CN114306651A - Application of doped titanium dioxide in preparation of sound-sensitive agent - Google Patents
Application of doped titanium dioxide in preparation of sound-sensitive agent Download PDFInfo
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- CN114306651A CN114306651A CN202011054491.XA CN202011054491A CN114306651A CN 114306651 A CN114306651 A CN 114306651A CN 202011054491 A CN202011054491 A CN 202011054491A CN 114306651 A CN114306651 A CN 114306651A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
- C01G23/00—Compounds of titanium
- C01G23/04—Oxides; Hydroxides
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Abstract
The invention relates to an application of doped titanium dioxide in preparing a sound-sensitive agent, wherein the doped titanium dioxide comprises titanium dioxide and transition metal doped in the titanium dioxide. The doped titanium dioxide can be used for preparing the sound-sensitive agent, has good killing effect on tumors, and has good biological safety and biodegradability.
Description
Technical Field
The invention relates to the field of functional nano materials and tumor treatment preparations, in particular to application of doped titanium dioxide in preparing a sound-sensitive agent.
Background
Cancer is a disease threatening the life safety of human beings, and the main means for treating cancer clinically at present are surgical excision, chemotherapy and radiotherapy. However, each of these three treatments has its own limitations: the surgical resection treatment is not thorough and cannot solve the metastatic tumor, and chemotherapy and radiotherapy have great side effects and can stimulate the tumor to generate drug resistance and reduce the drug treatment effect.
Acoustic dynamic forceTherapy (SDT) is a novel high-permeability tumor therapy, and the main killing mechanism is to use ultrasound as an excitation source to stimulate sonosensitizers to generate Reactive Oxygen Species (ROS), thereby killing tumor cells. The existing sound-sensitive agent mainly comprises organic sound-sensitive agents such as porphyrin and derivatives thereof and titanium dioxide (TiO)2) Are representative inorganic sonosensitizers. However, the organic sonosensitizers are not easily soluble in water, have low efficiency and certain phototoxicity, while the inorganic sonosensitizers have high potential toxicity due to low sonodynamic efficiency and long-term retention in the body. Therefore, the development of a safe and efficient tumor sound-sensitive preparation, the biocompatibility and biodegradability of the sound-sensitive preparation are ensured, the tumor growth is effectively inhibited, and the sound-sensitive preparation is a key problem to be solved in the process of treating the cancer by using sound power.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide an application of doped titanium dioxide in preparing a sound-sensitive agent, and the doped titanium dioxide can be used for preparing the sound-sensitive agent in preparing the sound-sensitive agent, and has good killing effect on tumors and good biosafety and biodegradability.
The invention aims to disclose the application of doped titanium dioxide in preparing a sound-sensitive agent, wherein the doped titanium dioxide comprises titanium dioxide and transition metal doped in the titanium dioxide; the transition metal comprises one or more of iron (Fe), copper (Cu) and manganese.
Preferably, the doped titanium dioxide is Fe-doped TiO2，TiO2As a semiconductor material, the band gap of the semiconductor material under the excitation of external energy can be reduced by doping elements with the atomic radius and the electronegativity similar to those of the semiconductor material, so that the acoustic dynamic effect of the semiconductor material is improved. Fe-doped TiO of the invention2The band gap of the crystal is about 2.3-3.0 eV (depending on the doping ratio), and the TiO is2Has a bandgap of about 3.2 eV.
The doping element Fe can not only improve the acoustodynamic effect, but also ensure that the doped titanium dioxide participates in the Fenton-like reaction to lead high-concentration hydrogen peroxide (H) in the tumor cells2O2) Is converted into a hydroxyl radical and is converted into a hydroxyl free radical,thereby achieving the effect of killing tumor cells.
Further, the preparation method of the doped titanium dioxide comprises the following steps:
under a protective atmosphere, uniformly mixing a transition metal precursor and a titanium precursor in an oil phase at 100-160 ℃, and then reacting the obtained mixture at 260-280 ℃ to obtain doped titanium dioxide after complete reaction;
the transition metal precursor comprises one or more of organic metal salts of iron, copper and manganese.
Furthermore, the molar ratio of the transition metal element in the transition metal precursor to the titanium element in the titanium precursor is 1 (1-8), preferably 1 (1-4).
Further, the transition metal precursor is selected from one or more of iron acetylacetonate, copper acetylacetonate and manganese acetylacetonate.
Further, the titanium precursor is selected from titanium acetylacetonate.
Further, the mixture is uniformly mixed at 100-160 ℃ and then reacts for 0.5 h. Reacting for 0.5-1 h at 260-280 ℃.
Further, the oil phase comprises benzyl ether, oleic acid, oleylamine and dodecanediol. The volume ratio of the benzyl ether to the oleic acid to the oleylamine is 20:5: 1.
Furthermore, the particle size of the doped titanium dioxide is 2-5 nanometers.
Further, the atmosphere for protection is an inert gas atmosphere such as nitrogen.
Further, the method also comprises the steps of adding ethanol into the product after the reaction is completed, centrifuging to take the precipitate and washing.
Furthermore, the doped titanium dioxide is connected with an amphiphilic polymer, and the molecular weight of a hydrophilic chain segment of the amphiphilic polymer is 2kDa-5 kDa. Because the surface of the doped titanium dioxide is hydrophobic, in practical application, the hydrophobic end of the amphiphilic polymer and the hydrophobic end of the surface of the titanium dioxide are in electrostatic interaction, and the hydrophilic end is wrapped outside the hydrophobic end of the amphiphilic polymer and the titanium dioxide. Thus, the water solubility of the doped titanium dioxide can be improved, and the biocompatibility of the doped titanium dioxide can be improved.
Further, the hydrophobic chain segment of the amphiphilic polymer is C18-PMH. The hydrophilic end is polyethylene glycol (PEG).
Preferably, the amphiphilic polymer is C18PMH-PEG, method of synthesis thereof references "Wang, C., Cheng, L.,&Liu,Z..(2011).Drug delivery with upconversion nanoparticles for multi-functional targeted cancer cell imaging and therapy.Biomaterials,32(4),1110-1120”。
further, the sonosensitizer is used in the presence of hydrogen peroxide. When the doping element is Fe, not only the acoustodynamic effect can be improved, but also the doped titanium dioxide can participate in Fenton-like reaction to lead high-concentration hydrogen peroxide (H) in tumor cells to be2O2) Converted into hydroxyl free radical to kill tumor cell.
Further, the sonosensitizers are used for sonodynamic treatment of tumors.
Further, the ultrasonic power of the acoustic dynamic therapy is 2-10W/cm2The frequency is 10-50 kHz, and the action time is 1-30 min.
Further, the tumor includes breast cancer, colon cancer, bladder cancer, and the like.
Under external energy excitation, such as ultrasonic conditions, electrons in the Valence Band (VB) are excited into the Conduction Band (CB), forming holes in the valence band. Bound electrons must gain sufficient energy to transition from the valence band to the conduction band in order to be free electrons or holes. The minimum of this energy is the bandgap. The smaller the band gap, the easier the electron transition. Transition metal of doped metal and doped TiO of the invention2In the above formula, Ti is a transition metal element, and TiO2The semiconductor is doped with elements with similar atomic radius and electronegativity, so that the band gap of the semiconductor under the excitation of external energy can be reduced, and the acoustic dynamic effect of the semiconductor is improved.
The doped titanium dioxide sound-sensitive agent provided by the invention can be used for remarkably inhibiting the growth of tumors through ultrasonic irradiation after being injected into veins and reaching a focus part, and has great application value in the aspect of cancer treatment.
By the scheme, the invention at least has the following advantages:
(1) the doped titanium dioxide prepared by the invention has lower band gap and good acoustodynamic effect and Fenton-like effect.
(2) When the doped titanium dioxide obtained by the invention is used as a sound sensitizer, the doped titanium dioxide has good killing effect on tumors.
(3) When the doped titanium dioxide obtained by the invention is used as a sound-sensitive agent, the doped titanium dioxide can be biologically metabolized, and has good biological safety.
The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clearly understood and to implement them in accordance with the contents of the description, the following description is made with reference to the preferred embodiments of the present invention and the accompanying detailed drawings.
Drawings
FIG. 1 is a transmission electron microscope image of the iron-doped titanium dioxide sonosensitizer synthesized in the first example;
FIG. 2 is an energy dispersive X-ray spectroscopy spectrum of an iron-doped titanium dioxide sonosensitizer synthesized in the first example;
FIG. 3 is an X-ray diffraction pattern of the iron-doped titanium dioxide sonosensitizer synthesized in the first example;
FIG. 4 is a graph of the detection of ROS production by PEG-modified iron-doped titanium dioxide sonosensitizers under ultrasound conditions using DPBF probes in example two;
FIG. 5 is a graph showing the Fenton-like reaction effect of PEG-modified iron-doped titanium dioxide sonosensitizers detected by a TMB probe in example II;
FIG. 6 is the killing effect of PEG modified iron-doped titanium dioxide sonosensitizer on mouse breast cancer cells in example III;
FIG. 7 is a tumor growth inhibition curve for mice of different experimental groups;
FIG. 8 is a hematoxylin-eosin staining image of tumor within 30 days after intravenous injection of PBS or PEG modified iron-doped titanium dioxide sonosensitizer in example five;
FIG. 9 shows the results of the measurement of the titanium content in the organs and tissues of the mouse at different time points.
Detailed Description
The following examples are given to further illustrate the embodiments of the present invention. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
The first embodiment is as follows: synthesis and characterization of iron-doped titanium dioxide acoustic sensitizers:
synthesis of iron-doped titanium dioxide sonosensitizer (Fe-TiO) by high-temperature thermal decomposition strategy of metal organic precursor2) The method comprises the following steps:
firstly, uniformly mixing Fe precursor ferric acetylacetonate, Ti precursor titanium acetylacetonate, dibenzyl ether, oleic acid, oleylamine and dodecanediol, wherein the feeding molar ratio of the ferric acetylacetonate to the titanium acetylacetonate is 1:4, and the volume ratio of the dibenzyl ether to the oleic acid to the oleylamine is 20:5: 1. Heating the mixture to 140 ℃ under the protection of nitrogen;
secondly, keeping the temperature of the system at 140 ℃ for about 0.5 hour;
thirdly, heating the reaction system to 280 ℃, reacting for 1 hour, then stopping heating, and naturally cooling the reaction system to room temperature;
and fourthly, adding absolute ethyl alcohol with the same volume into the reaction product, centrifuging to obtain precipitate, and repeatedly washing with cyclohexane for multiple times to obtain the iron-doped titanium dioxide sound-sensitive agent with the particle size of 2-5 nanometers.
Then, the iron-doped titanium dioxide sound-sensitive agent is characterized, and the size and the morphology of the iron-doped titanium dioxide sound-sensitive agent are observed by using a transmission electron microscope (as shown in figure 1), and the result shows that the iron-doped titanium dioxide sound-sensitive agent has an ultra-small structure and uniform particle size distribution. Meanwhile, the signals of Fe, Ti and O are obvious through energy dispersive X-ray spectroscopy (EDX) (as shown in figure 2). Characterization of its crystal structure and pure TiO by X-ray diffractometer2The results of the structure of the nano-particles (as shown in figure 3) show that the iron-doped titanium dioxide sound-sensitive agent has obvious TiO2Characteristic peak, X diffraction peak and TiO2Substantially identical to the standard card (No. 21-1272).
Example two: iron-doped titanium dioxide acoustic sensitizer modification and acoustic-dynamic and chemical-dynamic effects
10mg of the iron-doped titanium dioxide prepared in example one were dispersed in chloroform, and 50mg of C were added18And (3) stirring the mixture at room temperature for 2 hours, blowing chloroform by using nitrogen, adding water, and dissolving again to obtain the PEG-modified iron-doped titanium dioxide aqueous solution.
The acoustic power and chemical power effects of the iron-doped titanium dioxide acoustic sensitizer are detected by two probes, namely 1, 3-diphenyl isobenzofuran (DPBF) and 3,3',5,5' -tetramethyl benzidine (TMB), respectively, the acoustic power effect is evaluated by the DPBF, and the chemical power effect is evaluated by the TMB. Wherein the ultrasonic irradiation condition is 40kHz and 3W/cm2The concentration of the sonosensitizer in the aqueous solution was 50. mu.g/mL. In addition, when detecting the TMB probe, H is also added into the PEG modified iron-doped titanium dioxide aqueous solution2O2，H2O2The concentration in the aqueous solution was 50. mu. mol/mL. As shown in fig. 4, under the action of ultrasound, the iron-doped titanium dioxide sonosensitizer significantly reduces the absorption characteristic peak (416 nm) of DPBF, i.e. means the generation of singlet oxygen; and with the extension of the ultrasonic irradiation time, the lower the ultraviolet absorption characteristic peak of the DPBF at 416 nanometers, which shows that the longer the ultrasonic irradiation time is, the more the output of the singlet oxygen is. As shown in FIG. 5, when the sonosensitizer is mixed with hydrogen peroxide, a distinct characteristic peak is generated at 662 nm by TMB, which represents the generation of hydroxyl radical; and as the ultrasonic irradiation time is prolonged, the higher the ultraviolet absorption characteristic peak of TMB at 662 nm, which shows that the longer the ultrasonic irradiation time is, the more the yield of hydroxyl radicals is.
Example three: killing of tumor cells by iron-doped titanium dioxide sonosensitizers
PEG-modified iron-doped titanium dioxide sonosensitizers of different concentrations were incubated with Human Umbilical Vein Endothelial Cells (HUVEC) and mouse breast cancer cells (4T1), respectively, for 12 hours, after which the sonosensitizer cytotoxicity was evaluated by MTT assay. The experiments were performed in 4 groups, including Control group (Control) and H2O2Group, US group, H2O2+ US group, wherein the test conditions of the control group are "material only or H only2O2(50. mu. mol) or sonication of cells onlyPhysical (40kHz, 3W/cm)2，10min)”。H2O2Test conditions of the group are "addition of Material and H2O2(50. mu. mol) ". The test conditions in the US group were "sonication of cells on the basis of added material (40kHz, 3W/cm)2，10min)”。H2O2The test conditions of the + US group are "addition of H on the basis of addition of material2O2(50. mu. mol) and sonication of the cells (40kHz, 3W/cm)2，10min)”。
Wherein the control group was subjected to five tests including TiO2Group, Fe3O4Packet, Fe-TiO2Grouping, applying only H2O2Grouping (Onlyh)2O2) Only performing ultrasonic probe irradiation grouping (Only US); h2O2Group, US group, H2O2+ US groups three further experiments were performed, including TiO2Group, Fe3O4Packet, Fe-TiO2And (4) grouping. In each of the above groups, TiO2Grouping mice injecting pure TiO2，Fe3O4Grouping mice to inject pure Fe3O4，Fe-TiO2Grouping mice were injected with PEG-modified iron-doped titanium dioxide prepared in example two, with application of H alone2O2Grouping mice to be injected with H2O2And only carrying out ultrasonic probe irradiation grouping and only carrying out ultrasonic probe irradiation on the mouse. As shown in FIG. 6, the PEG-modified iron-doped titanium dioxide sonosensitizer of the present invention has a certain killing effect on tumor cells. Moreover, the iron-doped titanium dioxide sonosensitizers show a high cell killing effect when tumor cells are treated with additional hydrogen peroxide and sonication.
Example four: acoustodynamic treatment of tumors with iron-doped titanium dioxide sonosensitizers
Five experiments were performed, Control and Fe-TiO respectively2(i.v.) group, US group, TiO2+ US (i.t.) group, Fe-TiO2Group + US (i.v.). Of these, PBS was annotated only to the tail vein of the control group. Fe-TiO2Group (i.v.) only intravenous PEG-modified iron-doped titanium dioxide sonosensitizers. US group only hyperimmunized tumorsAnd (4) performing acoustic treatment. TiO22+ US (i.t.) group tumor was injected with pure TiO2 and sonicated simultaneously. Fe-TiO2The + US (i.v.) group was prepared by injecting PEG-modified iron-doped titanium dioxide sonosensitizer prepared in example two into mice of a subcutaneous breast cancer model via tail vein and exposing the tumor site to ultrasonic irradiation, wherein the concentration of sonosensitizer was 4mg/mL and the injection dose was 200 μ L. From the growth curve of the tumor (fig. 7), there was little significant inhibition of the tumor by ultrasound irradiation alone, relative to the control group; the iron-doped titanium dioxide sound-sensitive agent without ultrasonic treatment has a certain inhibition effect on tumor growth; after ultrasonic treatment, the iron-doped titanium dioxide sound-sensitive agent has a remarkable inhibition effect on the growth of tumors.
Example five: biotoxicity evaluation of iron-doped titanium dioxide sonosensitizers
PBS and the PEG modified iron-doped titanium dioxide sound-sensitive agent prepared in example two were injected into healthy mice through tail vein, wherein the concentration of the sound-sensitive agent was 4mg/mL, and the injection dose was 200. mu.L. Mice injected with PBS were designated as a Control group (Control group). Mice were sacrificed randomly 1, 7 and 30 days after injection, the heart, liver, spleen, lung and kidney were dissected and divided into two portions, one portion of the organ was fixed in 4% formaldehyde solution (formalin), paraffin was embedded, hematoxylin-eosin staining was further performed according to a conventional procedure, and safety after injection of iron-doped titanium dioxide sonosensitizer was evaluated. Fig. 8 shows that the iron-doped titanium dioxide sound-sensitive agent has no obvious side effect on mice after being injected.
The other part of each organ and tissue was dissolved in aqua regia (volume ratio: 1:2) containing perchloric acid, and the content of titanium element in each organ was measured. The titanium content in the organs and tissues of the mice decreased significantly with time, indicating that the iron-doped titanium dioxide sonosensitizer was gradually metabolized from the mouse body (as shown in fig. 9). The above results all demonstrate the biological safety of iron-doped titanium dioxide sonosensitizers.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, it should be noted that, for those skilled in the art, many modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention.
Claims (10)
1. The application of doped titanium dioxide in preparing a sound-sensitive agent, wherein the doped titanium dioxide comprises titanium dioxide and transition metal doped in the titanium dioxide; the transition metal comprises one or more of iron, copper and manganese.
2. The use according to claim 1, wherein the process for the preparation of doped titanium dioxide comprises the following steps:
under a protective atmosphere, uniformly mixing a transition metal precursor and a titanium precursor in an oil phase at 100-160 ℃, reacting the obtained mixture at 260-280 ℃, and obtaining the doped titanium dioxide after the reaction is completed;
the transition metal precursor comprises one or more of organic metal salts of iron, copper and manganese.
3. Use according to claim 2, characterized in that: the molar ratio of the transition metal element in the transition metal precursor to the titanium element in the titanium precursor is 1 (1-8).
4. Use according to claim 2, characterized in that: the transition metal precursor is selected from one or more of iron acetylacetonate, copper acetylacetonate and manganese acetylacetonate.
5. Use according to claim 2, characterized in that: the titanium precursor is selected from titanium acetylacetonate.
6. Use according to any one of claims 1 to 5, characterized in that: the particle size of the doped titanium dioxide is 2-5 nanometers.
7. Use according to claim 1, characterized in that: the doped titanium dioxide is connected with an amphiphilic polymer, and the molecular weight of a hydrophilic chain segment of the amphiphilic polymer is 2kDa-5 kDa.
8. Use according to claim 1, characterized in that: the sonosensitizer is used in the presence of hydrogen peroxide.
9. Use according to claim 1 or 8, characterized in that: the sonosensitizer is used for the sonodynamic treatment of tumors.
10. Use according to claim 9, characterized in that: the ultrasonic power of the acoustic dynamic therapy is 2-10W/cm2The frequency is 10-50 kHz, and the action time is 1-30 min.
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| CN116519116A (en) * | 2023-03-30 | 2023-08-01 | 苏州大学 | Doped zinc-copper piezoelectric acoustic sensitizer and preparation method and application thereof |
| CN117860704A (en) * | 2024-03-12 | 2024-04-12 | 天津医科大学总医院 | Nanocomposite Fe/TNT@NM and preparation method and application thereof |
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