CN117224673A - Titanium-based nano material for enhancing acoustic power treatment of bladder cancer - Google Patents
Titanium-based nano material for enhancing acoustic power treatment of bladder cancer Download PDFInfo
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Abstract
The invention discloses a titanium-based nano material for enhancing acoustic power treatment of bladder cancer, and relates to the technical field of biomedical materials. The titanium-based nanomaterial of the invention comprises titanium dioxide and Ru. The invention uses ruthenium complex Ru and hollow nanosphere TiO for the first time 2 Develop a safe and nontoxic titanium-based nano material TiO with low cost and simple preparation 2 Ru-PEG. The titanium-based nano material TiO of the invention 2 Ru-PEG can significantly increase the generation rate of ROS, providing a new strategy for improving sonodynamic therapy; the titanium-based nano material TiO of the invention 2 Ru-PEG can be effectively absorbed by bladder cancer cells, and is explosively generated after being combined with oxygen in cells under ultrasonic irradiation 1 O 2 、O 2.‑ The mitochondria are damaged to cause apoptosis of tumor cells, so that the effect of enhancing acoustic power to treat bladder cancer is achieved; the titanium-based nano material TiO of the invention 2 The Ru-PEG has the advantages of simple preparation method, high yield, good repeatability and potential of large-scale production.
Description
Technical Field
The invention relates to the technical field of biomedical materials, in particular to a titanium-based nanomaterial for enhancing acoustic power treatment of bladder cancer.
Background
Bladder cancer is one of common tumors of urinary systems in China and ten cancers worldwide, and the problems of continuously rising incidence, high recurrence rate, poor life treatment and the like still plagues the treatment of bladder cancer. With the increase of the aging population in China, the prevalence of bladder cancer may continuously rise, and new therapeutic methods for bladder cancer are urgently needed to be explored. According to the European surgical Association (EAU) guidelines in 2020, the treatment of bladder cancer has mainly involved surgical treatment, infusion of chemotherapeutic drugs, targeted drug therapy, and the like. Although these traditional therapeutic methods have good clinical therapeutic effects, invasive treatments such as surgery greatly increase psychological stress and treatment cost of patients, and chemotherapy seriously weakens the anti-tumor effect of the drug due to the problems of periodic urine dilution, off-target spots, obvious systemic side effects and the like. There is still room for improvement in patients with poor life treatment, high treatment cost, and huge psychological stress after bladder cancer treatment. Therefore, a new strategy for bladder cancer treatment is sought, the stability and the permeability of the bladder perfusion medicine are improved, the purpose of noninvasive treatment is achieved, and the method has important clinical value and scientific significance for preventing the metastasis and recurrence of bladder cancer.
In recent years, with the development of nanotechnology, attention and importance of researchers have been paid to therapeutic means based on nanotechnology. In order to improve the accurate therapeutic effect of bladder cancer and reduce the risk of metastasis and recurrence of bladder cancer, various novel therapeutic methods are applied to the treatment of bladder cancer. Wherein photodynamic therapy (Photodynamic therapy, PDT) is a method of irradiating a tumor site with a specific laser light to activate a photosensitizer selectively accumulated in tumor tissue, causing a photochemical reaction to kill the tumor. The method can realize accurate and effective treatment with little side effect. Although having a certain effect in treating non-muscular-layer invasive bladder cancer, the optical fiber is limited by the laser penetration ability, and even if the optical fiber is inserted into the bladder cavity through the urethra, a certain treatment effect can be improved, but the optical fiber still brings pain to a patient, and the treatment effect on the bladder cancer with metastasis is not obvious. In addition, the sustained toxicity of porphyrin-based photosensitizers also greatly limits the application of PDT in bladder cancer.
In order to improve tissue penetration and reduce toxicity of photosensitizers, sonodynamic therapy (Sonodynamic therapy, SDT) was developed for bladder cancer treatment, which is a method of exciting sonosensitizers accumulated in tumor cells under non-invasive conditions by Ultrasound (US) to induce sonochemical reactions to produce singlet oxygen @, which is a method of treating bladder cancer using ultrasonic waves (US) 1 O 2 ) A method of treatment that causes death of tumor cells. Compared with the traditional bladder perfusion chemoradiotherapy and photodynamic therapy, SDT is considered as one of the high-efficiency non-invasive cancer treatment modes, and ultrasonic radiation can penetrate through soft tissues with the thickness of tens of centimeters, so that an endoscope or other intravesical intervention means are not needed. In view of accurate positioning of acoustic power treatment, good penetrability, noninvasive treatment, good compliance and less side effect; meanwhile, the unique anatomical position of the bladder cancer is in the ultrasonic penetration depth range, and the application of the acoustic power therapy to treat the bladder cancer has great potential and is expected to become a new strategy for treating the bladder cancer. However, existing sonosensitizers are limited to organic dyes (e.g., porphyrins) or TiO 2 Derivatized nanomaterials tend to be poorly stable or produce 1 O 2 Is inefficient. Therefore, the nanometer sound sensitive agent with good biocompatibility, high sound sensitive efficiency, good stability and clear action principle is a research hot spot of the current sound power treatment.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a titanium-based nanomaterial for enhancing the acoustic power treatment of bladder cancer.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: a titanium-based nanomaterial comprising titanium dioxide and Ru. The invention uses hollow nanosphere TiO 2 After ruthenium complex Ru is loaded, tiO is obviously reduced 2 The band gap of Ru-PEG decreases from 4.73eV to 3.76eV, which activates the transfer between electrons, thus enhancing the separation of electron-hole pairs, increasing the ROS formation rate, and reducing the generation rate of ROS in cells under ultrasonic irradiationExplosive generation after oxygen incorporation 1 O 2 、O 2.- Injury to mitochondria causes apoptosis of tumor cells, thereby achieving the effect of enhancing acoustic power to treat bladder cancer.
As a preferred embodiment of the titanium-based nanomaterial of the present invention, the titanium dioxide is hollow nanosphere titanium dioxide.
The invention also provides a preparation method of the titanium-based nanomaterial, which comprises the following steps:
(1) Respectively dissolving titanium dioxide and Ru in DMSO to obtain a titanium dioxide solution and a Ru solution;
(2) Dropwise adding the Ru solution into the titanium dioxide solution, reacting and centrifuging to obtain TiO2-Ru precipitate;
(3) Dissolving DSPE-PEG-2000 in ultrapure water to obtain DSPE-PEG-2000 solution; and (3) suspending TiO2-Ru sediment by using DSPE-PEG-2000 solution, reacting, and centrifuging to obtain sediment, namely the titanium-based nano material.
As a preferred embodiment of the preparation method of the titanium-based nanomaterial, the reaction in the step (2) is a light-shielding stirring reaction for 12 hours
As a preferred embodiment of the preparation method of the titanium-based nanomaterial, the reaction in the step (3) is stirred at a rotation speed of 300-1000r for 3-8h.
The invention also provides application of the titanium-based nano material in preparation of sound-sensitive agents.
The invention also provides an acoustic sensitizer, which comprises the titanium-based nanomaterial.
The invention also provides application of the titanium-based nanomaterial in tumor sonodynamic therapy.
The invention also provides application of the titanium-based nano material in preparing antitumor drugs.
As a preferred embodiment of the use according to the invention, the tumour comprises bladder cancer.
The invention has the beneficial effects that: the invention uses ruthenium complex Ru and hollow nanosphere TiO for the first time 2 Develop a safe and nontoxic titanium-based nano material TiO with low cost and simple preparation 2 Ru-PEG. The inventionBright titanium-base nano material TiO 2 Ru-PEG can significantly increase the generation rate of ROS, providing a new strategy for improving sonodynamic therapy; the titanium-based nano material TiO of the invention 2 Ru-PEG can be effectively absorbed by bladder cancer cells, and is explosively generated after being combined with oxygen in cells under ultrasonic irradiation 1 O 2 、O 2. -damaging mitochondria to cause apoptosis of tumor cells, thereby achieving the effect of enhancing acoustic power for treating bladder cancer; the titanium-based nano material TiO of the invention 2 The Ru-PEG has the advantages of simple preparation method, high yield, good repeatability and potential of large-scale production.
Drawings
FIG. 1 is a diagram of TiO 2 The preparation process of Ru-PEG and the principle schematic diagram for enhancing the acoustic dynamic therapy of bladder cancer.
FIG. 2 is a diagram of TiO 2 The results were characterized by TEM, SEM, zeta potential, fourier IR spectrum, mapping elemental analysis, UV-VIS-NIR, BET mesoporous analysis, XRD, XPS of Ru-PEG.
Fig. 3: A-C are high-resolution XPS maps of Ru3P1, ru3d5 and Ti2P3 valence states respectively; d is Ru, tiO 2 、TiO 2 Singlet oxygen of Ru; e is Ru, tiO 2 、TiO 2 -band gap of Ru; f is Ru, tiO 2 、TiO 2 -valence band of Ru; g is TiO 2 Band gap and electron transfer schematic of Ru-PEG.
Fig. 4: A-C is flow cytometry for detecting TiO 2 Uptake of Ru-PEG in MB49 cells and SV-HUC-1 cells; D-I is TiO 2 Influence of Ru-PEG on the viability of the different cells.
FIG. 5 is a diagram of TiO 2 Cytotoxicity results of Ru-PEG.
Fig. 6: a is a cell (Calcein-AM/PI) staining result diagram; b is a cell clone staining chart; c is a scratch condition diagram photographed by a microscope; d is a semi-quantitative analysis cloning result; e is the result of semi-quantitative analysis cloning.
Fig. 7: a is a schematic diagram of the sonodynamic treatment process of MB49 tumor-bearing mice; B-D is TiO detection by small animal imager 2 Near infrared fluorescence distribution of Ru-PEG in vivo; e is a tumor entity photograph of each group of mice; F-G is tumor body of mice in each groupProduct change; H-I is the tumor inhibition rate of mice in each group.
Fig. 8: a is H & E staining results of each group of tumor sections; b is the tissue morphology of the heart, liver, spleen, lung and kidney of each group of nude mice; c is liver and kidney function index of each group of mice.
Detailed Description
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Example 1 titanium-based nanomaterial TiO 2 Preparation of Ru-PEG
The embodiment provides a titanium-based nanomaterial TiO 2 The preparation method of Ru-PEG, as shown in figure 1, comprises the following steps:
(1) Hollow nano spherical TiO 2 Is prepared from the following steps: placing 0.86ml of tetraethyl silicate (TEOS), 0.46ml of ammonia water, 23ml of ethanol and 4.3ml of ultrapure water into a flask at a low speed of 400r for stirring for 4 hours at normal temperature, centrifuging for 10 minutes by 10000r, and re-suspending by 5ml of ethanol to obtain a re-suspension solution A; adding 0.2g of hydroxypropyl cellulose (HPC) into a mixed solution of 90ml of ethanol and 0.48ml of ultrapure water, and stirring at a low speed of 400r for 3 hours to obtain a mixed solution A; 4ml of tetrabutyl titanate is dissolved in 18ml of ethanol solution to obtain a mixed solution B; slowly dripping the heavy suspension solution A into the mixed solution A at a low speed of 600r, stirring for 0.5h, and then dripping the mixed solution B into the mixed solution under the stirring of 600r at a low speed (0.5 ml/min); after the dripping is finished, the mixture is placed in silicone oil and heated to 85 ℃ to reflux for 100min, and immediately centrifuged (4000 r 10 min) and resuspended in 20ml of ultrapure water to obtain a resuspension solution B; adding 4ml of NaOH with concentration of 2.5M into the resuspension solution B in a dropwise manner, stirring at a low speed of 300r for 6 hours, immediately centrifuging (8000 r for 10 minutes) to obtain a precipitate, placing the precipitate in a drying chamber at 65 ℃ for 12 hours, weighing the mass of the precipitate, and resuspension the precipitate by using ultrapure water required by calculation of 150 mg/ml; according to the volume V of ultrapure water required for resuspension 1 According to V 2 ＝V 1 After 12000, the required concentrated hydrochloric acid volume V is calculated 2 Adding into the heavy suspension solution, stirring at low speed for 0.5h, centrifuging (8000 r for 10 min) to obtain precipitate,repeatedly washing the precipitate with 40ml of ionized water for 3 times, and re-suspending with 10ml of ultrapure water to obtain hollow nanosphere-shaped TiO 2 。
(2) Preparation of Ru: dppz (0.100 g,0.355 mmol) and cis-Ru (phen) 2 Cl 2 (0.188 g,0.355 mmol) in a solvent of ethanol and water (3:1) to give [ Ru (phen) 2 dppz](PF6) 2 The method comprises the steps of carrying out a first treatment on the surface of the Will [ Ru (phen) 2 dppz](PF6) 2 Reflux under nitrogen for 8 hours to give the product as an orange solid; then use PF6 - Exchange Cl - The starting material was purified by a silica gel column (CH 3CN: toluene=1:1), volatiles were removed under reduced pressure, and the remaining solids were purified by CH 3 And (3) recrystallizing CN and diethyl ether to obtain red crystals, namely Ru.
(3)TiO 2 Preparation of Ru-PEG:
1) 20mg of hollow nanosphere TiO 2 Dissolving in 1ml DMSO solution to obtain TiO 2 A solution; 9mg Ru is dissolved in 1ml DMSO solution to obtain Ru solution; slowly and continuously dropwise adding TiO into Ru solution 2 Stirring in the solution for 12h in dark, centrifuging (8000 r 10 min), and cleaning with ultrapure water for one time to obtain TiO 2 Ru precipitation;
2) Weighing 20mg DSPE-PEG-2000, dissolving in 10ml ultra pure water to obtain solution, and re-suspending TiO with the solution 2 Precipitating Ru, stirring at low speed (500 r) for 5 hr, centrifuging, cleaning the precipitate with ultrapure water, and re-suspending with 10ml ultrapure water to obtain TiO 2 -Ru-PEG。
TiO 2 Characterization of Ru-PEG: evaluation of TiO by Transmission Electron Microscopy (TEM), scanning Electron Microscopy (SEM), ultraviolet-visible Spectrophotometer (UV-VIS-NIR), fourier Infrared spectrometer, mapping elemental analysis, mesoporous analysis, X-ray diffraction (XRD), ray photoelectron Spectrometry (XPS), electron Spin Resonance (ESR), ZETA potential 2 Stability of Ru-PEG and mechanism to enhance acoustic dynamics. The results are shown in FIG. 2. As can be seen from FIGS. 2A-B, tiO 2 Ru-PEG is in a hollow spherical shape with a surface roughness and a diameter of about 250nm, the thickness of a shell layer is about 40-50nm, and the thickness of an outermost surface modified PEG layer is about 2-5nm; FIG. 2C is Ru-PEG, tiO 2 -PEG、TiO 2 Zeta potential of Ru-PEG; FIG. 2D is Ru, tiO 2 、TiO 2 Fourier infrared spectrum of Ru;FIGS. 2E-F illustrate the detection of TiO using elemental analysis 2 Ru-PEG and enzyme-labeled instrument for detecting TiO 2 -Ru-PEG absorbance at wavelength 410 nm; the above results all show that the hollow nanosphere TiO 2 Ruthenium complex Ru can be successfully loaded, and novel sound sensitizer TiO is proved 2 Successful synthesis of Ru-PEG. By calculation at 410nm wavelength Ru-PEG and TiO 2 Ru-PEG absorption Strength, calculated TiO 2 Ru-PEG loaded Ru loading rate of about 40%, which is hollow nanosphere TiO 2 The combination with the metal complex Ru provides the basis. From the elemental analysis results, the loaded metal ruthenium complex Ru is mainly concentrated in the shell layer of the hollow nanospheres. As can be seen from fig. 2G, H, detection of TiO by mesoporous analysis 2 、TiO 2 -Ru，TiO 2 TiO after Ru loading 2 Ru is still a mesoporous material with a specific surface area of 29.3368m 2 Increase/g to 271.0138m 2 The pore diameter is reduced from 13.4774nm to 4.5933nm, which shows that the metal ruthenium complex can be enriched in the shell pores of the hollow nanospheres, which is consistent with the result of element analysis, and TiO is carried after the Ru complex is loaded 2 The Ru specific surface area is significantly increased, increasing the contact surface with oxygen increases the ROS generation efficiency, thus enhancing the sonodynamic therapy. The absorption intensity (figure 2I), XRD (figure 2J) and XPS total spectrum (figure 2K) of the ultraviolet visible light graduation meter at different wavelengths are measured to analyze Ru and TiO 2 、TiO 2 The structure of Ru, the result shows that TiO 2 Ru has a stable structure after synthesis and its valence state is mainly Ru3P, ru3d, ti2P, these results also indirectly prove that TiO 2 Ru successfully loaded to synthesize hollow nanosphere TiO 2 Ru, validated hollow nanosphere TiO 2 Ru-PEG can be successfully prepared at low cost and stably.
In order to explore the mechanism of TiO2-Ru-PEG enhanced sonodynamic therapy, the results are shown in FIGS. 3A-C by comparing high resolution XPS maps of the Ru3P1, ru3d5, ti2P3 valences: because of the interaction between Ti and Ru, the characteristic peaks of Ru3d5 and Ti2P3 are slightly shifted, and the distances are respectively 0.38eV and 0.35eV, which shows that Ru is coordinated with the hollow nanosphere TiO by Ti-Ru 2 Binding, which is consistent with the results of mesoporous analysis and mapping elemental analysis, i.e., ru and TiO 2 Is combined with TiO in a Ti-Ru coordination mode 2 Causing TiO in shell pores of hollow nanospheres 2 The specific surface area of Ru increases and the pore size correspondingly decreases. TiO (titanium dioxide) 2 Ru3P1 valence state of Ru is 495.18eV, and Ru3P1 valence state of Ru is 484.28eV, indicating that the loaded ruthenium complex Ru is in TiO 2 Significant binding energy migration in Ru systems occurs in the highly oxidized state, which is TiO 2 Ru can generate singlet oxygen with high efficiency after being contacted with oxygen, and can obviously enhance the sound power treatment under the irradiation of ultrasound. Hollow nanosphere TiO is conferred by binding in the form of chemical bonds 2 Ru-PEG stable structures, which are vital for biological applications, without color change for at least one month. Ru and TiO were measured by ESR and ultraviolet-visible absorption spectroscopy, XPS 2 、TiO 2 Singlet oxygen, band gap and valence band of Ru, as can be seen from FIGS. 3D-F, tiO 2 Ru-PEG is more efficient in generating singlet oxygen. Ru, tiO 2 、TiO 2 The Ru band gaps were 3.99eV, 4.73eV, 3.76eV, respectively. Ru, tiO 2 、TiO 2 The Ru conduction band was 2.85eV, 2.69eV, 2.26eV, respectively. Obviously, tiO 2 After loading the metal ruthenium complex Ru, the TiO is obviously reduced 2 The bandgap of Ru. By calculating Ru and TiO 2 、TiO 2 The valence band and conduction band of Ru are combined with the change of Ru3d5 and Ti2P3 valence binding energy in XPS high resolution to obtain TiO 2 Schematic of band gap and electron transfer of Ru-PEG, as shown in FIG. 3G, tiO under ultrasound irradiation 2 TiO after ultrasonic irradiation of Ru-PEG 2 And Ru electrons transfer to enhance the separation efficiency of electron hole pairs, thereby remarkably enhancing the generation of active oxygen such as singlet oxygen and the like and enhancing the sound power curative effect.
Example 2
This example is conducted on the titanium-based nanomaterial TiO prepared in example 1 2 The safety and the sonodynamic curative effect of Ru-PEG are verified in vitro, and the specific experimental method is as follows:
(1) Cell culture: the cells used in this experiment were normal bladder epithelial cells SV-HUC-1 and murine bladder cancer cells MB49. All cells were incubated at pH7.4, 37℃and 5% CO 2 Contains 10% of the tireBovine serum was cultured in DMEM medium, and cells were gently blown down after digesting the cells with pancreatin when cell densities of 80% -90% were reached to form a cell suspension for subsequent cell experiments.
(2) Cellular uptake process of TiO 2-Ru-PEG:
1) Synthesis of coumarin-6 tagged TiO 2 Ru-PEG: coumarin-6 with final concentration of 2ug/mL is added to TiO 2 Stirring in Ru-PEG solution for 8h in dark, centrifuging at 8000r for 10min, collecting precipitate, cleaning with ultrapure water for three times, and finally re-suspending with 10ml ultrapure water to obtain coumarin-6 labeled TiO 2 -Ru-PEG；
2) MB49 cells at 5X10 4 cell/mL density was inoculated in 12-well plate culture plates (1 mL/well), and after adherence, tiO was labeled with coumarin-6 at 14. Mu.g/mL (as Ru basis weight) after adherence 2 Ru-PEG (green) treatment for different times respectively; the cells were treated with lysosome probe Lyso-tracker (red) and nuclear probe DPAI (blue) for 1h and 15min, respectively, and the TiO was observed with a fluorescence microscope 2 Ru-PEG enters the cell.
3) Flow cytometry detected the selective absorption of TiO 2-Ru-PEG: MB49 cells and SV-HUC-1 cells at 2X 10 4 cells/mL were seeded in 6cm dishes (6 mL/dish) and after attachment, coumarin-6 labeled TiO was used 2 Ru-PEG (quantified in Ru, 14. Mu.g/mL) was treated for different times (0, 2, 4, 8, 12 h) respectively; washing the supernatant with PBS three times, digesting the collected cells with pancreatin, washing with PBS once, filtering the cell suspension with 200 mesh nylon net, and detecting TiO by flow cytometry 2 Uptake of Ru-PEG in MB49 cells and SV-HUC-1 cells.
The results are shown in FIG. 4. As can be seen from FIG. 4A, MB49 vs. TiO 2 Uptake of Ru-PEG is time-dependent, tiO 2 After incubation of cells for 1h with Ru-PEG (coumarin-6 label), the lysosomes showed weak green fluorescence signals, and with the extension of drug incubation time, the green fluorescence signals from lysosomes were gradually enhanced, and after incubation for 8h, tiO 2 The green signal of Ru-PEG spreads throughout the cytoplasmic environment, indicating TiO 2 Ru-PEG has good permeability to MB49 cells, and is easily taken up by bladder cancer cells MB49Endocytosis is time dependent. As can be seen from FIGS. 4B-C, both MB49 cells and SV-HUC-1 cells were uptake of TiO 2 After 8h of Ru-PEG, a substantially saturated state is reached, but at the same time the uptake of TiO by MB49 cells 2 Ru-PEG was more potent than SV-HUC-1 cells, indicating TiO 2 Ru-PEG has good biocompatibility.
(3)TiO 2 Influence of Ru-PEG on the viability of different cells
100ul of cells were seeded in each well of a 96-well plate at a concentration of 4X10 4 cell suspension of cell/ml SV-HUC-1, MB49 in 5% CO 2 Incubate in a humidified environment at 37℃for 24 hours. SV-HUC-1, MB49 are classified into control group, US group, ru-PEG group, and TiO 2 PEG group, tiO 2 Ru-PEG group. After the cells are attached, ru-PEG and TiO with different concentrations (2, 4, 7, 14 and 28) ug are respectively added into each group by taking Ru concentration as quantification 2 -PEG、TiO 2 After 8h incubation of Ru-PEG with cells, the cells of the ultrasound group were subjected to an intensity of 1MHz,1.5w/cm 2 After the incubation is finished, MTT (5 mg/mL,20 mu L/hole) is added to each hole, the supernatant is sucked and removed, DMSO (150 mu L/hole) is continuously added to each hole, and the mixture is oscillated on a constant temperature shaking table for 10min to fully dissolve water-insoluble blue-violet formazan crystals, and finally the absorbance value is read at 570nm on a multifunctional enzyme-labeled instrument. The results are shown in FIG. 4D. To confirm TiO 2 Ultrasonic accurate time of acoustic power treatment by Ru-PEG, setting different ultrasonic time to irradiate MB49 cells, comparing whether TiO exists or not 2 Cell viability change with Ru-PEG incubation, which shows an ultrasound intensity of 1MHz,1.5w/cm 2 The cell viability of the individual US group was 95.2% with a duty cycle of 40% and an irradiation time of 1min, whereas TiO 2 The survival rate of Ru-PEG+US group cells is 52.9%, the damage of ultrasound to cells is negligible when the ultrasound time is 1min, and the presence of the sonosensitizer remarkably enhances the toxicity to MB49 cells and inhibits the activity of MB49 cells. As shown in FIG. 4E, tiO is added alone 2 Ru-PEG was incubated with cells for 48h with MB49 cell viability of 94.5%, 93%, 89.2%, 80.5%, 70.7%, respectively, inThe viability of MB49 cells under the ultrasonic irradiation is respectively 80.1%, 71.5%, 60.7%, 52.4% and 32.1%, and obviously, the higher the concentration of TiO2-Ru-PEG is, the lower the viability of MB49 cells is, and after the ultrasonic irradiation, the viability of MB49 cells is further reduced, thus showing TiO 2 Ru-PEG has excellent photodynamic therapy effect. As shown in FIGS. 4F-G, ru-PEG and TiO at the same concentration 2 -PEG、TiO 2 The most obvious effect of Ru-PEG on MB49 cell viability is TiO 2 Ru-PEG, in particular viability US+TiO of MB49 cells after ultrasound irradiation 2 The Ru-PEG group is lower, so that TiO is visible 2 Ru-PEG compared to Ru-PEG, tiO 2 PEG can significantly enhance the sonodynamic effect. As shown in FIGS. 4H-I, different concentrations of TiO 2 Cell viability after 48h incubation of Ru-PEG and SV-HUC-1 alone was 98.7%, 95.3%, 92.9%, 91.6%, 89.9%, respectively; whereas after 48h incubation with ultrasound, MB49 cell viability was 96.9%, 94.4%, 92.8%, 89.9%, 86.7%, respectively, demonstrating TiO 2 Ru-PEG with a concentration below 28ug/ml has little effect on the viability of the SV-HUC-1 cells, tiO 2 Ru-PEG has good biocompatibility.
(4)TiO 2 Cytotoxicity of Ru-PEG
1) Intracellular ROS content assay
MB49 cells at 5X10 4 Inoculating cell/ml density into 12-well plate culture plate (1 ml/well), dividing into 8 groups after cell adhesion, adding 9.4ug/ml Ru-PEG, tiO 2 -PEG、TiO 2 Ru-PEG incubation of cells for 5h with the intensity of 1MHz,1.5w/cm for the cells of the ultrasound group 2 After the cells were continuously cultured for 0.5h by ultrasonic irradiation at 40% duty ratio for 1min, the supernatant was removed, washed 3 times with PBS, and 0.5ml of serum-free medium 1:1000 dilution DCFH-DA (Biyundian S0033M) probe, DHE (diethyl ether) and DPBF (singlet oxygen detection probe) were stained for 30min in the absence of light, and each group was photographed using a fluorescence microscope. ROS production was detected for each treatment group using DCFH-DA.
As shown in FIG. 5A, the green fluorescence in each of the MB49 cells was changed, and Ru-PEG and TiO were not irradiated with ultrasound 2 -PEG、TiO 2 Ru-PEG incubated with cells alone, each group showed slight green in cellsColor fluorescence. Ru-PEG+US, tiO at the same concentration after ultrasonic irradiation 2 -PEG+US、TiO 2 The contrast of the intracellular fluorescence intensity of the Ru-PEG+US group is obviously enhanced without ultrasonic irradiation, in particular TiO 2 The intracellular fluorescence intensity of the-Ru-PEG+US group was more pronounced than that of the other groups, while semi-quantitative analysis of the fluorescence of each group (FIG. 5E) revealed TiO 2 The group-Ru-PEG+US has the strongest fluorescence, indicating TiO 2 Ru-PEG can generate large amounts of ROS upon ultrasound irradiation after uptake by MB49 cells. Detection of singlet oxygen for each treatment group using DPBF 1 O 2 The situation is generated. As shown in FIG. 5B, the green fluorescence in each of the MB49 cells was changed, and Ru-PEG and TiO were not irradiated with ultrasound 2 -PEG、TiO 2 Ru-PEG incubated with cells alone, the cells of each group showed intense green fluorescence. Ru-PEG+US, tiO at the same concentration after ultrasonic irradiation 2 -PEG+US、TiO 2 The fluorescence intensity in the Ru-PEG+US group cells is significantly reduced compared with that in the absence of ultrasound irradiation, in particular TiO 2 The intracellular fluorescence intensity of the-Ru-PEG+US group was weakest compared to the other groups, while semi-quantitative analysis of the fluorescence of each group (FIG. 5F) revealed TiO 2 The group-Ru-PEG+US has the weakest green fluorescence, indicating TiO 2 Ru-PEG can generate a large amount of singlet oxygen upon ultrasound irradiation after uptake by MB49 cells 1 O 2 . Detection of superoxide anion O for each treatment group with DHE 2 .- As a result of the formation, as shown in FIG. 5C, red fluorescence in each of the MB49 cells was changed, and Ru-PEG and TiO were not subjected to ultrasonic irradiation 2 -PEG、TiO 2 Ru-PEG incubated with cells alone, each group showed slight red fluorescence in the cells. Ru-PEG+US, tiO at the same concentration after ultrasonic irradiation 2 -PEG+US、TiO 2 The contrast of the intracellular fluorescence intensity of the Ru-PEG+US group is obviously enhanced without ultrasonic irradiation, in particular TiO 2 The intracellular fluorescence intensity of the-Ru-PEG+US group was strongest compared to the other groups, while semi-quantitative analysis of the fluorescence of each group (FIG. 5G) revealed TiO 2 The red fluorescence of the group-Ru-PEG+US is strongest, indicating TiO 2 Ru-PEG can generate a large amount of superoxide anions O after MB49 is ingested by cells by ultrasonic irradiation 2 .- 。
2) Mitochondrial membrane potential and morphology changes
MB49 cells at 5X10 4 Inoculating cell/ml density into 12-well plate culture plate (1 ml/well), dividing into 8 groups after adhering cells, adding 9.4ug/ml Ru-PEG, tiO 2 -PEG、TiO 2 Ru-PEG incubation of cells for 5h with the intensity of 1MHz,1.5w/cm for the cells of the ultrasound group 2 The cells were continuously cultured in an incubator at 37℃for 1 hour under ultrasonic irradiation at 40% duty cycle for 20 minutes at 37℃with the addition of 0.5ml of JC-1 staining working solution according to the kit instructions (Biyun C2006) and incubation in the incubator at 37℃in the absence of light, the supernatant was aspirated after the incubation was completed, the cells were washed 2 times with 1ml of ice-bath JC-1 staining buffer, and 1ml of cell culture medium was added after the washing was completed and observed under a fluorescence microscope. After the incubation, the effect of staining cells of each treatment group was observed under a fluorescence microscope. The decrease in mitochondrial membrane potential (Δψm) is associated with early apoptosis. The J-aggregates or monomers in JC-1 labeled mitochondria exhibit red and green fluorescence, respectively, and the decrease in cells (. DELTA.ψm) can be detected by the transition of JC-1 from red fluorescence to green fluorescence.
As a result, as shown in FIG. 5D, each group and normal cells emitted strong orange-red fluorescence without ultrasonic irradiation, tiO alone 2 The Ru-PEG groups emitted weaker green light, indicating a limited decrease in cell (. DELTA.. Di-elect cons.m) for each group of drug. After ultrasonic irradiation, ru-PEG+US and TiO 2 -PEG+US、TiO 2 -red light is reduced and green light is enhanced in Ru-PEG+US group cells, wherein TiO 2 The change of the-Ru-PEG+US group is most remarkable, indicating that TiO 2 Ru-PEG can obviously cause depolarization of mitochondria under the irradiation of ultrasound so as to promote early apoptosis of cells, and the TiO is verified 2 Ru-PEG enhances the effect of sonodynamic therapy.
(5)TiO 2 Ru-PEG anti-tumor Effect
1) Staining of live dead cells (Calcein-AM/PI)
MB49 cells at 5X10 4 Inoculating cell/ml density into 12-well plate culture plate (1 ml/well), dividing into 8 groups after adhering cells, adding 9.4ug/ml Ru-PEG, tiO 2 -PEG、TiO 2 Ru-PEG incubation of cells for 5h with the intensity of 1MHz,1.5w/cm for the cells of the ultrasound group 2 Duty cycle40% of the cells were subjected to ultrasonic irradiation for 1min and the cells were cultured for 5h. According to the instruction book of the kit (Biyun C2015M), preparing a working solution for detecting the Calcein-AM/PI, adding 0.5ml of the working solution for detecting the Calcein-AM/PI into each group of cells, incubating the cells at 37 ℃ in a dark place for 30min, and observing the cell staining effect of each treatment group under a fluorescence microscope after the incubation is finished.
As a result, as shown in FIG. 6A, the cell density of each group without ultrasonic irradiation was 80-90%, the cell profile morphology was good and the number was large, and green fluorescence was observed, indicating that most cells were living, only TiO was present 2 The Ru-PEG group showed weak red fluorescence, indicating TiO 2 Ru-PEG alone can lead to small cell death. After ultrasonic irradiation, tiO 2 The cell density of the Ru-PEG+US group is obviously reduced by about 40%, green light is obviously weakened, and red light is obviously enhanced, which shows that TiO is irradiated by ultrasonic waves 2 Ru-PEG can significantly induce apoptosis, indicating TiO 2 Ru-PEG has the effect of enhancing sonodynamic therapy.
2) Clone formation
MB49 cells with the density of 2000cells are inoculated into a 6-hole plate (2 mL/hole), 9.4 mug/mL Ru-PEG, tiO2-PEG and TiO2-Ru-PEG are respectively added after the MB49 cells are completely adhered, and the MB49 cells are further incubated for 5 hours by using the intensity of 1MHz and 1.5w/cm 2 The colony formation was observed daily by culturing at 37 ℃ after 1min of ultrasonic irradiation at a duty ratio of 40%, washing three times with pre-chilled PBS55 after 14 days, fixing cells with 4.0% paraformaldehyde for 15min, staining with 0.5% methyl violet for 15min, and after natural air drying, photographing and counting, and calculating the colony formation rate by (number of clones/number of inoculated cells) ×100%.
As a result, as shown in FIG. 6B, the purple areas of the proliferation of the cells of the groups not irradiated with ultrasound were significantly enlarged, while the purple areas of the proliferation of the cells of the groups after the irradiation with ultrasound were reduced, wherein TiO 2 The group-Ru-PEG+US is most evident, and the cloning results by semi-quantitative analysis are shown in FIG. 6D, tiO 2 Ru-PEG significantly inhibited proliferation of MB49 cells under ultrasound irradiation.
3) Scratch test
Will have a density of 5x10 4 MB49 cells of cells, 70. Mu.LSeed in wells of a scratch card (Ibidi GmbH) placed in six well plates, after incubation for 24h cell attachment the scratch card was removed and 2mL of complete medium was added to each well, 9.4. Mu.g/mL (as Ru basis) of Ru-PEG, tiO, respectively 2 -PEG、TiO 2 Ru-PEG and photographed under a microscope to record the scratch for 0h, after incubation in an incubator for a further 5h with an intensity of 1MHz,1.5w/cm 2 The culture was performed at 37℃after 1min of ultrasonic irradiation at a duty cycle of 40%. The scratch was photographed every 2 hours with a microscope and recorded.
As shown in FIG. 6C, after incubating the cells for 12 hours, the cells of each group not irradiated with ultrasound were compared with the scratches of 0 hours, the cells had significantly migrated, the control group had been exposed to the cells, and the scratches of each group after irradiation with ultrasound were relatively more apparent than the scratches of the group not irradiated with ultrasound, wherein TiO 2 The group-Ru-PEG+US is most evident, and the cloning results by semi-quantitative analysis are shown in FIG. 6E, tiO 2 Ru-PEG significantly inhibited proliferation of MB49 cells under ultrasound irradiation.
Example 3
This example is conducted on the titanium-based nanomaterial TiO prepared in example 1 2 The safety and the sonodynamic effect of Ru-PEG are verified in vivo, and the specific experimental method is as follows:
(1) Construction of MB49 tumor-bearing mouse model
Female BALB/c mice (4-6 weeks old, weight 18-20 g, purchased from medical laboratory animal center, SPF grade, guangdong province) were bred in Guangdong Ji Ni European Biotechnology Co., ltd (animal pass number: SYXK (Guangdong) 2022-0298), and all of the following experiments were in accordance with the principles of animal protection, animal welfare and ethics and in accordance with the relevant regulations of the national laboratory animal welfare. After 7 days of quarantine of mice, 150. Mu.l of the mice were at a density of 7.5X10 7 MB49 cell suspension (PBS and matrigel volume 1:1) of cells/ml was subcutaneously implanted into left armpit (sufficient blood flow, loose skin) of mice, the state and the tumorigenesis of the mice were observed every other day, and after about 7 days, tumors up to 6-8 mm in size were randomly grouped and subjected to related experiments.
(2) In vivo verification of TiO2-Ru-PEG safety
Indocyanine green (ICG) is currently the only food drug in the united statesThe near infrared imaging reagent approved by the matter administration (FDA) for clinic is a tricarbocyanine dye with near infrared characteristic absorption peak, and the maximum emission wavelength is between 795 and 845 nm. 1.5. Mu.g/ml TiO labeled with 100ul ICG 2 Intratumoral injection of Ru-PEG solution on two BALB/C tumor-bearing mice using a small animal imager at 0, 10min, 30min, 2h, 4h, 6h, 8h, 12h, 24h, 30 h, respectively 2 Near infrared fluorescence distribution of Ru-PEG in vivo, one of the nude mice was dissected at 4h to remove important organs and tumors.
The results are shown in fig. 7B-D, with no fluorescence distribution in nude mice at 0 hours without nanodrug injection; the fluorescence is strongest within 30min after intratumoral injection, relatively weakens and maintains relatively stable fluorescence intensity after 4h, and the fluorescence in the nude mice starts to be obviously weakened after 24h, which indicates TiO 2 Ru-PEG can stably diffuse in tumor and stay in tumor for a long time, can be safely metabolized out of the body, and has better biocompatibility.
(3)TiO 2 Ru-PEG in vivo sonodynamic efficacy
40 MB49 tumor-bearing mice weighing approximately 20g were divided into 8 groups of 5 mice each, wherein: a first group: intratumoral injection of saline as Control group (Control); second group: intratumoral injection of Ru-PEG; third group: intratumoral injection of TiO 2 -PEG; fourth group: intratumoral injection of TiO 2 Ru-PEG; fifth group: ultrasound irradiation group (US) after tumor viscera injection with physiological saline; sixth group: ultrasonic irradiation (Ru-PEG+US) 8h after intratumoral injection of Ru-PEG; seventh group: intratumoral injection of TiO 2 post-PEG 8h ultrasound irradiation (TiO 2 -peg+us); eighth group: intratumoral injection of TiO 2 8h after Ru-PEG ultrasound irradiation (TiO 2 Ru-PEG+US); as shown in FIG. 7A, the concentration of the injection was calculated as Ru during the sonodynamic treatment of the whole MB49 tumor-bearing mice, 10mg/kg was injected into each mouse (20 g), and 1MHz ultrasonic intensity was 1.5w/cm after 1 hour of intratumoral injection 2 The tumor was irradiated at a duty cycle of 40% for 10 min. Mice were weighed at 2 day intervals, tumor size was measured and tumor volume was calculated: v=ab 2 And (2), a is the length of the tumor, and b is the width of the tumor. After 14 days of treatment, the eyeball is taken out of blood, and serum is collected after centrifugation and stored at-80 ℃ for hematogenesisDetecting chemical indexes; collecting important viscera (heart, liver, spleen, lung and kidney) and tumor, cleaning with PBS, fixing part with 4% paraformaldehyde for 24 hr, and performing H&E staining, performing immunohistochemical and TUNEL staining analysis on the tumor blank slices, and further verifying TiO 2 Ru-PEG for enhancing the effect of sonodynamic therapy in vivo. The results are shown in fig. 7 and 8.
As shown in FIG. 7E, control, ru-PEG and TiO are respectively from top to bottom 2 -PEG、TiO 2 -Ru-PEG、US、Ru-PEG+US、TiO 2 -PEG+US、TiO 2 -Ru-peg+us group; from the tumor solid photographs, it is known that Control, ru-PEG, tiO, which is not irradiated by ultrasound, are 2 -PEG、TiO 2 The tumor volume of the Ru-PEG group is obviously increased, and the tumor volume of the US, ru-PEG+US and TiO under ultrasonic irradiation is obviously increased 2 -PEG+US、TiO 2 Ru-PEG+US group, except that the tumor volume of US group was almost unchanged from that of control group, ru-PEG+US, tiO 2 -PEG+US、TiO 2 The tumor volumes of the group-Ru-PEG+US were reduced, with TiO 2 The tumor volume of the-Ru-PEG+US group was minimal, indicating TiO 2 Ru-PEG significantly enhances sonodynamic therapy after ultrasound irradiation, significantly inhibiting tumor proliferation.
As can be seen from FIG. 7F, control, ru-PEG, tiO 2 -PEG、TiO 2 The tumor volume of the Ru-PEG and US groups is continuously increased along with the change of time, and Ru-PEG+US and TiO 2 The PEG+US group relatively inhibited the increase in tumor volume, but the effect was not significant. While TiO 2 The Ru-PEG+US group significantly inhibited the increase in tumor volume, as seen in TiO 2 Ru-PEG has excellent sonodynamic curative effect under ultrasonic irradiation and can obviously inhibit the growth of tumor.
As can be seen from FIG. 7G, control, ru-PEG, tiO after 14 days of different treatments 2 -PEG、TiO 2 The weight of Ru-PEG and US group tumors is relatively large, and Ru-PEG+US and TiO 2 -PEG+US、TiO 2 The weight of the tumor in the group-Ru-PEG+US is relatively small, wherein TiO 2 The most obvious weight reduction of Ru-PEG+US group tumor shows that TiO 2 Ru-PEG has remarkable sonodynamic effect on ultrasonic irradiation and remarkably inhibits the growth of tumors.
As can be seen from FIGS. 7H-I, Control、Ru-PEG、TiO 2 -PEG、TiO 2 -Ru-PEG、US、Ru-PEG+US、TiO 2 -PEG+US、TiO 2 Tumor inhibition rates of the-Ru-PEG+US groups were 0%, 18%, 22.7%, 22.8%, 11%, 28.6%, 29.4%, 66.7%, respectively, indicating TiO 2 Ru-PEG significantly inhibited tumor growth after ultrasound irradiation, tiO 2 Ru-PEG has the effect of enhancing the acoustic dynamic therapeutic effect of bladder cancer.
As shown in fig. 8A, to better evaluate TiO 2 Ru-PEG enhanced sonodynamic therapy for various groups of tumor slices H&Carefully observing E dyeing results, and controlling, ru-PEG and TiO 2 -PEG、TiO 2 The Ru-PEG and US groups can see a large number of tumor cells with obvious nucleoli, and the tumor tissues are very compact. Ru-PEG+US, tiO 2 -PEG+US、TiO 2 Ru-PEG+US group tumor cell number reduction, loose arrangement, blurred boundary and cell nucleus shrinkage, necrosis phenomenon and TiO 2 The group-Ru-PEG+US is most evident, further proving TiO 2 Ru-PEG has better photodynamic therapy effect. Tunel (apoptosis marker) is an important index for detecting apoptosis, as shown in Control, ru-PEG, tiO 2 -PEG、TiO 2 Neither Ru-PEG nor US group showed obvious apoptosis, but Ru-PEG+US and TiO after combined ultrasonic irradiation 2 -PEG+US、TiO 2 Apoptosis is visible in the group-Ru-PEG+US, whereas TiO 2 Apoptosis appears obviously in the group of-Ru-PEG+US, indicating TiO 2 Ru-PEG can induce apoptosis under ultrasonic irradiation, tiO 2 Ru-PEG has an enhanced photodynamic therapy effect. Ki67 (cell proliferation marker) is an important index for biopsy grading of tissue specimens, as shown in Control, ru-PEG, tiO 2 -PEG、TiO 2 The high expression Ki67 of the Ru-PEG and US groups shows that the tumor has larger malignancy degree and is in active proliferation state, and after ultrasonic irradiation, ru-PEG+US and TiO 2 -PEG+US、TiO 2 A decrease in the Ki67 expression level of the Ru-PEG+US group indicates an inhibition of tumor proliferation, wherein TiO 2 The most significant decrease in Ki67 expression level in the Ru-PEG+US group indicates TiO 2 Ru-PEG significantly inhibited tumor growth after ultrasound irradiation.
As shown in fig. 8B, the tissues of the heart, liver, spleen, lung and kidney of each group of nude mice were normal, the structure was clear, and no abnormal tissues were seen; the clear cell demarcation, regular arrangement and no inflammatory change can be seen under a high-power microscope, which indicates TiO 2 Ru-PEG has good biocompatibility. By collecting blood from each group of nude mice and detecting ALB, AST, ALB liver function important index and UREA, CREA, UA kidney function important index, as shown in FIG. 8C, ru-PEG, tiO 2 -PEG、TiO 2 -Ru-PEG、US、Ru-PEG+US、TiO 2 -PEG+US、TiO 2 The liver and kidney function indexes of the-Ru-PEG+US group and the Control group are not obviously different, and further prove that the TiO is 2 Ru-PEG has good biocompatibility.
Finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made to the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention.
Claims (10)
1. A titanium-based nanomaterial, characterized in that the titanium-based nanomaterial comprises titanium dioxide and Ru.
2. The titanium-based nanomaterial of claim 1, wherein the titanium dioxide is hollow nanosphere titanium dioxide.
3. The method for preparing a titanium-based nanomaterial according to any one of claims 1 to 2, characterized by comprising the steps of:
(1) Respectively dissolving titanium dioxide and Ru in DMSO to obtain a titanium dioxide solution and a Ru solution;
(2) Dropwise adding Ru solution into titanium dioxide solution, reacting and centrifuging to obtain TiO 2 Ru precipitation;
(3) Dissolving DSPE-PEG-2000 in ultrapure water to obtain DSPE-PEG-2000 solution; heavy weight using DSPE-PEG-2000 solutionSuspended TiO 2 And (3) Ru precipitation and reaction, and centrifuging to obtain a precipitate, namely the titanium-based nano material.
4. The method of claim 3, wherein the reaction in the step (2) is a light-shielding stirring reaction for 12 hours.
5. The method for preparing a titanium-based nanomaterial according to claim 3, wherein the reaction in step (3) is performed at a rotation speed of 300 to 1000r with stirring for 3 to 8 hours.
6. Use of the titanium-based nanomaterial of any of claims 1-2 in the preparation of a sonosensitizer.
7. A sonosensitizer, characterized in that it comprises a titanium-based nanomaterial according to any of claims 1 to 2.
8. Use of the titanium-based nanomaterial of any of claims 1-2 in the sonodynamic treatment of tumors.
9. Use of the titanium-based nanomaterial of any one of claims 1-2 in the preparation of an antitumor drug.
10. The use of claim 9, wherein the tumor comprises bladder cancer.
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