammonium hydroxide) and magnetically stirred at room temperature for 3 days; finally, the product Ti 3 C 2 The nanoplatelets were collected by centrifugation (centrifugation at 13000 rpm) and washed three times with ethanol and water to remove residual TPAOH.
In this embodiment, the multilayer structure Ti is obtained after hydrofluoric acid (HF) etching 3 C 2 As shown in FIG. 1, the SEM image of (C) is shown as Ti obtained after intercalation of a cationic intercalating agent (TPAOH) 3 C 2 A TEM electron micrograph of the nanoplatelets is shown in figure 2.
2) Positively charged CuO 2 Preparation of nanodots:
5mL of 0.01mol/L CuCl 2 Aqueous solution, 0.5g PVP (MV 10000), 5mL of 0.02mol/L NaOH aqueous solution and 100. Mu.L of H having a concentration of 30wt% 2 O 2 The aqueous solution was magnetically stirred at 600rpm for 30 minutes at room temperature; then the solution is ultrafiltered 3 times at 4500rpm for 40 minutes by using a ultrafilter tube with a molecular weight cut-off of 30000; finally, the product obtained by ultrafiltration, namely CuO with positive charge 2 The nanodots were redispersed in aqueous solution and dialyzed against dialysis bags for 24 hours to remove residual PVP.
3) Nanocomposite (Ti) 3 C 2 /CuO 2 -BSA) preparation:
ti prepared by the method 3 C 2 Nanoplatelets, cuO 2 Nanodots and BSA (66 kDa, michelin) were stirred (600 rpm) at room temperature for 4 hours at a molar ratio of 1:1:2, 1:2:2, 1:3:2, respectively, and the product was collected by centrifugation (13000 rpm) for 10 minutes and washed 3 times with PBS to give Ti 3 C 2 /CuO 2 -BSA nanoparticles; the obtained nanoparticles were dispersed in physiological saline solution and stored in a refrigerator at 4 ℃ for subsequent experiments.
For Ti prepared in different molar ratios in this example 3 C 2 /CuO 2 TEM electron microscope observation of BSA nanoparticles shows the results in FIG. 3-5, FIG. 3 is Ti provided in example 1 of the present invention 3 C 2 /CuO 2 Nanoparticles prepared at a molar ratio of 1:2:2/BSA, FIG. 4 is a Ti as provided in example 1 of the present invention 3 C 2 /CuO 2 Nanoparticles prepared at a molar ratio of 1:1:2/BSA, FIG. 5 is Ti as provided in example 1 of the present invention 3 C 2 /CuO 2 Nanoparticles prepared at a molar ratio of 1:3:2. As can be seen from fig. 3 to 5, the nano particles prepared under the condition of the molar ratio of 1:2:2 have uniform size, no agglomeration and stacking, and CuO 2 Nanodots successfully pass self-assembly with Ti 3 C 2 The optimal molar ratio is adopted.
For the present embodiment Ti 3 C 2 /CuO 2 Ti prepared under the condition that the molar ratio of the BSA is 1:2:2 3 C 2 /CuO 2 HADDF-STEM detection of BSA nanoparticle, the results are shown in FIG. 6, FIG. 6 is Ti provided in example 1 of the present invention 3 C 2 /CuO 2 HADDF-STEM map of BSA nanoparticles. As can be seen from fig. 6, the nanoparticles prepared at a molar ratio of 1:2:2 are uniform in size, have no agglomeration and stacking, and CuO 2 Nanodots successfully pass self-assembly with Ti 3 C 2 The optimal molar ratio is adopted.
For the present embodiment Ti 3 C 2 /CuO 2 Ti prepared under the condition that the molar ratio of the BSA is 1:2:2 3 C 2 /CuO 2 The energy dispersive spectrum of the BSA nanoparticle is shown in FIG. 7, and FIG. 7 is Ti provided in example 1 of the present invention 3 C 2 /CuO 2 -energy scattering mapping graph of BSA nanoparticles. As can be seen from FIG. 7, the nano-sheet was successfully loaded with Ti, cu, O, C element, confirming Ti 3 C 2 /CuO 2 Successful synthesis。
For the present embodiment Ti 3 C 2 /CuO 2 Ti prepared under the condition that the molar ratio of the BSA is 1:2:2 3 C 2 /CuO 2 The results of atomic force microscope observation of the BSA nanoparticles are shown in FIGS. 8 to 9, and FIG. 8 is Ti provided in example 1 of the present invention 3 C 2 /CuO 2 FIG. 9 is an atomic force microscope image of BSA nanoparticles, and FIG. 1 shows an AFM (atomic force microscope) measurement of Ti according to the present invention 3 C 2 /CuO 2 Layer thickness profile of BSA nanoparticles. The thickness of the nanoparticle was found to be 1.2nm.
Respectively for Ti prepared in step 1) of this example 3 C 2 Nanosheets and CuO prepared in step 2) 2 Nanodots, ti prepared in step 3) 3 C 2 /CuO 2 BSA nanoparticle (Ti) 3 C 2 /CuO 2 Molar ratio of/BSA 1:2:2), ti prepared with reference to step 3) but without BSA addition 3 C 2 /CuO 2 Nanoparticle (Ti) 3 C 2 /CuO 2 Molar ratio of 1:2) was measured for Dynamic Light Scattering (DLS), and the results are shown in fig. 10, and fig. 10 is a DLS chart provided in example 1 of the present invention. As can be seen from FIG. 10, ti prepared in this example 3 C 2 /CuO 2 The hydrated particle size of the BSA nanoparticles was about 189nm.
Example 2
Ti prepared in example 1 3 C 2 /CuO 2 BSA nanoparticle (Ti) 3 C 2 /CuO 2 1:2:2 molar ratio/BSA):
1) In vitro culture of U87 glioma cells and HUVEC human venous endothelial cells, evaluation of Ti 3 C 2 /CuO 2 -BSA nanoparticles are toxic to tumor cells, the specific process comprising:
2 96-well culture plates are arranged, each plate is divided into 7 groups, and 5 compound wells are arranged in each group; a plate with a density of 1X 10 by adding 100uL per well 4 Glioma cells, b plates were added at a density of 5X 10 at 100uL per well 3 Human vein endothelial cells are cultured for 24 hours, and after the cells are attached, ti with different concentrations is added in an equal ratio dilution 3 C 2 /CuO 2 The BSA nanoparticle is cultured for 24 hours, then CCK-8 is added for co-incubation for 1 hour, the cell survival rate in each hole is detected, and the absorbance at 450nm is measured by a microplate reader.
Ti 3 C 2 /CuO 2 The evaluation result of the BSA nanoparticle on the cytotoxicity of the tumor is shown in FIG. 11, and FIG. 11 is a bar chart of the cytotoxicity of the U87 glioma by different material concentrations provided by the embodiment of the invention. As can be seen from FIG. 11, the cell activity gradually decreased with increasing Ti concentration, and when the Ti concentration reached 50. Mu.g/ml, the cell activity was 40%.
2) 30 ICR mice were randomly divided into 4 groups, 5 mice per group, and were injected with Ti via tail vein at different doses 3 C 2 /CuO 2 BSA nanoparticles (control, 5mg/kg,10mg/kg,15 mg/kg) were sacrificed after 30 days, specific observations included:
2.1 general status: the mental state, diet, body temperature, etc. were observed daily. Growth curve: the body weight of the mice was measured by an electronic scale every two days.
The body weight curves of the mice with different concentration material groups are shown in fig. 12, and fig. 12 is a body weight curve of the mice with different concentration material groups provided by the embodiment of the invention. As can be seen from fig. 12, there was no significant difference in body weight among the mice in each group.
2.2 Main organ and hematological index changes: blood is taken from the retrobulbar veins of the mice after 30 days, and the blood index detection is carried out; after blood collection, mice were sacrificed and major organs (heart, liver, spleen, lung, kidney) were collected and fixed with 4% paraformaldehyde, and the major organ histological structures were observed by staining of tissue specimens.
The results of the HE staining of the main organs of the mice with different concentration material groups are shown in fig. 13, and fig. 13 is a graph of HE staining of the main organs of the mice with different concentration material groups according to the embodiment of the present invention. As can be seen from FIG. 13, the major organs of each group of mice were not significantly damaged.
Example 3
Ti prepared in example 1 3 C 2 /CuO 2 BSA nanoparticle (Ti) 3 C 2 /CuO 2 Sonodynamic/chemodynamic co-therapy tumor efficacy evaluation with BSA molar ratio of 1:2:2):
firstly, detecting tetramethyl benzidine (TMB) color development reactions at different reaction times by using an ultraviolet spectrophotometer and an enzyme-labeled instrument, and performing 1, 3-diphenyl isobenzofuran (DPBF) color fading reactions; singlet oxygen (1O) generated by analysis of 5, 5-dimethyl-1-pyrroline-N-oxide (DMPO), BMPO (CAS: 387334-31-8) and electron spin resonance spectroscopy (ESR) 2 ) And hydroxyl radicals (. OH). Second, the cell level uses the ROS fluorescent probe DCFH-DA (2, 7-dichlorflurescindicetate) to observe the ROS production efficiency.
The 96-well culture plate is divided into 10 areas, 5 compound wells are arranged in each area, and 3 culture plates are arranged in total. 100uL of glioma cells with the density of 1 multiplied by 104 are added into each hole, after the cells are adhered to the wall for 24 hours, the cells are grouped according to different powers and ultrasonic time, the culture is continued for 24 hours, then CCK-8 is added for co-incubation for 1 hour, the survival rate of the cells in each hole is detected, and the absorbance at 450nm is measured by an enzyme-labeling instrument.
Experimental grouping and corresponding processing methods: control group-cells were not subjected to any treatment; a simple low-intensity ultrasonic group, wherein the cells to be treated are subjected to therapeutic ultrasonic irradiation through the bottom of the culture plate; ti (Ti) 3 C 2 Group-adding Ti of the same Ti concentration 3 C 2 A nanoparticle; cuO (CuO) 2 Group-adding CuO of the same Cu concentration 2 A nanoparticle; ti (Ti) 3 C 2 /CuO 2 Group- -adding Ti of the same Ti and Cu concentration 3 C 2 /CuO 2 A nanoparticle; low intensity ultrasound+Ti 3 C 2 /CuO 2 Group-adding method and Ti 3 C 2 /CuO 2 And (3) carrying out therapeutic ultrasonic irradiation on the cells to be treated through the bottom of the culture plate, simultaneously, further analyzing the killing effect of the synergistic treatment mode on the breast cancer cells, placing the cells in the culture box for culturing for 1h after different treatments, and respectively staining the living cells and the dead cells through Calcein-AM and propidium iodide (Propidium iodide) and observing the survival condition of the cells under a fluorescence microscope. To further quantitatively analyze the apoptosis state of the cells, the cells are digested, collected, stained and passed throughFlow cytometry performs quantitative analysis of apoptosis status by fluorescence intensity of dye. Ultrasonic irradiation conditions: frequency 1MHz, duty cycle 50%, sound intensity: 1.5W/cm 2 And irradiating with ultrasound for 5s.
Density of 1 x 10 by subcutaneous injection through nude mice 7 After glioma cells establish a nude glioma transplantation tumor model, the maximum diameter and the minimum diameter of the tumor of the mice are measured to calculate the tumor volume. According to a random principle, 6 groups of tumor-bearing mice are respectively a control group, a US group and Ti 3 C 2 Group of CuO 2 Group of Ti 3 C 2 /CuO 2 Each group had 5 tumor-bearing mice. In the experiment, the injection dosage of the nanoparticles is 10mg/kg, the nanoparticles are respectively injected by tail vein on the 1 st day and the 3 rd day of treatment, and ultrasonic irradiation is respectively carried out on the treatment groups related to ultrasonic treatment on the 2 nd day and the 4 th day 24 hours after the nanoparticle injection; ultrasonic irradiation conditions: frequency 1MHz, duty cycle 50%, sound intensity: 1.5W/cm 2 And irradiating by ultrasonic for 5min. Experimental grouping and corresponding processing methods: the control group, tumor-bearing mice, did not undergo any treatment; the pure low-intensity ultrasonic group-tumor-bearing mice are only subjected to therapeutic ultrasonic irradiation; ti (Ti) 3 C 2 Group-tumor-bearing mice via tail vein injection of Ti 3 C 2 Nanoparticles; cuO (CuO) 2 Group-tumor-bearing mice were injected with CuO via tail vein 2 Nanoparticles; ti (Ti) 3 C 2 /CuO 2 Group-tumor-bearing mice via tail vein injection of Ti 3 C 2 /CuO 2 Nanoparticles; low intensity ultrasound+Ti 3 C 2 /CuO 2 Group-nanoparticle injection method with Ti 3 C 2 /CuO 2 Group, while therapeutic ultrasound irradiation is performed.
The observation of the therapeutic effect comprises the following aspects:
1) Tumor growth curve: the longest diameter (L) and the shortest diameter (W) of the tumor were measured by vernier calipers every two days, respectively, by the formula v=l·w 2 And/2, calculating the tumor volume until the whole treatment course is finished, and drawing a tumor growth curve. Tumor Inhibition Rate (IR) = (control tumor mass-treatment tumor mass)/control tumor mass x 100%.
2) Tumor pathology changes after treatment: after the treatment course is finished for 15 days, the group A tumor-bearing mice are sacrificed to obtain tumor specimens, and the volumes and the weights of tumor tissues are respectively weighed and recorded; 4% paraformaldehyde fixation for further pathological examination of the tumor by staining of general tissue sections.
The experimental results are shown in fig. 14 to 16, wherein fig. 14 is a real image of tumors of different groups provided by the embodiment of the present invention, fig. 15 is a graph of relative tumor volume versus time of different groups provided by the embodiment of the present invention, and fig. 16 is a graph of HE and immunofluorescence staining of tumor tissues of different groups provided by the embodiment of the present invention. As can be seen from FIG. 14, ti was found in the 6 different treatment groups 3 C 2 /CuO 2 Tumor min in +us group; as can be seen from FIG. 15, ti was found in the 6 different treatment groups 3 C 2 /CuO 2 The tumor treatment effect of +US group is best; as can be seen from FIG. 16, ti was found in the 6 different treatment groups 3 C 2 /CuO 2 The tumor in +US group had the most necrotic areas with bleeding, while the proliferation activity of tumor tissue was the lowest.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (8)
1. A method for preparing a nanocomposite for preparing a tumor sonodynamic and chemodynamic synergistic therapeutic drug, comprising the following steps: to a two-dimensional structure Ti 3 C 2 Nanosheets, positively charged CuO 2 Mixing the nano dots with bovine serum albumin, and carrying out solid-liquid separation to obtain a nano composite material;
the nanocomposite comprises: an inorganic nanomaterial and BSA molecules modified on the surface of the inorganic nanomaterial; the inorganic nanomaterial includes: two-dimensional structure Ti 3 C 2 Nanoplatelets and are loaded on the two-dimensional structure Ti 3 C 2 Positively charged CuO on nanoplatelet surface 2 Nano dots;
the two-dimensional structure Ti 3 C 2 Nanosheets with positive chargesCuO 2 The molar ratio of nanodots to bovine serum albumin is 1: (1-5): (1-5).
2. The method of claim 1, wherein the two-dimensional structure Ti 3 C 2 The nano-sheet is prepared by the following steps:
ti is mixed with 3 AlC 2 Sequentially carrying out hydrofluoric acid etching treatment and tetrapropylammonium hydroxide intercalation treatment on the powder to obtain a two-dimensional structure Ti 3 C 2 A nano-sheet.
3. The method according to claim 2, wherein the Ti 3 AlC 2 The powder is prepared according to the following steps:
mixing titanium powder, aluminum powder and graphite powder, and pressing to obtain Ti 3 AlC 2 A biscuit;
subjecting the Ti to 3 AlC 2 Sintering the biscuit in the atmosphere of protective gas to obtain Ti 3 AlC 2 A bulk material;
for the Ti 3 AlC 2 Grinding the bulk material to obtain Ti 3 AlC 2 And (3) powder.
4. The method according to claim 2, wherein the specific steps of sequentially performing the hydrofluoric acid etching treatment and the tetrapropylammonium hydroxide intercalation treatment include:
i) Ti is mixed with 3 AlC 2 Mixing the powder with HF water solution, and carrying out solid-liquid separation to obtain Ti after hydrofluoric acid etching treatment 3 C 2 A material;
ii) Ti to be subjected to hydrofluoric acid etching treatment 3 C 2 Mixing the material with tetrapropylammonium hydroxide, and carrying out solid-liquid separation to obtain the two-dimensional structure Ti 3 C 2 A nano-sheet.
5. The method according to claim 4, wherein in step i), the concentration of the aqueous HF solution is 30 to 50wt%; the Ti is 3 AlC 2 The ratio of powder to aqueous HF solution was 10g: (40-100) mL;
in the step i), the temperature of mixing is 15-35 ℃; the rotation speed of the mixing is 400-1000 rpm; the mixing time is 1-5 days.
6. The process according to claim 4, wherein in step ii) Ti is used as 3 AlC 2 The Ti of the powder gauge which is subjected to the hydrofluoric acid etching treatment 3 C 2 The ratio of the material to tetrapropylammonium hydroxide used was 10g: (40-100) mL;
in the step ii), the temperature of mixing is 15-35 ℃; the rotation speed of the mixing is 400-1000 rpm; the mixing time is 1-5 days.
7. The method of preparation according to claim 1, wherein the positively charged CuO 2 The nano-dots are prepared according to the following steps:
mixing soluble salt of copper, polyvinylpyrrolidone and hydrogen peroxide in alkaline aqueous solution for reaction, and ultrafiltering to obtain CuO with positive charge 2 Nano dots.
8. The use of the nanocomposite material prepared by the preparation method of any one of claims 1-7 in the preparation of a drug for the photodynamic synergistic treatment of tumors.
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