CN110882389A - Titanium monoxide nano material and preparation method and application thereof - Google Patents
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Abstract
The invention discloses a titanium monoxide nano material and a preparation method thereof. The titanium monoxide nano material obtained by the invention can generate a large amount of active oxygen under the ultrasonic condition, can be effectively used for the sonodynamic treatment of tumors, and has a sonodynamic treatment effect obviously better than that of the existing commercial nano material. The invention discloses an application of a titanium monoxide nano material in an anti-tumor preparation.
Description
Technical Field
The invention belongs to the field of nano material preparation and biomedicine, and particularly relates to a titanium monoxide nano material as well as a preparation method and application thereof.
Background
Cancer remains one of the most serious diseases threatening human health, and has become one of the problems to be overcome in urgent need worldwide. Photodynamic therapy (PDT) has achieved good efficacy over the past few decades as a non-invasive treatment. However, due to the limited tissue penetration depth of light, PDT is often used to treat relatively small superficial tumors. Furthermore, severe skin phototoxicity following systemic administration of photosensitizers is another problem facing the clinical use of PDT.
As an alternative to PDT, sonodynamic therapy (SDT) uses active oxygen generated by ultrasound-triggered sonosensitizers to kill cancer cells with minimal damage to healthy tissue. Unlike light, ultrasound penetrates tissue to a significantly greater depth than light, and thus can be used to treat deep or large-sized tumors using sonodynamic forces. Thus, SDT has significant advantages over traditional PDT and has become a promising non-invasive tumor treatment strategy. Like the photosensitizers of PDT, the choice of sonosensitizer is critical for SDT. The acoustic sensitivity agent is mainly divided into inorganic and organic acoustic sensitivity agents. Most of the organic sonosensitizers are porphyrin derivatives and other fat-soluble micromolecules, the water solubility is poor, the stability under the ultrasonic condition is poor, the in-vitro clearing is fast, and the enrichment degree of tumor parts is low, so the traditional SDT has an unsatisfactory curative effect. In addition, most organic sonosensitizers are also photosensitizers, and phototoxicity and skin sensitivity remain a very problematic problem in the cancer treatment phase.
Compared with organic sonosensitizers, inorganic nano sonosensitizers have higher chemical stability and lower phototoxicity, however, the existing TiO has2Nanoparticles are used as sonosensitizers, and the low quantum yield of active oxygen generation is mainly due to the rapid electron-hole recombination, and the poor treatment effect of SDT limits the further use of SDT. Therefore, the development of a novel efficient and safe acoustic sensitizer has important significance for enhancing the ultrasonic treatment of tumors. Although there are prior art methods of forming TiO by sintering2Nano material, noble metal and grapheneAnd other transition metal oxides, but the treatment effect is still unsatisfactory, and various problems such as unstable performance caused by complex synthesis method and poor controllability of component ratio need to be improved.
Disclosure of Invention
In order to avoid the defects of the prior art, the invention provides a titanium monoxide (TiO) nano material and a preparation method and application thereof, aiming at synthesizing the titanium monoxide nano material which has higher yield and high purity, has high quantum yield of active oxygen of the obtained nano material, and has excellent biocompatibility and dispersibility by a one-step method, and applying the titanium monoxide nano material to the sonodynamic therapy and the chemodynamic therapy of tumors.
The invention provides a titanium monoxide nano material, which is a nano rod, and the surface of the titanium monoxide nano material is provided with an amphiphilic molecule modification layer.
Optionally, the particle size range of the titanium monoxide nano-rod is 1-500 nm.
Optionally, the length range of the titanium monoxide nanorod is 10-120 nm. The size range can have better nanometer characteristics and biomaterial applicability. The rodlike titanium monoxide nanometer material can reduce the electron hole recombination rate, thereby being beneficial to improving the quantum yield of active oxygen.
The invention provides a preparation method of the titanium monoxide nano material, which comprises the following steps:
s10: preparing a titanium source and a reductive high-boiling-point organic solvent, mixing the titanium source and the reductive high-boiling-point organic solvent to obtain a mixed solution;
s20: heating the mixed solution to a second temperature range, and reacting to obtain a hydrophobic titanium monoxide nano material; optionally, the second temperature range is 200-350 ℃.
Optionally, after obtaining the hydrophobic titanium monoxide nanomaterial, the method further comprises the steps of:
s30: and (3) carrying out surface modification on the hydrophobic titanium monoxide nanometer material by using amphiphilic molecules to obtain the hydrophilic titanium monoxide nanometer material. The titanium monoxide nano material subjected to surface modification is changed from oil phase to water phase, so that the nano rod has better biocompatibility and application potential in the field of biomedical materials.
Optionally, before the step S20 of heating the mixed liquid to the second temperature interval, the method further includes the steps of:
s11: the mixed liquid is heated to a first temperature interval so as to remove moisture and oxygen in the mixed liquid. By utilizing the step, the yield and the purity of the titanium monoxide nano material can be improved, the titanium monoxide nano rod is prevented from being oxidized due to water oxygen of the solvent, and the yield and the purity of the titanium monoxide nano material are reduced.
Optionally, the first temperature range for removing moisture and oxygen in the mixed solution to be reacted is 100-160 ℃.
Optionally, the titanium source used in step S10 is selected from one or more of titanium tetrachloride, tetrabutyl titanate, difluorooxytitanium, oxytitanium sulfate, titanyl acetylacetonate, titanium sulfate, and titanium isopropoxide.
Optionally, the reducing high-boiling organic solvent used in step S10 carries an amino group;
preferably, the reductive high-boiling organic solvent used in step S10 comprises one or more of oleylamine and its derivatives, high-boiling enamines, diaminodiphenylmethane, and acetamides.
Alternatively, in step S10, other solvents such as octadecene, dodecanol, benzyl ether, etc. may be used in combination with the reductive high-boiling point organic solvent. The use of these solvents may provide a higher boiling range for some lower boiling reductive high boiling organic solvents, thereby increasing the range of choices for reductive organic solvents.
Optionally, the amphiphilic molecule used in step S30 is one or more of phospholipid polyethylene glycol, allyl polyethylene glycol, thiol polyethylene glycol, and methoxy polyethylene glycol.
Optionally, the reaction time of step S30 is 1-120 min. Preferably, the reaction time of step S30 is 10-50 min. The coverage rate of the modification layer of the titanium monoxide nanorod can be regulated and controlled in different reaction time, so that the amphiphilic characteristic of the titanium monoxide nanorod is regulated and controlled, the reaction time of the titanium monoxide nanorod can be regulated and controlled as required, target materials with different hydrophilic characteristics or different sound sensitivity characteristics are prepared, and the application scenes of the titanium monoxide nanorod are increased or the requirements under different scenes are met.
Optionally, the reaction environment of each step is an inert gas environment atmosphere. The inert gas atmosphere can improve the yield and the purity of the titanium monoxide nano material, avoid the oxidation of the titanium monoxide nano rod due to solvent water oxygen, and reduce the yield and the purity of the titanium monoxide nano material.
Optionally, the reaction environment of each step is nitrogen or argon atmosphere.
Optionally, the reaction environment of each step is a low vacuum reaction condition. However, the boiling point of the reducing high-boiling organic solvent is lowered under the reaction condition of low vacuum, thereby reducing the selection range of the organic solvent or limiting the adjustment range of the reaction temperature.
The invention further discloses application of the titanium monoxide nano material in an anti-tumor preparation.
Furthermore, the titanium monoxide nano material is mainly applied to the preparation of a sound sensitive preparation and/or a chemical power preparation in an anti-tumor preparation.
The invention has the beneficial effects that:
1. the synthesized TiO nano material has the advantages of regular shape, uniform size, simple and rapid synthesis method, high yield, high purity and convenience for repeated and large-scale production;
2. the TiO nano material prepared by the invention has good biocompatibility in the presence of H2O2Under the condition of (2), a large amount of hydroxyl free radicals can be generated, and the compound can be used for the chemodynamic treatment of tumors;
3. the TiO nano material prepared by the invention can generate a large amount of active oxygen under the ultrasonic condition, the performance of the acoustic power of the TiO nano material is obviously stronger than that of a commercial acoustic sensitive nano material, and the TiO nano material can be used for the acoustic power treatment of tumors.
The invention has higher yield through one-step synthesisHigh purity titanium monoxide nano rod, the obtained titanium monoxide nano rod has high quantum yield of active oxygen, and H exists2O2Generates a large amount of hydroxyl free radicals at any time, has excellent biocompatibility and dispersibility, and has great potential in sonodynamic treatment and chemodynamic treatment of tumors and preparation.
Drawings
FIG. 1 is an X-ray diffraction pattern of a TiO nanomaterial obtained in example A1 of the present invention;
FIG. 2 is a transmission electron microscope image of the TiO nano material obtained in example A1 of the present invention;
FIG. 3 is a diagram showing the in vitro acoustic dynamics of the PEG-TiO nanomaterial of the present invention;
FIG. 4 is a chemical kinetic diagram of the PEG-TiO nanomaterial measured by different probes according to the present invention;
FIG. 5 is a graph of toxicity evaluation of different concentrations of PEG-TiO nanomaterials on HUEVCs and 4T1 cells;
FIG. 6 is a diagram showing the killing effect of different concentrations of PEG-TiO nanomaterials;
FIG. 7 is a graph showing the tumor treatment curve of the TiO nanomaterial on tumor-bearing mice.
Detailed Description
The following examples are given to illustrate the present invention, and the following examples are carried out on the premise of the technical solution of the present invention, and give detailed embodiments and specific procedures, but the scope of the present invention is not limited to the following examples.
Example A1 preparation of TiO nanomaterials
(1) 110 microlitres of TiCl4Adding into 20mL oleylamine and 10mL octadecene, heating to 140 deg.C, and maintaining for 30min for removing water and oxygen;
(2) heating the mixture to 320 ℃, keeping the temperature for 1 hour, and then cooling to room temperature;
(3) adding excessive ethanol into the obtained product for precipitation, and repeatedly washing and centrifuging the product for multiple times by using dichloromethane to obtain the hydrophobic TiO nano material.
As shown in FIG. 1, which is an X-ray diffraction pattern of the TiO nanomaterial obtained in example 1, corresponding to JCPDS standard cards 23-1078, it was confirmed that the synthesized product was TiO.
FIG. 2 is a transmission electron microscope image of the TiO nanomaterial obtained in example A1, from which it can be seen that the sample has a uniform morphology, a uniform rod-like morphology, and a size of 1-50 nm.
Example A2 preparation of TiO nanomaterials
(1) 110 microlitres of TiCl4Adding into 30mL diaminodiphenylmethane, heating to 140 deg.C, and maintaining for 30min for removing water and oxygen;
(2) heating the mixture to 220 ℃, keeping the temperature for 1 hour, and then cooling to room temperature;
(3) adding excessive ethanol into the obtained product for precipitation, and repeatedly washing and centrifuging the product for multiple times by using dichloromethane to obtain the hydrophobic TiO nano material.
Example B1 polyethylene glycol modification of TiO nanomaterial surface
Collecting chloroform solution containing 5mg TiO nano material synthesized in A1, adding chloroform solution containing 25mg polyethylene glycol grafted polymaleic anhydride-1-octadecene (C18PMH-PEG), and ultrasonic treating for 30min to completely mix; then carrying out reduced pressure rotary evaporation to remove the organic solvent in the film to form a film; adding ultrapure water, and performing ultrasonic dispersion to obtain an aqueous solution; removing redundant polyethylene glycol molecules in the solution by centrifugal ultrafiltration to obtain a polyethylene glycol modified TiO (PEG-TiO) nano material aqueous solution.
Example C1 Acoustic dynamic Performance of in vitro TiO nanomaterials
50 μ g/mL of PEG-TiO nanomaterial and 20 μ g/mL of 1,3 Diphenylisobenzofuran (DPBF) were dissolved in 3.0mL of phosphate buffer (pH 7.4) and sonicated (40kHz, 3.0W/cm)2) The solutions were tested for uv absorption at different times. DPBF is a probe for detecting active oxygen, and the absorption of the characteristic peak at 420nm gradually decreases with the generation of active oxygen.
FIG. 3 is a representation of the acoustic dynamics of PEG-TiO nanomaterials in vitro (using 1,3 diphenyl isobenzofuran probes); with the prolongation of the ultrasonic time, the absorption value of the characteristic peak of the DPBF at 420nm is observed to be gradually reduced, which shows that the PEG-TiO nano material can generate a large amount of active oxygen under the ultrasonic condition, and the PEG-TiO nano material has good acoustic dynamic performance in vitro.
Example C2 chemical kinetics of PEG-TiO nanomaterials
Mixing 50 mu g/mL PEG-TiO nano material with H with different concentrations2O2(0,0.02,0.05,0.1,0.2,0.5, and 1.0mM) were mixed in 1.0mL of an acetate-acetate buffer (0.1M, pH 4.5), followed by addition of 1.0mM o-phenylenediamine or 0.5 mM 3,3,5, 5-tetramethylbenzidine, incubation for 30min, and then uv absorption was tested. O-phenylenediamine (OPDA) and 3,3,5, 5-Tetramethylbenzidine (TMB) are probes for detecting hydroxyl radicals, and the hydroxyl radicals cause the probes to generate color reaction, so that the solution is changed from colorless to yellow or blue, and the absorption value of the corresponding characteristic peak is higher and higher.
FIG. 4 shows the chemical kinetics of the PEG-TiO nanomaterial measured with different probes. O-phenylenediamine (OPDA) and 3,3,5, 5-Tetramethylbenzidine (TMB) are probes for detecting hydroxyl radicals, wherein (a) is an o-phenylenediamine probe and (b) is a 3,3,5, 5-tetramethylbenzidine probe. When o-phenylenediamine is used as a probe, H is followed2O2The concentration of the PEG-TiO is increased, and the absorption value of the PEG-TiO at 416nm is gradually increased, which indicates that the PEG-TiO is in H2O2In the presence of the catalyst, hydroxyl radicals are generated, so that the o-phenylenediamine is developed. Similarly, when 3,3,5, 5-tetramethylbenzidine was used as a probe, it was also found that the ultraviolet absorption value at 654nm of the characteristic peak thereof also varied with H2O2The concentration gradually increases. The above results indicate that PEG-TiO can be used as a good Fenton-like reagent in the presence of H2O2Under the condition, a large amount of hydroxyl free radicals can be generated, which suggests that the compound has good application prospect in the chemical dynamic therapy of tumors.
Example C3 in vitro cell assay of TiO nanomaterials
PEG-TiO nano materials with different concentrations are incubated with human umbilical vein endothelial cells (HUEVCs) or mouse breast cancer (4T1) cells for 24h, and then the standard is usedThe quasi-MTT method was used to test the cellular activity. PEG-TiO nano material and H with different concentrations2O2After mixing, the cells were incubated with 4T1 cells for 24h to evaluate the effect of its chemodynamic therapy. PEG-TiO nano material ultrasonic (40kHz, 3.0W/cm)2) The treatment effect of the acoustodynamic force of the cells was evaluated by incubating the cells with 4T1 for 24 hours after 3 min. PEG-TiO nano material and H with different concentrations2O2After mixing, ultrasound was performed for 3min, and then the PEG-TiO nanomaterial was incubated with 4T1 cells for 24h to evaluate the effect of the PEG-TiO nanomaterial combined therapy of sonodynamic-chemical dynamic therapy.
FIG. 5 is a graph of toxicity evaluation of different concentrations of PEG-TiO nanomaterials on HUEVCs and 4T1 cells. The TiO nano materials with different concentrations do not cause any obvious toxicity to HUEVCs cells, and the PEG-TiO nano material has good biocompatibility. Interestingly, the PEG-TiO nano material has certain toxicity to 4T1 cells, mainly because 4T1 is a cancer cell line and H in the cancer cells2O2The concentration of the PEG-TiO nano material is far higher than that of normal cells, and the PEG-TiO nano material and H2O2The generated hydroxyl free radical is reacted, so that the PEG-TiO nano material has certain toxicity to 4T1 cells.
Fig. 6 is a graph showing the chemokinetic killing performance of PEG-TiO nanomaterials with different concentrations (a) on 4T1 at the cell level, (b) acoustic kinetic killing performance (US) and chemokinetic-acoustic kinetic killing performance. With H2O2The killing effect of the PEG-TiO nano material on 4T1 cells is further enhanced due to the increase of the content, mainly H2O2The chemical power performance of the PEG-TiO nano material is further enhanced. After the PEG-TiO nano material is mixed with 4T1 cells and irradiated by ultrasound for 3min, the activity of the 4T1 cells is obviously reduced, which shows that the PEG-TiO nano material has good sonodynamic treatment effect in vitro; PEG-TiO nano material and H with different concentrations2O2After mixing and then carrying out ultrasonic treatment for 3min, the activity of 4T1 cells is further reduced, and the treatment effect of the composition is stronger than that of a single chemical dynamic treatment group and a single acoustic dynamic treatment group, which shows that the PEG-TiO nano material has good curative effect on treating tumors by combining the acoustic dynamic treatment and the chemical dynamic treatment.
Example C4 therapeutic experiment of PEG-TiO nanomaterial in vivo
FIG. 7 is a graph showing the tumor treatment curve of the TiO nanomaterial on tumor-bearing mice. 4T1 tumor-bearing mice (tumor size: -100 mm)3) Randomized into 5 groups (5 per group):
group (1) was a control group (control) to which only PBS was injected;
the group (2) was an ultrasonic group (US) of ultrasonic waves only (40kHz, 3.0W/cm)2，5min)；
Group (3) is material group (TiO NRs), PEG-TiO nano rod is injected (intravenous injection, 10 mg/kg);
group (4) is TiO2Ultrasonic treatment group (TiO)2NPs + US), injectable commercial nano TiO2Nanoparticles (intratumoral injection i.t., 2.5mg/kg) + ultrasound (40kHz,3.0W/cm25min, 50% duty cycle);
group (5) is TiO ultrasound treatment group (TiO NRs + US), PEG-TiO nanorod (intravenous i.v., 10mg/kg) + US (40kHz, 3.0W/cm)25 minutes). Tumors were treated with ultrasound irradiation 24 hours after intravenous injection or 1 hour after intratumoral injection and repeated on days 1 and 2. Tumor size was measured and recorded every two days. Tumor volume was determined by the following equation: volume is length x width2/2。
Compared with the control group, the group (3) is the independent chemical dynamic treatment group which only shows weak treatment effect, and in the group (5), after the PEG-TiO nano material is combined and irradiated, the growth of the tumor is obviously inhibited, and the treatment effect of the PEG-TiO nano material is obviously stronger than that of the commercial TiO2 nano material.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
Claims (10)
1. A titanium monoxide nanomaterial, characterized in that: the titanium monoxide nano material is a titanium monoxide nano rod, and the surface of the titanium monoxide nano rod is provided with an amphiphilic molecule modification layer.
2. A method for preparing a titanium monoxide nanomaterial as defined in claim 1, comprising the steps of:
s10: preparing a titanium source and a reductive high-boiling-point organic solvent, and mixing the titanium source and the reductive high-boiling-point organic solvent to obtain a mixed solution;
s20: heating the mixed solution to a second temperature range, and reacting to obtain a hydrophobic titanium monoxide nano material; optionally, the second temperature range is 200-350 ℃.
3. The method of claim 2, further comprising the steps of:
s30: and (3) carrying out surface modification on the hydrophobic titanium monoxide nanometer material by using amphiphilic molecules to obtain the hydrophilic titanium monoxide nanometer material.
4. The method of claim 2, wherein before the step of heating the mixture to the second temperature range in step S20, the method further comprises the steps of:
s11: heating the mixed solution to a first temperature range so as to remove moisture and oxygen in the mixed solution; optionally, the first temperature range is 100-160 ℃.
5. The method of claim 2, wherein: the titanium source is one or more of titanium tetrachloride, tetrabutyl titanate, difluorooxytitanium, titanyl sulfate, acetylacetonatotitanyl, titanium sulfate and titanium isopropoxide.
6. The method of claim 2, wherein: the reducing high-boiling organic solvent; preferably, the reductive high-boiling organic solvent comprises one or more of oleylamine, high-boiling enamine, diaminodiphenylmethane, acetamide.
7. The production method according to claim 3, characterized in that: the amphiphilic molecule is one or more of phospholipid polyethylene glycol, allyl polyethylene glycol, sulfhydryl polyethylene glycol and methoxy polyethylene glycol.
8. The production method according to any one of claims 2 to 4, characterized in that: the reaction environment of each step is inert gas atmosphere.
9. Use of a titanium monoxide nanomaterial obtained by the method of any one of claims 1 to 8 in an anti-tumour formulation.
10. Use according to claim 9, characterized in that: the anti-tumor preparation is a sound sensitive preparation and/or a chemical power preparation.
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|---|---|---|---|---|
| CN112807430A (en) * | 2020-12-28 | 2021-05-18 | 景香香 | Application of nano enzyme-based material |
| RU2758402C1 (en) * | 2021-04-15 | 2021-10-28 | Федеральное государственное бюджетное учреждение науки Институт химии твердого тела Уральского отделения Российской академии наук | Method for producing a single crystal of titanium monoxide |
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