CN108187047B - Nano titanium photo-thermal preparation and preparation method and application thereof - Google Patents

Nano titanium photo-thermal preparation and preparation method and application thereof Download PDF

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CN108187047B
CN108187047B CN201810089749.6A CN201810089749A CN108187047B CN 108187047 B CN108187047 B CN 108187047B CN 201810089749 A CN201810089749 A CN 201810089749A CN 108187047 B CN108187047 B CN 108187047B
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张晗
陈世优
谢中建
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Abstract

The invention provides a nano titanium photo-thermal preparation which comprises two-dimensional titanium nano sheets and a biocompatible material coated on the surfaces of the two-dimensional titanium nano sheets. The nano titanium photothermal preparation provided by the invention has high photothermal conversion efficiency, good biocompatibility, safety and no toxicity, and can be used for photothermal treatment including tumors. The invention also provides a preparation method of the nano titanium photo-thermal preparation, which comprises the following steps: providing a titanium raw material, and stripping the titanium raw material by adopting a liquid phase stripping method to obtain a two-dimensional titanium nanosheet; providing a biocompatible material, and mixing the two-dimensional titanium nanosheets and the biocompatible material at 10-30 ℃ for 3-6h to obtain the nano titanium photo-thermal preparation. The invention also provides a preparation method of the nano titanium photo-thermal preparation, and the preparation method is simple and easy to operate. The invention also provides application of the nano titanium photothermal preparation in preparation of a photothermal treatment medicament.

Description

Nano titanium photo-thermal preparation and preparation method and application thereof
Technical Field
The invention relates to the field of biomedical nano materials, in particular to a nano titanium photo-thermal preparation and a preparation method and application thereof.
Background
At present, for the treatment of cancer, novel therapies such as immunotherapy and cell therapy have been developed in addition to conventional surgical therapy, radiotherapy and chemotherapy. However, although the current therapy can prolong the life of the patient to a certain extent, the current therapy still has the limitations of large side effects, incomplete removal of tumor cells, no cure and the like. Therefore, the development of new therapies remains a hotspot in the cancer field.
The near-infrared phototherapy based on the nano-materials is a novel and potential therapy, particularly near-infrared light response photo-thermal therapy, and solves the problems that light waves are easy to absorb and scatter, have nucleic acid toxicity and poor tissue penetration in short-wavelength light therapy such as ultraviolet light, visible light and the like. The near infrared light wavelength is about 700-1000 nm, and has the advantages of low absorption and high penetrability (more than 1 cm).
Currently, the conventional photothermal therapy materials mainly include gold nanoparticles, carbon nanotubes, graphene and the like. However, the conventional photothermal material cannot give consideration to both photothermal conversion efficiency and biocompatibility.
Therefore, there is a need to find a safe and nontoxic photothermal material with high photothermal conversion efficiency and good biocompatibility for photothermal therapy including tumor.
Disclosure of Invention
In order to solve the problems, the invention provides a safe and nontoxic nano titanium photothermal preparation with high photothermal conversion efficiency and good biocompatibility.
The invention provides a nano titanium photo-thermal preparation, which comprises two-dimensional titanium nano sheets and a biocompatible material coated on the surfaces of the two-dimensional titanium nano sheets.
Wherein the mass ratio of the two-dimensional titanium nanosheet to the biocompatible material is 1: 1-10.
Wherein the mass ratio of the two-dimensional titanium nanosheet to the biocompatible material is 1: 1.
Wherein the thickness of the two-dimensional titanium nanosheet is 1-50 nm.
Wherein the length and width of the two-dimensional titanium nanosheet are 10-50 nm.
Wherein the biocompatible material comprises one or more of hyaluronic acid, dextran and derivatives thereof, chitosan and derivatives thereof, pectin, carboxymethylcellulose, albumin, liposomes, cell membranes, polyvinylpyrrolidone, polylactic acid-glycolic acid copolymer, polyethyleneimine, polyacrylic acid, and polyethylene glycol and derivatives thereof.
Wherein, the biocompatible material is polyethylene glycol and derivatives thereof, and the molecular weight of the polyethylene glycol and the derivatives thereof is 200-20000.
The nano titanium photothermal preparation provided by the first aspect of the invention has high photothermal conversion efficiency, good biocompatibility, safety and no toxicity, and can be used for photothermal treatment including tumors.
The invention provides a preparation method of a nano titanium photothermal preparation, which comprises the following steps:
providing a titanium raw material, and stripping the titanium raw material by adopting a liquid phase stripping method to obtain a two-dimensional titanium nanosheet;
providing a biocompatible material, and mixing and stirring the two-dimensional titanium nanosheets and the biocompatible material at 10-30 ℃ for 3-6h to obtain the nano titanium photo-thermal preparation.
The liquid phase stripping method specifically comprises the following operations:
adding the titanium raw material into a solvent, and carrying out ultrasonic treatment for 8-15h by using a probe in an ice bath environment; after the probe ultrasound is finished, continuing to perform water bath ultrasound, wherein the water bath ultrasound time is 3-10h, and the water bath temperature is kept at 5-15 ℃; and after ultrasonic treatment, centrifuging and drying to obtain the two-dimensional titanium nanosheet.
The second aspect of the invention provides a preparation method of a nano titanium photothermal preparation, the preparation method is simple and easy to operate, and the prepared nano titanium photothermal preparation has high photothermal conversion efficiency and good biocompatibility.
In a third aspect, the invention provides the use of the nano titanium photothermal preparation as described above in the preparation of a medicament for photothermal therapy.
In conclusion, the beneficial effects of the invention include the following aspects:
1. the nano titanium photothermal preparation provided by the invention has high photothermal conversion efficiency, good biocompatibility, safety and no toxicity, and can be used for photothermal treatment including tumors;
2. the preparation method of the nano titanium photo-thermal preparation provided by the invention is simple and easy to operate.
Drawings
FIG. 1 is a transmission electron microscope picture of a two-dimensional titanium nanosheet prepared in example 1;
FIG. 2 is an atomic force micrograph of two-dimensional titanium nanoplates prepared in example 1;
fig. 3 is an absorption spectrum of a liquid phase stripping process of two-dimensional titanium nanosheets in example 1;
FIG. 4 is a photograph of two-dimensional aqueous dispersions of titanium nanoplates at different concentrations;
FIG. 5 is an absorption spectrogram of two-dimensional titanium nanosheet aqueous dispersions of different concentrations;
FIG. 6 is an extinction coefficient of a two-dimensional aqueous dispersion of titanium nanoplates;
FIG. 7 is a temperature rise curve of two-dimensional titanium nanosheet aqueous dispersion at different concentrations;
FIG. 8 shows the photothermal conversion efficiency of a two-dimensional aqueous dispersion of titanium nanoplates;
FIG. 9 is a graph showing the results of cytotoxicity assays for two-dimensional titanium nanoplates;
FIG. 10 is a graph of the effect of two-dimensional titanium nanoplates on mouse body weight;
FIG. 11 is a graph showing the effect of two-dimensional titanium nanosheets on causing tissue and organ damage in mice;
FIG. 12 is a graph showing the effect of two-dimensional titanium nanosheets of different concentrations on the photothermal killing ability of cells;
fig. 13 is a measurement of the killing ability of PEG 2000-coated two-dimensional titanium nanoplates at a concentration of 50ppm to cells under different illumination times;
FIG. 14 shows the temperature change at the tumor site during photothermal treatment of a mouse tumor;
FIG. 15 is a graph showing the temperature change at the tumor site in photothermal therapy of a mouse tumor;
FIG. 16 is the change in tumor volume after photothermal treatment of tumor-bearing mice.
Detailed Description
While the following is a description of the preferred embodiments of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.
The two-dimensional titanium nanosheets, titanium nanoparticles or titanium mentioned in the invention refer to elemental titanium unless otherwise specified.
The invention provides a nano titanium photo-thermal preparation, which comprises two-dimensional titanium nano sheets and a biocompatible material coated on the surfaces of the two-dimensional titanium nano sheets.
In the embodiment of the invention, the thickness of the two-dimensional titanium nanosheet is 1-50 nm. Optionally, the thickness of the two-dimensional titanium nanoplates is 3-5 nm. Optionally, the thickness of the two-dimensional titanium nanoplates is 5-10 nm. Optionally, the thickness of the two-dimensional titanium nanoplates is 10-50 nm. Further optionally, the thickness of the two-dimensional titanium nanoplates is 1nm, 5nm, 10nm, 15nm, 20nm, 25nm, 30nm, 35nm, 40nm, 45nm, or 50 nm.
In the embodiment of the invention, the length and width of the two-dimensional titanium nanosheet are 10-50 nm. Optionally, the length and width dimensions of the two-dimensional titanium nanosheets are 30-40 nm. Optionally, the length and width dimensions of the two-dimensional titanium nanosheets are 10-30 nm. Further optionally, the two-dimensional titanium nanoplates have a length and width dimension of 10nm, 15nm, 20nm, 25nm, 30nm, 35nm, 40nm, 45nm, or 50 nm.
In the embodiment of the invention, the mass ratio of the two-dimensional titanium nanosheet to the biocompatible material is 1: 1-10. Optionally, the mass ratio of the two-dimensional titanium nanoplates to the biocompatible material is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1: 10.
In the embodiment of the invention, the two-dimensional titanium nanosheet has absorption from a visible light region to a near infrared light region. Optionally, the light absorption wavelength range of the two-dimensional titanium nanosheets is 200-2000 nm.
In an embodiment of the present invention, the photothermal conversion efficiency of the two-dimensional titanium nanosheet is greater than or equal to 70%.
The two-dimensional titanium nanosheet provided by the invention has the advantages of environmental friendliness, biocompatibility, full-spectrum strong absorption, higher photo-thermal conversion efficiency and the like, and has excellent photo-thermal performance.
In an embodiment of the present invention, the biocompatible material includes one or more of hyaluronic acid, dextran and derivatives thereof, chitosan and derivatives thereof, pectin, carboxymethyl cellulose, albumin, liposomes, cell membranes, polyvinylpyrrolidone, polylactic acid-glycolic acid copolymer, polyethyleneimine, polyacrylic acid, and polyethylene glycol and derivatives thereof. Further optionally, the biocompatible material comprises at least one of polyethylene glycol and derivatives thereof, polylactic-co-glycolic acid, albumin, liposomes, and cell membranes. Further optionally, the biocompatible material comprises polyethylene glycol and derivatives thereof, the molecular weight of the polyethylene glycol and derivatives thereof is between 200 and 20000. Alternatively, the end of the polyethylene glycol may be modified with an amino group. Optionally, the biocompatible material is adsorbed on the surface of the two-dimensional titanium nanoplates by electrostatic interaction.
In the embodiment of the invention, the nano titanium photothermal preparation further comprises a targeting material, and the targeting material is connected to the two-dimensional titanium nanosheet or the biocompatible material through a chemical bond. Optionally, the targeting material is folic acid, which is linked to the polyethylene glycol by an amide bond.
In the embodiment of the invention, the nano titanium photothermal preparation can be dispersed in normal saline, phosphate buffer solution or deionized water for subsequent application.
The nano titanium photothermal preparation provided by the first aspect of the invention has high photothermal conversion efficiency, good biocompatibility, safety and no toxicity, and can be used for photothermal treatment including tumors.
The invention provides a preparation method of a nano titanium photothermal preparation, which comprises the following steps:
providing a titanium raw material, and stripping the titanium raw material by adopting a liquid phase stripping method to obtain a two-dimensional titanium nanosheet;
providing a biocompatible material, and mixing and stirring the two-dimensional titanium nanosheets and the biocompatible material at 10-30 ℃ for 3-6h to obtain the nano titanium photo-thermal preparation.
In the embodiment of the invention, the two-dimensional titanium nanosheets and the biocompatible material are mixed for 3-6 hours at 25 ℃.
In the embodiment of the invention, the specific preparation method of the nano titanium photothermal preparation comprises the following steps: dissolving a biocompatible material in a proper amount of a first solvent to obtain a biocompatible material solution, dispersing two-dimensional titanium nanosheets in a proper amount of a second solvent to obtain a two-dimensional titanium nanosheet dispersion solution, mixing the biocompatible material solution and the two-dimensional titanium nanosheet dispersion solution at 10-30 ℃, and stirring for 3-6h to obtain the nano titanium photo-thermal preparation.
Optionally, the first solvent is a solvent capable of dissolving the biocompatible material, such as deionized water when the biocompatible material is polyethylene glycol.
Optionally, the second solvent comprises deionized water.
In the embodiment of the invention, the stirring speed is 100-700 r/min.
In the embodiment of the invention, after stirring, the obtained mixture is centrifugally dried to obtain the two-dimensional titanium nanosheet coated with the biocompatible material, and the nano titanium photo-thermal preparation is obtained.
In an embodiment of the present invention, the liquid phase stripping method specifically includes the following operations:
adding the titanium raw material into a solvent, and carrying out ultrasonic treatment for 8-15h by using a probe in an ice bath environment; after the probe finishes ultrasonic treatment, continuing to perform ultrasonic treatment in a water bath for 3-10h, and keeping the temperature of the water bath at 5-15 ℃; and after ultrasonic treatment, centrifuging and drying to obtain the two-dimensional titanium nanosheet.
Optionally, the solvent comprises at least one of isopropanol, ethanol, water, and methyl pyrrolidone.
Optionally, the concentration of the titanium raw material in the solvent is 1-7 mg/mL.
Optionally, the power of the probe ultrasound is 200-. Further optionally, the power of the probe ultrasound is 240W.
Optionally, the time of the probe ultrasound is 10 h.
Optionally, the probe ultrasound is discontinuous ultrasound, and the ultrasound on/off time is selected to be 2/4s, i.e. 2s ultrasound first, then the ultrasound probe is turned off for 4s, and so on after 2s ultrasound is continued.
Optionally, the ultrasonic power of the water bath is 300-. Further optionally, the ultrasonic power of the water bath is 360W.
Optionally, the time of the water bath ultrasound is 8 h.
Optionally, the water bath temperature is maintained at 10 ℃.
Optionally, after the ultrasound, centrifugation is performed, the operation of centrifugation comprising: firstly, adopting a centrifugal force of 1800-; and then continuously centrifuging the supernatant by adopting the centrifugal force of 10000-13000g to obtain a precipitate, namely the two-dimensional titanium nano sheet. Further optionally, firstly, centrifuging for 30min by using a centrifugal force of 2000g, and taking supernate; and then, continuously centrifuging the supernatant by adopting 12000g of centrifugal force to obtain a precipitate, and drying the precipitate to obtain the two-dimensional titanium nanosheet. Alternatively, the drying manner is not limited, and may be vacuum drying, for example.
The prior art generally employs a liquid phase exfoliation method for exfoliating a two-dimensional layered material. The invention adopts the liquid phase stripping method to strip the two-dimensional non-layered metal material for the first time, and the success is achieved.
The second aspect of the invention provides a preparation method of a nano titanium photothermal preparation, the preparation method is simple and easy to operate, and the prepared nano titanium photothermal preparation has high photothermal conversion efficiency and good biocompatibility.
In a third aspect of the embodiments of the present invention, there is provided a use of the nano titanium photothermal preparation as described above in the preparation of a drug for photothermal therapy.
Example 1:
a preparation method of a nano titanium photothermal preparation comprises the following steps:
(1) preparing a two-dimensional titanium nanosheet;
500mg of titanium powder was added to 100ml of isopropyl alcohol. Then, the probe ultrasound 240W and the ultrasound 10h are selected. The on/off time of sonication was chosen to be 2/4s and sonication was performed in an ice bath environment. After the probe is subjected to ultrasonic treatment, water bath ultrasonic treatment is adopted. The ultrasonic power of the water bath is 360W. The ultrasonic time is 8 h. The temperature of the water bath was maintained at 10 ℃.
And obtaining the required metal simple substance titanium nanosheet by a centrifugal method after the ultrasonic treatment. First, centrifugation was carried out for 30min using a centrifugal force of 2000 g. The supernatant was collected and centrifuged again at 12000g to obtain a precipitate. And (4) precipitating, and drying in vacuum to obtain the two-dimensional titanium nanosheet.
(2) Providing a PEG2000 solution, dispersing the two-dimensional titanium nanosheets prepared in the step (1) in a proper amount of water to obtain a two-dimensional titanium nanosheet dispersion liquid, mixing the two-dimensional titanium nanosheet dispersion liquid with the PEG2000 solution, wherein the mass ratio of the two-dimensional titanium nanosheets to the PEG2000 is 1:1, mixing and stirring for 5 hours at 25 ℃, and centrifugally drying to obtain PEG 2000-coated two-dimensional titanium nanosheets, namely the nano titanium photo-thermal preparation.
As shown in fig. 1, fig. 1 is an electron microscope topography of the two-dimensional titanium nanosheet prepared in step (1). The size of the particles is less than 50 nm. FIG. 2 shows an atomic force micrograph. As can be seen from the figure, the thickness of the two-dimensional titanium nanosheet is about 3 nm. Therefore, through observation of a transmission electron microscope and an atomic force microscope, the two-dimensional metal simple substance titanium nanosheet can be indeed stripped through a liquid phase stripping method.
As shown in fig. 3a, the absorption spectra of two-dimensional titanium nanoplates at the same concentration, stripped in Isopropanol (IPA) and water, respectively. It is clear that the absorption spectrum of the exfoliated two-dimensional titanium nanoplates in IPA has a higher absorption value and a larger slope (i.e., the upper one of the curves in fig. 3 a). This indicates that relatively large titanium particles can be sufficiently exfoliated into smaller titanium nanoplates in IPA. Further, comparing the absorption values of the same concentration of elemental metal titanium at different stripping times (referred to as water bath ultrasonic time) (as shown in fig. 3 b), it is found that the absorption spectrum is increasing and a saturated state occurs as the stripping time increases.
Example 2:
a preparation method of a nano titanium photothermal preparation comprises the following steps:
(1) preparing a two-dimensional titanium nanosheet;
500mg of titanium powder was added to 100ml of isopropyl alcohol. Then selecting a probe ultrasonic wave of 200W and an ultrasonic wave of 15 h. The on/off time of sonication was chosen to be 2/4s and sonication was performed in an ice bath environment. After the probe is subjected to ultrasonic treatment, water bath ultrasonic treatment is adopted. The ultrasonic power of the water bath is 300W. The ultrasonic time is 10 h. The temperature of the water bath is kept at 15 ℃;
and obtaining the required metal simple substance titanium nanosheet by a centrifugal method after the ultrasonic treatment. First, centrifugation was carried out for 35min using a centrifugal force of 1800 g. And taking the supernatant, continuously centrifuging the supernatant by adopting 10000g to obtain a precipitate, and drying in vacuum to obtain the two-dimensional titanium nanosheet.
(2) Providing a PEG2000 solution, dispersing the two-dimensional titanium nanosheets prepared in the step (1) in a proper amount of water to obtain a two-dimensional titanium nanosheet dispersion liquid, mixing the two-dimensional titanium nanosheet dispersion liquid with the PEG2000 solution, wherein the mass ratio of the two-dimensional titanium nanosheets to the PEG2000 is 1:10, mixing and stirring for 3 hours at 30 ℃, and centrifugally drying to obtain PEG 2000-coated two-dimensional titanium nanosheets, namely the nano titanium photo-thermal preparation.
Example 3:
a preparation method of a nano titanium photothermal preparation comprises the following steps:
(1) preparing a two-dimensional titanium nanosheet;
500mg of titanium powder was added to 100ml of isopropyl alcohol. Then selecting a probe to perform ultrasonic treatment at 250W for 8 h. The on/off time of sonication was chosen to be 2/4s and sonication was performed in an ice bath environment. After the probe is subjected to ultrasonic treatment, water bath ultrasonic treatment is adopted. The ultrasonic power of the water bath is 380W. The ultrasonic time is 3 h. The temperature of the water bath is kept at 5 ℃;
and obtaining the required metal simple substance titanium nanosheet by a centrifugal method after the ultrasonic treatment. Centrifugation was first carried out for 20min using a centrifugal force of 2200 g. And taking the supernatant, continuously centrifuging the supernatant by adopting 13000g to obtain a precipitate, and drying in vacuum to obtain the two-dimensional titanium nanosheet.
(2) Providing a PEG2000 solution, dispersing the two-dimensional titanium nanosheets prepared in the step (1) in a proper amount of water to obtain a two-dimensional titanium nanosheet dispersion liquid, mixing the two-dimensional titanium nanosheet dispersion liquid with the PEG2000 solution, wherein the mass ratio of the two-dimensional titanium nanosheets to the PEG2000 is 1:5, mixing and stirring for 6 hours at 10 ℃, and centrifugally drying to obtain PEG 2000-coated two-dimensional titanium nanosheets, namely the nano titanium photo-thermal preparation.
Effects of the embodiment
(1) Testing of absorption Spectroscopy and photothermal Properties
Preparing two-dimensional titanium nanosheet aqueous dispersion with different concentrations to measure absorption spectrum and photo-thermal performance. The absorption spectrum was measured using an ultraviolet-spectrophotometer. The photothermal experiment adopts 808nm laser. 10,25,50 and 100ppm of aqueous dispersions of two-dimensional titanium nanoplates (as shown in FIG. 4) were prepared, respectively. The prepared water dispersion is respectively filled into a quartz ratioAnd (4) placing the sample into a clamping groove of an ultraviolet spectrophotometer to measure the absorbance. The absorption curves for the different concentrations are shown in fig. 5. The extinction coefficient of the two-dimensional titanium nanosheet obtained according to the absorption at 808nm is 20.8Lg-1cm-1(as shown in fig. 6). This value is higher than that of black phosphorus (14.8 Lg)-1cm-1). For measurement of a photothermal experiment, 1ml of two-dimensional titanium nanosheet aqueous dispersion is added into a cuvette, irradiated by 808nm laser, and a temperature curve is recorded by a thermocouple. Fig. 7 shows a graph of temperature rise with laser irradiation time for different concentrations. Quantitative calculation can obtain the photothermal conversion efficiency of the two-dimensional titanium nanosheet to be 73.4% (as shown in fig. 8).
The photothermal conversion efficiency (73.4%) of the two-dimensional titanium nanosheet is highest in all reported photothermal agents, is higher than that of a novel two-dimensional photothermal agent of the traditional gold nanoparticle (21%), and comprises MoS2(24.4%) black phosphorus quantum dots (28.4%) Ti3C2The nano-sheet (30.6%) and tellurium quantum dot (45.5%), therefore, the two-dimensional titanium nano-sheet photothermal conversion efficiency value is obviously higher than other photothermal agents currently under study. Therefore, the two-dimensional titanium nanosheet prepared by the method disclosed by the invention is good in photo-thermal performance.
(2) Biotoxicity testing of two-dimensional titanium nanosheets
Dispersing two-dimensional titanium nanosheets with different masses in a cell culture medium, co-incubating with different cells, and determining the activity of the cells. Firstly, respectively paving hepatocellular carcinoma cell SMMC-7721, melanoma cell B16 and macrophage J774A.1 in a 96-well plate, and preparing for experiments after the cells are attached to the wall. Two-dimensional titanium nanosheet dispersions with the concentrations of 0,10,25,50 and 100ppm are prepared by a DMEM high-glucose medium, 100 mu l of the dispersion is taken to replace the medium in the 96-well plate, after incubation for 24 hours, the activity of cells in each well is measured by using a CCK8 kit, and 3 parallel wells are arranged in each group of experiments. As shown in fig. 9, in various cells, the cell viability did not decrease significantly with increasing concentrations of two-dimensional titanium nanoplatelets (from 0 to 100ppm), compared to the control without nanoplatelets. This indicates that the two-dimensional titanium nanosheets are not significantly cytotoxic.
The toxicity of the two-dimensional titanium nanosheets was also tested in model animals. Dispersing the two-dimensional titanium nanosheets and the PEG 2000-coated two-dimensional titanium nanosheets in normal saline respectively to obtain 100ppm of dispersion liquid for later use. A6-week-old female Balb/c nude mouse was subcutaneously injected with 100. mu.l of physiological saline (control), 100. mu.l of a 100ppm dispersion of two-dimensional titanium nanoplates (represented by "titanium nanoplates" in the figure), and 100. mu.l of a 100ppm dispersion of PEG-coated two-dimensional titanium nanoplates (represented by "polyethylene glycol-coated titanium nanoplates" in the figure) under the right forelimb of the mouse. The body weight of the mice was measured on days 1,3,5,7,9,11,13, and 15 after injection, respectively, and on day 15 the mice were sacrificed, and their major organs, heart, liver, spleen, lung, and kidney, were taken, subjected to H & E staining, and it was observed whether the nanosheets caused tissue organ damage in the mice. As shown in fig. 10, the two-dimensional titanium nanosheets do not affect changes in body weight thereof; as shown in fig. 11, the two-dimensional titanium nanoplates did not cause damage to tissues and organs of mice.
In conclusion, the two-dimensional titanium nanosheet is nontoxic to cancer cells, normal cells and in vivo conditions in vitro, and has the advantages of biocompatibility, safety and no toxicity.
(3) Cell killing capability determination of two-dimensional titanium nanosheet photothermal effect
Respectively paving SMMC-7721, B16 and J774A.1 cells in a 96-well plate, incubating two-dimensional titanium nanosheets dispersed in a cell culture medium with different concentrations with the cells after the cells adhere to the wall, wherein the concentrations of the two-dimensional titanium nanosheets are respectively 0,5,10,20,30 and 50ppm, and 3 parallel wells are arranged in each experimental group. After 2 hours of incubation, the cells were irradiated with a laser at 808nm at 1W cm-2The cells were assayed for viability using the CCK8 kit, 24 hours after irradiation, with a power of 10 minutes. As shown in FIG. 12, the photothermal effect of the two-dimensional titanium nanosheets at a low concentration (5ppm) has partial cell killing capability, the killing capability is already very significant (20% for cancer cells and 80% for macrophages) under the condition of 10ppm, and the photothermal effect of the two-dimensional titanium nanosheets can basically kill the cells completely at a concentration of more than 30 ppm. And the two-dimensional titanium nanosheets coated with PEG2000 or uncoated with the PEG2000 have consistent photo-thermal effect killing capability.
Similarly, PEG 2000-coated two-dimensional titanium nanoplates were co-incubated with SMMC-7721 cells at 50ppm, followed by 808nm,1W cm-2The killing power was measured at different illumination times (0,2,5,8,10 minutes), as shown in fig. 13, only 2 minutes of illumination was sufficient to completely kill all cells.
In conclusion, the photothermal effect of the two-dimensional titanium nanosheet can be used for cell killing, and a good cell killing effect can be achieved under the near-infrared light condition with low concentration and short time, so that the excellent photothermal conversion efficiency is shown.
(4) Tumor photothermal treatment effect determination of two-dimensional titanium nanosheet photothermal effect
Will be 5X 106SMMC-7721 cells were injected subcutaneously into female Balb/c nude mice, and approximately 10 days later, the tumor volume reached 100-3And the liver cancer model is used as a target of two-dimensional titanium nanosheet photothermal therapy. Two-dimensional titanium nanosheets coated with PEG2000 were dispersed in a phosphate buffer at a concentration of 100 ppm. When treating tumor, 100 mul of nano-sheet dispersion is injected into tumor, then the mouse is anesthetized, and laser with wavelength of 808nm is utilized to treat tumor at 1Wcm-2The tumor site containing the titanium nanoplates was irradiated for 5 minutes at the power of (a) to perform photothermal therapy on the tumor. Fig. 14 is a graph showing the temperature change of the tumor site per minute recorded by an infrared detector, and fig. 15 is a graph showing the temperature change of the tumor site during the treatment process, wherein the two graphs show that the temperature rise caused by the two-dimensional titanium nanosheets is very rapid and can be increased by 20 ℃ within 1 minute when the photothermal treatment is carried out. And after about 1 minute, the temperature slowly increased gradually to remain stable. Subsequently, the tumor volumes were measured on days 1,3,5,7,9,11,13, and 15 after the treatment, respectively, and as shown in fig. 16, it was found that the tumor size rapidly decreased after the photothermal treatment, the tumor tissue was killed during the entire treatment, the tumor growth was inhibited, and a good therapeutic effect was obtained.
Therefore, photothermal formulations comprising two-dimensional titanium nanoplates can be effectively used for photothermal treatment of tumors.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (10)

1. A nano titanium photo-thermal preparation is characterized by comprising two-dimensional titanium nano sheets and a biocompatible material coated on the surfaces of the two-dimensional titanium nano sheets; the two-dimensional titanium nanosheet is obtained by stripping a titanium raw material by adopting a liquid phase stripping method.
2. The nano-titanium photothermal formulation according to claim 1 wherein the mass ratio of the two-dimensional titanium nanoplates to the biocompatible material is 1: 1-10.
3. The nano-titanium photothermal formulation according to claim 2 wherein the mass ratio of the two-dimensional titanium nanoplates to the biocompatible material is 1: 1.
4. The nano-titanium photothermal formulation according to claim 1 wherein the thickness of said two-dimensional titanium nanoplates is from 1 to 50 nm.
5. The nano-titanium photothermal formulation according to claim 1 wherein the two-dimensional titanium nanoplates have a length and width dimension of 10-50 nm.
6. The nano-titanium photothermal preparation according to claim 1, wherein the biocompatible material comprises one or more of hyaluronic acid, dextran, chitosan, pectin, carboxymethyl cellulose, albumin, liposome, cell membrane, polyvinylpyrrolidone, polylactic acid-glycolic acid copolymer, polyethyleneimine, polyacrylic acid, and polyethylene glycol and derivatives thereof, wherein the derivatives of polyethylene glycol comprise polyethylene glycol terminally modified with amino group.
7. The nano-titanium photothermal preparation according to claim 6, wherein the biocompatible material is polyethylene glycol and its derivatives, and the molecular weight of the polyethylene glycol and its derivatives is 200-.
8. A preparation method of a nano titanium photothermal preparation is characterized by comprising the following steps:
providing a titanium raw material, and stripping the titanium raw material by adopting a liquid phase stripping method to obtain a two-dimensional titanium nanosheet;
providing a biocompatible material, mixing the two-dimensional titanium nanosheets and the biocompatible material at 10-30 ℃, and stirring for 3-6h to obtain the nano titanium photo-thermal preparation.
9. The method for preparing the nano-titanium photothermal preparation according to claim 8, wherein the liquid phase exfoliation method specifically comprises the following operations:
adding the titanium raw material into a solvent, and carrying out ultrasonic treatment for 8-15h by using a probe in an ice bath environment; after the probe ultrasound is finished, continuing to perform water bath ultrasound, wherein the water bath ultrasound time is 3-10h, and the water bath temperature is kept at 5-15 ℃; and after ultrasonic treatment, centrifuging and drying to obtain the two-dimensional titanium nanosheet.
10. Use of the nano-titanium photothermal formulation of any one of claims 1-7 for the preparation of a medicament for photothermal therapy.
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