CN114259560B - Doped metal sulfide and preparation and application thereof - Google Patents
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Abstract
The invention relates to a doped metal sulfide and preparation and application thereof. The preparation method of the doped metal sulfide comprises the following steps: under the protective atmosphere, uniformly mixing a doped metal source and a doped metal source in an oil phase at 100-160 ℃, then reacting the obtained mixture with a sulfur source at 240-320 ℃, and obtaining the doped metal sulfide after the reaction is completed; the invention also discloses application of the doped metal sulfide in preparation of sound sensitive agent. The doped metal sulfide can be used for preparing sound-sensitive agents, and has good killing effect on tumors, and good biosafety and biodegradability.
Description
Technical Field
The invention relates to the field of functional nano materials and tumor treatment preparations, in particular to a doped metal sulfide and preparation and application thereof.
Background
Cancer is one of the major diseases threatening human health in the 21 st century. The current mainstream treatment methods, including surgery, chemotherapy and radiotherapy, have different degrees of side effects, and have great limitations on the treatment of metastasis, which seriously affect the life quality of patients.
Sonodynamic therapy (Sonodynamic therapy, SDT) is a novel high permeability tumor treatment method, and its main killing mechanism is active oxygen (ROS) generated by sonosensitizer under the action of ultrasound and cavitation effect generated by ultrasound irradiation. ROS include hydroxyl radicals (. OH), singlet oxygen [ ] 1 O 2 ) And the like, can cause a series of biochemical reactions such as reduction of mitochondrial membrane potential, DNA fragmentation, cytoskeletal contraction, chromatin concentration and the like in cells, and lead to tumor cellsApoptosis.
The existing sound-sensitive agent mainly comprises porphyrin, derivatives thereof and other organic sound-sensitive agents and titanium dioxide (TiO 2 ) Is a representative inorganic sound sensitizer. However, organic sonosensitizers are not readily soluble in water and have some phototoxicity, whereas inorganic sonosensitizers have greater potential toxicity due to low sonodynamic efficiency and long-term residence in the body. Therefore, the development of a safe and efficient tumor sonosensitizer is a key problem to be solved in the process of sonodynamic treatment of cancers.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide the doped metal sulfide and the preparation and application thereof, and the doped metal sulfide can be used for preparing the sound-sensitive agent, and has good killing effect on tumors, and also has good biological safety and biodegradability.
A first object of the present invention is to provide a method for preparing a doped metal sulfide, comprising the steps of:
under the protective atmosphere, uniformly mixing a doped metal source and a doped metal source in an oil phase at 100-160 ℃, then reacting the obtained mixture with a sulfur source at 240-320 ℃, and obtaining the doped metal sulfide after the reaction is completed;
wherein the doped metal source is one or more of ferric salt, manganese salt and cupric salt;
the doped metal source is one or more of vanadium salt, titanium salt and molybdenum salt.
Preferably, the doped metal source is ferric salt, the doped metal source is vanadium salt, and the prepared doped metal sulfide is Fe-VS 2 ，VS 2 As a semiconductor material, by doping elements with atomic radii and electronegativity similar to those of the semiconductor material, the band gap of the semiconductor material under the excitation of external energy can be reduced, and the acoustic dynamics effect of the semiconductor material can be improved. Fe-VS of the present invention 2 Is about 2.33eV, while VS 2 Is about 2.48eV.
In addition, the doping element Fe not only can improve the sound dynamics effect, but also hasHas therapeutic effects such as participation in Fenton's reaction, and can be used for treating tumor with high concentration hydrogen peroxide (H 2 O 2 ) Is converted into hydroxyl free radicals, thereby achieving the effect of killing tumor cells.
Further, the molar ratio of metal in the doped metal source to metal in the doped metal source is 1: (4-10).
Further, the ferric salt is selected from one or more of ferric trichloride, ferric acetylacetonate and ferrous acetylacetonate. Preferably, the iron salt is ferric trichloride.
Further, the vanadium salt is selected from vanadium chloride (VCl) 4 ) And/or vanadium acetylacetonate. Preferably, the vanadium salt is vanadium chloride.
Further, the sulfur source is selected from elemental sulfur and/or thioacetamide. Preferably, the sulfur source is elemental sulfur.
Further, the molar ratio of the sulfur source to the metal in the doped metal source is (2-5): 1.
further, the oil phase comprises oleylamine and octadecene.
Further, the molar ratio of the oleylamine to the octadecene is 1: (0.5-1.5).
Further, the reaction temperature of the catalyst and the sulfur source is 300-320 ℃ and the reaction time is 0.5-2 h.
Further, the protective atmosphere is an inert gas atmosphere such as nitrogen.
Further, the reaction is completed, and the method also comprises the steps of adding ethanol into the product, centrifuging to obtain precipitate and washing.
Preferably, the preparation method of the doped metal sulfide comprises the following steps:
a) Uniformly mixing a doped metal source, oleylamine and octadecene, and heating to 120-160 ℃;
b) Maintaining the temperature at 120-160 ℃, adding a doped metal source, and reacting to obtain a primary reactant;
c) Heating to 240-320 deg.c, adding sulfur source and reaction to obtain doped metal sulfide. At these temperatures, the sulfur source may react directly with the metal.
A second object of the present invention is to provide a doped metal sulfide prepared by the above preparation method, wherein the particle size of the doped metal sulfide is 80 to 150 nm.
Preferably, the doped metal sulfide of the present invention is Fe doped VS 2 (Fe-VS 2 )。
A third object of the present invention is to disclose the use of the above-mentioned doped metal sulphide for the preparation of a sonosensitizer.
Further, the doped metal sulfide is connected with an amphiphilic polymer, and the molecular weight of a hydrophilic chain segment of the amphiphilic polymer is 2kDa-5kDa. Because the surface of the doped metal sulfide is hydrophobic, in practical application, the hydrophobic end of the amphiphilic polymer and the hydrophobic end of the surface of the metal sulfide are subjected to electrostatic interaction, and the hydrophilic end is wrapped outside the hydrophobic end of the amphiphilic polymer and the metal sulfide. Thus, the water solubility of the doped metal sulfide can be improved, and the biocompatibility of the doped metal sulfide can be improved.
Further, the hydrophobic chain segment of the amphiphilic polymer is C 18 -PMH. The hydrophilic end is polyethylene glycol (PEG).
Preferably, the amphiphilic polymer is C 18 PMH-PEG, methods of synthesis referred to in the literature as "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, sonosensitizers are used in sonodynamic treatment of tumors.
Further, the ultrasonic power of the sonodynamic therapy is 2-10W/cm 2 The frequency is 10-50 kHz, and the action time is 1-30 min. In practical application, an ultrasonic probe is used as a sound source for ultrasonic irradiation.
Further, tumors include 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. To be a free electron or hole, the bound electron must acquire enough energy to transition from the valence band to the conduction band. The minimum of this energy is the band gap. The smaller the band gap, the easier the electron transition. The doped metal source and the doped metal source are both transition metal elements. The sulfide of the doped metal is a semiconductor, and by doping the elements with the atomic radius and electronegativity similar to the elements with the atomic radius and electronegativity, the band gap of the doped metal under the excitation of external energy can be reduced, so that the acoustic dynamics effect of the doped metal is improved.
After the sound-sensitive agent containing the doped metal sulfide provided by the invention is injected intravenously and reaches a focus part, the sound-sensitive agent containing the doped metal sulfide can obviously inhibit the growth of tumors by ultrasonic irradiation, and the sound-sensitive agent containing the doped metal sulfide has great application value in the aspect of cancer treatment.
By means of the scheme, the invention has at least the following advantages:
(1) The doped metal sulfide prepared by the method has a lower band gap and good acoustic dynamic effect.
(2) When the doped metal sulfide obtained by the invention is used as a sound sensitizer, the doped metal sulfide has good killing effect on tumors.
(3) When the doped metal sulfide obtained by the invention is used as a sound sensitive agent, the doped metal sulfide can be biologically metabolized, and has good biological safety.
The foregoing description is only an overview of the present invention, and is presented in terms of preferred embodiments of the present invention and the following detailed description of the invention in conjunction with the accompanying drawings.
Drawings
FIG. 1 is a schematic illustration of the synthesis of Fe-doped VS in example one 2 A sonosensitizer transmission electron microscope image;
FIG. 2 is a schematic representation of the synthesis of Fe-doped VS in example one 2 An X-ray diffraction pattern of the sound-sensitive agent;
FIG. 3 is a synthetic Fe-doped VS of example one 2 Element TEM-mapping characterization results of the sound sensitive agent;
FIG. 4 is a schematic diagram of a DPBF probe for detecting Fe-doped VS in the second embodiment 2 ROS release of the sound sensitizer under ultrasonic irradiation;
FIG. 5 is a schematic illustration of detection of Fe doped VS with TMB probe in example two 2 ROS release of the sound sensitizer under ultrasonic irradiation;
FIG. 6 is a plot of VS doped with Fe at different concentrations in the third embodiment 2 Killing human umbilical vein endothelial cells by the sound sensitizer;
FIG. 7 is a plot of VS doped with Fe at different concentrations in the third embodiment 2 Killing mouse breast cancer cells by the combination of the sound sensitizer and ultrasonic irradiation;
FIG. 8 is an intravenous Fe-doped VS of example four 2 Magnetic resonance imaging pictures of mice at different time points after the sound sensitive agent;
FIG. 9 is an intravenous Fe-doped VS of example four 2 Magnetic resonance signal intensity of mice at different time points after the sonosensitizer;
FIG. 10 is an intravenous Fe-doped VS of example four 2 Photoacoustic imaging pictures of mice at different time points after the acoustic sensitizer;
FIG. 11 is a fine intravenous Fe-doped VS of example four 2 Photoacoustic signal intensity of mice at different time points after the sonosensitizer;
FIG. 12 is an intravenous Fe-doped VS of example five 2 Mouse tumor growth curve after sonosensitizer;
FIG. 13 is an intravenous Fe-doped VS of example five 2 Mouse survival curve after sonosensitizer;
FIG. 14 is an intravenous Fe-doped VS of example five 2 Tumor hematoxylin-eosin staining images after 4 days of sonosensitizer;
FIG. 15 is an intravenous Fe-doped VS of example six 2 Sonosensitizer Fe-doped VS in main organs of mice after 0.5, 1, 7 and 30 days 2 Content of sound sensitive agent;
FIG. 16 is an intravenous PBS and an intravenous Fe-doped VS in example six 2 The images of the main organ hematoxylin-eosin staining of the mice after 7 days and 30 days of the sonosensitizer;
FIG. 17 is an intravenous PBS and an intravenous Fe-doped VS in example six 2 Mouse blood biochemical index and blood normothermia after 7 days and 30 days of sound sensitizerThe gauge detects the data.
Detailed Description
The following describes the embodiments of the present invention in further detail with reference to examples. The following examples are illustrative of the invention and are not intended to limit the scope of the invention.
Embodiment one: synthesis and characterization of Fe-doped VS 2 Acoustic sensitizer:
fe doped VS synthesized by high temperature oil phase method 2 The sound sensitizer comprises the following steps:
first, doping metal source FeCl 3 Uniformly mixing oleylamine and octadecene (the mol ratio of oleylamine to octadecene is 1:0.5-1.5), and heating a reaction system to 120 ℃ under the protection of nitrogen;
a second step of adding a doped metal source VCl to the mixture while maintaining the system temperature at 120 DEG C 4 The method comprises the steps of carrying out a first treatment on the surface of the Wherein VCl 4 And FeCl 3 The molar ratio of (2) is 9.5:1;
thirdly, continuously heating the reaction system to 300 ℃, and adding a sulfur source (elemental sulfur dissolved in oleylamine) into the mixture, wherein S and VCl in the sulfur source 4 The molar ratio of (2) to (1) is 2.5:1, then the reaction is fully carried out for 1 hour at 320 ℃, the heating is stopped, and the temperature of the reaction system is reduced to room temperature;
fourthly, absolute ethyl alcohol is added into the reaction product, the sediment is centrifugally taken, and the sediment is repeatedly washed by cyclohexane to obtain Fe doped VS with the grain diameter of 80 to 150 nanometers 2 An acoustic sensitizer.
VS doped with Fe 2 The sonosensitizer was characterized and the transmission electron microscope image was shown in FIG. 1, which shows Fe doped VS 2 The sound-sensitive agent is of a two-dimensional nano-sheet structure. Fe doped VS 2 The X-ray diffraction pattern of the sonosensitizer is shown in FIG. 2, and the result shows that the Fe doped VS 2 The sound sensitizer has obvious VS 2 Characteristic peaks. Fe doped VS 2 The element TEM-mapping characterization result of the sound sensitive agent is shown in figure 3, figure 3a is an element combination diagram of figures 3b-d, figures 3b, c and d are element diagrams of Fe, S and V in sequence, and the result shows that the three elements are uniformly distributed in the sound sensitive agent, and the success of doping Fe into VS is proved 2 Among them.
Embodiment two: fe doped VS 2 Acoustic sensitizer modification and ROS release under ultrasonic irradiation
10mg of Fe-doped VS prepared in example one 2 Dispersing in dichloromethane by ultrasonic wave, adding 20mgC 18 PMH-PEG, stirring at room temperature for 30min, removing dichloromethane, and ultrasonic dispersing in water to obtain Fe doped VS 2 -PEG aqueous solution.
Detection of Fe-doped VS with two probes of 1, 3-biphenylyl-isocoumarone 2, 5-diphenyl-3, 4-benzofuran (DPBF) and 3,3', 5' -Tetramethylbenzidine (TMB) 2 ROS release of PEG sonosensitizer under ultrasound irradiation at 40kHz,3W/cm 2 The concentration of the sonosensitizer was 5. Mu.g/mL. The results are shown in FIG. 4, where under ultrasonic irradiation, fe-doped VS 2 The sound sensitizer can generate singlet oxygen, so that the ultraviolet absorption characteristic peak of DPBF at 416 nanometers is reduced; under ultrasonic irradiation, as shown in FIG. 5, fe-doped VS 2 The sonosensitizer may generate hydroxyl radicals that raise the characteristic peak of ultraviolet absorption of TMB at 654 nm. And in fig. 4-5, as the ultrasonic irradiation time is prolonged, the lower the ultraviolet absorption characteristic peak of the DPBF at 416 nanometers and the higher the ultraviolet absorption characteristic peak of the TMB at 654 nanometers are, which indicates that the longer the ultrasonic irradiation time is, the more the yield of singlet oxygen and hydroxyl free radicals is.
Embodiment III: fe doped VS 2 Killing of tumor cells by sonosensitizer:
different concentrations of Fe doped VS prepared in example two 2 PEG sonosensitizers incubated with Human Umbilical Vein Endothelial Cells (HUVEC) and mouse breast cancer cells (4T 1) for 12 hours, designated HUVEC group and Fe-VS, respectively 2 A group. In addition, the power used for the breast cancer cells of the mice after partial incubation is 4.5W/cm 2 Irradiating for 5 min with ultrasonic probe, and recording as Fe-VS 2 + US group. The results are shown in FIGS. 6 and 7, with Fe-doped VS at a concentration of 3.13-100. Mu.g/mL 2 The sonosensitizer has no significant cytotoxicity to normal cells (human umbilical vein endothelial cells). The compound has stronger cell killing effect on mouse breast cancer cells and is doped with VS along with Fe 2 Increasing concentration of sonosensitizer in miceThe greater the killing power of breast cancer cells. Furthermore, as can be seen from FIG. 7, fe-VS 2 The killing power of +US group to mouse breast cancer cells is higher than that of Fe-VS irradiated by an ultrasonic probe 2 A group.
Embodiment four: fe doped VS 2 Imaging of acoustic sensitizer retention within tumor:
fe-doped VS prepared in example two by intravenous injection 2 The PEG sonosensitizer aqueous solution was injected into mice of the subcutaneous breast cancer model, the tumor sites were exposed to ultrasound irradiation, and their magnetic resonance signals were tested, with sonosensitizer concentration of 1mg/mL, injection dose of 150. Mu.L, magnetic resonance conditions of TR (repetition time) 3000ms, TE (echo time) 82ms. A significant magnetic resonance signal was observed at the tumor site of the mice before (Pre in fig. 8a, 9), after (post (i.v.) in fig. 8b, 9) injection as shown in fig. 8 and 9; at different time points, photoacoustic imaging is shown in fig. 10 and 11, and fig. 10a, b, c, d are the results of magnetic resonance tests at 0h, 2h, 12h and 24h, respectively, showing Fe doped VS 2 The sonosensitizer can be rapidly enriched in the tumor site.
Fifth embodiment: fe doped VS 2 Acoustic power treatment of tumors with sonosensitizers
Four experimental groups, namely a Control group, a US group and Fe-VS group, are arranged 2 Group sum Fe-VS 2 + US group. Wherein, the control group is injected into mice of a subcutaneous breast cancer model by intravenous injection of PBS. Fe-VS 2 Group sum Fe-VS 2 The +US group is the Fe-doped VS prepared in example two 2 PEG sonosensitizer aqueous solution, wherein the sonosensitizer concentration is 1mg/mL, the injection dose is 150. Mu.L, fe-VS 2 The +US group is additionally at 40kHz,6.5W/cm 2 Irradiation was performed for 10 minutes under the conditions. The US group was also irradiated under the same conditions for 10 minutes.
Tumor volumes were measured at different time points in different experimental groups of mice using vernier calipers. The growth curve of the mouse tumor is shown in fig. 12, and compared with the Control group, the ultrasonic irradiation (US group) only has no obvious inhibition effect on the tumor; fe doped VS 2 Treatment with sonosensitizer (Fe-VS) 2 Group) has a certain inhibition effect on tumor growth; f (F)e-doped VS 2 Sonosensitizer in combination with ultrasonic irradiation treatment (Fe-VS 2 +us group) has a significant inhibitory effect on growth in the pair. The survival curves of mice are shown in FIG. 13, with Fe-doped VS 2 Sonosensitizer in combination with ultrasonic irradiation (Fe-VS 2 +us group) can greatly extend the survival of mice. HE staining of tumors 4 days after treatment of mice is shown in FIG. 12, and FIG. 12a, b, c, d shows Control group, US group, fe-VS group in order 2 Group sum Fe-VS 2 Test results in +US group, which indicate Fe doped VS 2 The tumor cell nuclei of the mice after the sound sensitizer and the ultrasonic irradiation are solidified, which indicates the apoptosis of cancer cells.
Example six: fe doped VS 2 Evaluation of biocompatibility and degradation performance of sound sensitive agent
PBS and Fe-doped VS prepared in example two were prepared by intravenous injection 2 PEG sonosensitizer is injected into healthy mice at a concentration of 1mg/mL at a dose of 200. Mu.L. Mice injected with PBS were designated as Control group (Control group). Mice were sacrificed at random 0.5, 1, 7 and 30 days post injection, heart, liver, spleen, lung and kidney tissues were removed after dissection and each divided into two parts, one part of the organ was fixed in 4% formaldehyde solution (formalin), paraffin was embedded, and further H was performed according to conventional procedures&E staining, evaluation of Fe doped VS 2 Safety of sonosensitizer after injection. Another part of each organ and tissue was dissolved in aqua regia, and then the content of vanadium element in each organ was measured. And simultaneously collecting a blood sample for blood biochemical and blood routine detection. The content test results of vanadium element in different organs of the mouse show that the content of vanadium element in each organ and tissue of the mouse is obviously reduced along with the increase of time, which shows that the Fe doped VS 2 The sonosensitizer is gradually metabolized away from the mouse body (fig. 15). At the same time, histological examination of the major organs further confirmed that Fe-doped VS 2 No significant side effects were observed in mice after the sonosensitizer injection (fig. 16), and the results in fig. 16a1-a5 for day 0 were those of the control group. Fe doped VS compared to control group 2 The blood biochemical index and blood test data of the mice after the sonosensitizer injection were both normal (fig. 17). The above knotResults all demonstrate Fe doped VS 2 Biosafety and biodegradability of the sonosensitizer.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, and it should be noted that it is possible for those skilled in the art to make several improvements and modifications without departing from the technical principle of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention.
Claims (6)
1. A method for preparing doped metal sulfide, which is characterized by comprising the following steps:
uniformly mixing a doped metal source and a doped metal source in an oil phase at 100-160 ℃ in a protective atmosphere, then reacting the obtained mixture with a sulfur source at 240-320 ℃, and obtaining the doped metal sulfide after the reaction is completed; the oil phase comprises oleylamine and octadecene; the mol ratio of the oleylamine to the octadecene is 1: (0.5 to 1.5);
wherein the doped metal source is ferric salt;
the doped metal source is vanadium salt;
the molar ratio of metal in the doped metal source to metal in the doped metal source is 1: (4-10); the molar ratio of the sulfur source to the metal in the doped metal source is (2-5): 1.
2. the method of manufacturing according to claim 1, characterized in that: the sulfur source is selected from elemental sulfur and/or thioacetamide.
3. A doped metal sulfide produced by the production method of any one of claims 1 to 2, the doped metal sulfide having a particle diameter of 80 to 150 nm.
4. Use of a doped metal sulphide according to claim 3 for the preparation of an acoustic sensitizer;
the doped metal sulfide is connected with an amphiphilic polymer, and the molecular weight of a hydrophilic chain segment of the amphiphilic polymer is 2kDa-5kDa.
5. The use according to claim 4, characterized in that: the sonosensitizer is used for sonodynamic treatment of tumors.
6. The use according to claim 5, characterized in that: ultrasonic power of the acoustic power treatment is 2-10W/cm 2 The frequency is 10-50 kHz, and the action time is 1-30 min.
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110101860A (en) * | 2019-04-28 | 2019-08-09 | 上海工程技术大学 | Nano metal sulfide flower of bismuth doping and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| Bottom-Up Synthesis of Metal-Ion-Doped WS2 Nanoflakes for Cancer Theranostics;Liang Cheng等;《ACS NANO》;20151007;第9卷(第11期);第1-33页 * |
| Liang Cheng等.Bottom-Up Synthesis of Metal-Ion-Doped WS2 Nanoflakes for Cancer Theranostics.《ACS NANO》.2015,第9卷(第11期), * |
| Multifunctional two-dimensional nanocomposites for photothermal-based combined cancer therapy;Xianwen Wang等;《Nanoscale》;20190703;第11卷;第15685-15708页 * |
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| WO2022061981A1 (en) | 2022-03-31 |
| CN114259560A (en) | 2022-04-01 |
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