CN113332427A - Fe2O3@ Pt multifunctional nano-particle and preparation method and application thereof - Google Patents

Fe2O3@ Pt multifunctional nano-particle and preparation method and application thereof Download PDF

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CN113332427A
CN113332427A CN202110523547.XA CN202110523547A CN113332427A CN 113332427 A CN113332427 A CN 113332427A CN 202110523547 A CN202110523547 A CN 202110523547A CN 113332427 A CN113332427 A CN 113332427A
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李翔
张田
傅译可
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ZJU Hangzhou Global Scientific and Technological Innovation Center
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Abstract

The invention discloses Fe2O3The @ Pt multifunctional nano-particle and the preparation method and the application thereof are disclosed, and the preparation method comprises the following steps: FeCl is added3·6H2O, NaCl and NaH2PO4Adding into ultrapure water, stirring and dissolving to obtain Fe2O3A precursor solution; subjecting said Fe to2O3Adding the precursor solution into a hydrothermal reaction kettle for reaction, and centrifugally washing after the reaction to obtain Fe2O3A solution; h is to be2PtCl6Adding the Fe into the water solution2O3Stirring the solution to obtain a first solution; reacting NaBH4Dropwise adding the solution into the first solution, stopping stirring after dropwise adding, and centrifugally washing to obtain Fe2O3@ Pt solution; mixing Fe2O3Adding the @ Pt solution into a strain bottle, adding methoxypolyethylene glycol mercapto (mPEG-SH), ultrasonically treating, stirring at room temperature, and centrifugally washing to obtain Fe2O3@ Pt multifunctional nanoparticles. Can effectively solve the problems of less types of the acoustic sensitivity agents and low acoustic power efficiency.

Description

Fe2O3@ Pt multifunctional nano-particle and preparation method and application thereof
Technical Field
The invention belongs to the field of biological nano materials, and particularly relates to Fe2O3The @ Pt multifunctional nano-particle and the preparation method and the application thereof.
Background
Tumors are currently one of the most serious diseases threatening human life. Therefore, the development of effective and safe cancer treatment modalities is an urgent task facing today's scientific community. Traditional treatment methods including surgery, chemotherapy, radiotherapy and the like can inhibit tumor growth, but have the defects of serious side effect, damage to immune system, poor patient compliance, low treatment efficiency and the like. Therefore, the development of minimally invasive and non-invasive therapeutic modalities is a new trend in biomedicine, which can replace the traditional therapeutic modalities, target cancer cells while maintaining the integrity of normal tissues/cells, have precise spatial and temporal resolution and controllability, reduce unexpected side effects and improve therapeutic effects, and have important significance in guaranteeing the human life health cause and improving the quality of human life.
New types of bio-nanomaterials have been studied by an increasing number of people as bio-pharmaceuticals. The classical non-invasive therapies at present include microwave therapy, radio frequency therapy, light therapy and acoustic therapy, which induce the nanomaterial to generate Reactive Oxygen Species (ROS) by introducing an external field to induce oxidative stress inside tumor cells, thereby killing the tumor cells. Compared to photodynamic therapy, sonodynamic therapy (SDT), a minimally invasive therapy with spatial and temporal controllability, excited by ultrasound, has a deeper tissue penetration depth (greater than 10cm) compared to light. SDT activates the specific accumulated sonosensitizer at the tumor site to generate enough ROS through ROS generated by bubble rupture induced by cavitation effect or mechanisms such as pyrolysis or sonoluminescence, and the like, thereby causing tumor ablation. Over the past few decades, research into sonosensitizers has increased dramatically. The traditional organic sound-sensitive agent has low molecular bioavailability, is easy to be quickly eliminated in vivo, thereby causing tumorsLess accumulation limits the acoustic-dynamic efficiency. There are therefore studies to load organic sonosensitizers into organic micro/nanoparticles for the protection of sonosensitizer molecules. Compared with organic sound-sensitive agents, inorganic materials have relatively high chemical/physiological stability and versatility, and show wide application prospects in biomedicine. Recently, new sonosensitizers such as TiO2 have been developed to enhance the efficiency of SDT, similar semiconductor materials can absorb the appropriate energy under ultrasonic irradiation and transfer it to the activator, the electrons then transition from the Valence Band (VB) to the Conduction Band (CB) and migrate to the catalyst surface for redox reactions, and the surface adsorbed O is removed2Conversion to toxic1O2. Therefore, it is apparent that a semiconductor having a suitable band gap structure is required to facilitate good separation of electrons and holes due to the reaction process, which has been pursued recently. Furthermore, the design of heterostructures is clearly essential to improve quantum yield. However, the related studies of sonosensitizers are still lacking. And solid tumors exhibit hypoxic characteristics. This greatly limits the efficiency of SDT due to the lack of an oxygen source in the reaction. In addition, oxygen consumption during SDT can exacerbate tumor hypoxia, thereby severely limiting SDT activity. To address this challenge, efforts should be made to find oxygen enhancement strategies for tumors.
Therefore, in the process of implementing the invention, the inventor finds that at least the following problems exist in the prior art:
less kinds of the acoustic sensitivity agent, lower acoustic power efficiency and the like.
Disclosure of Invention
It is an object of the embodiments of the present application to provide Fe2O3The @ Pt multifunctional nano-particle and the preparation method and the application thereof solve the problems of less types of the acoustic sensitivity agents and low acoustic power efficiency in the related technology.
According to a first aspect of embodiments herein, there is provided Fe2O3A method for preparing a @ Pt multifunctional nanoparticle, comprising:
FeCl is added3·6H2O, NaCl and NaH2PO4Adding into ultrapure water, stirringDissolving to obtain Fe2O3A precursor solution;
subjecting said Fe to2O3Adding the precursor solution into a hydrothermal reaction kettle for reaction, and centrifugally washing after the reaction to obtain Fe2O3A solution;
h is to be2PtCl6Adding the Fe into the water solution2O3Stirring the solution to obtain a first solution;
reacting NaBH4Dropwise adding the solution into the first solution, stopping stirring after dropwise adding, and centrifugally washing to obtain Fe2O3@ Pt solution;
mixing Fe2O3Adding the @ Pt solution into a strain bottle, adding methoxypolyethylene glycol mercapto (mPEG-SH), ultrasonically treating, stirring at room temperature, and centrifugally washing to obtain Fe2O3@ Pt multifunctional nanoparticles.
Preferably, the Fe2O3In a precursor solution, FeCl3·6H2O concentration of 0.02M, NaCl concentration of 1-2mM, NaH2PO4The concentration is 0.05-1 mM.
Preferably, in the hydrothermal reaction kettle, the reaction temperature is 220 ℃ and the reaction time is 5-10 h.
Preferably, said H2PtCl6The concentration of the aqueous solution is 20-120 mg/mL.
Preferably, said H2PtCl6An aqueous solution with said Fe2O3The volume ratio of the solution was 3: 125.
Preferably, the NaBH4The concentration of the solution is 0.1-0.2M, NaBH4Solution with Fe2O3The volume ratio of the solution was 1: 10.
Preferably, said Fe2O3@ Pt of Fe2O3Has a particle size of about 80-90nm, and is uniformly loaded with Pt nanoparticles having a particle size of about 4-10 nm.
According to a second aspect of the embodiments of the present application, there is provided Fe prepared by the preparation method of the first aspect2O3@ Pt multifunctional nanoparticles.
According to a third aspect of embodiments of the present application, there is provided Fe as described in the second aspect2O3The application of the @ Pt multifunctional nano-particles in preparing the oxygen-sensitized sonodynamic therapy preparation for the tumors.
The technical scheme provided by the embodiment of the application can have the following beneficial effects:
as can be seen from the above examples, the present application uses Pt and Fe2O3Heterojunction is formed, the generation of electrons in the ultrasonic process is improved, and the supply of an oxygen source is promoted through the catalytic action of Pt, so that the problems of less types of acoustic sensitizers and low acoustic power efficiency are solved, and a good tumor inhibition effect is achieved.
Examples of the present application are in Fe2O3Pt nanoparticles with the size of 4-10nm are successfully grown on the surface. Fe of the invention2O3In the @ Pt multifunctional nanoparticles, Fe2O3The nano-particles absorb proper energy under ultrasonic activation, so that electrons in a valence band in a semiconductor are transited to a conduction band, and then the electrons are driven from Fe under the law of lowest energy2O3Migrate to Pt, are captured by Pt nanoparticles on the surface and are adsorbed with O on the surface2Reduction reaction occurs to generate toxicity1O2. At the same time, Pt can also be combined with excessive H in the tumor2O2Reacting to produce O in sufficient quantity2It can provide reactant for SDT process, raise acoustic dynamic performance and kill tumor cell. The loading of PEG-SH is to improve the stability of the particles in vivo. Such a design verifies the semiconductor Fe2O3The feasibility of the acoustic sensitizer provides guiding significance for the application of the heterojunction in the field of tumor treatment. In the present invention, Fe having a uniform size and good dispersibility2O3Pt nanoparticles grow on the surfaces of the nanoparticles randomly, and an ultrasonic-excited oxygen-promoted acoustic dynamic treatment means is realized. To date, no Fe-based alloy has been developed in the art2O3An acoustic dynamic therapeutic means of nanoparticles. The present invention fills this gap. The preparation method is simple, and the dispersion stability is goodHas wide application foreground.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the application.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the present application and together with the description, serve to explain the principles of the application.
FIG. 1 shows Fe in the examples of the present application2O3The electron microscope pictures (a) and (b) of the nanoparticles are scanning electron micrographs and transmission electron micrographs.
FIG. 2 shows H at different concentrations2PtCl6Fe synthesized by2O3@ Pt nanoparticles, (a)500mg/mL, (b)300mg/mL, (c)100mg/mL, (d)20mg/mL,
fig. 3 is an electron microscope picture of FP nanoparticles in the example of the present application, where (a) is a scanning electron microscope picture, (b) is a transmission electron microscope picture, and (c) is a high-resolution transmission electron microscope picture.
FIG. 4 is an energy spectrum of FP nanoparticles in the present application example, which contains three elements of Fe, O and Pt.
FIG. 5 shows Fe in the examples of the present application2O3XRD patterns of nanoparticles and FP nanoparticles.
FIG. 6 shows Fe in the examples of the present application2O3Particle size distribution curves for nanoparticles and FP nanoparticles.
FIG. 7 is an XPS spectrum of FP nanoparticles in the examples of the present application.
FIG. 8 is FTIR spectra of FPs and stabilized FPs in the examples of the present application.
FIG. 9 shows different concentrations H of FP nanoparticles in the examples of the present application2O2The oxygen generating capacity.
FIG. 10 shows the degradation of DPBF by different materials after ultrasonic irradiation at different times in the examples of the present application, wherein (a) is Control and (b) is Fe2O3(c) FP nanoparticles, (d) FP + H2O2And (e) is the percentage degradation of DPBF by different materials.
FIG. 11 shows Fe in the examples of the present application2O3And solid diffuse reflectance spectra of FP nanoparticles, (a) solid diffuse reflectance spectra, (b) solid diffuse reflectance transfer curves.
FIG. 12 shows Fe in the examples of the present application2O3And the ac impedance spectrum of the FP nanoparticles.
FIG. 13 shows the cytotoxicity (with/without sonication) of Fe2O3 and FP nanoparticles after 24h incubation in the examples of the present application, wherein (a) is normoxia and (b) is hypoxia.
FIG. 14 shows ROS levels in different groups of the examples of this application, (a) is a fluorescence photograph of ROS, and (b) is a flow cytometer ROS level measurement.
FIG. 15 is a flow cytometer apoptosis assay in an embodiment of the present application.
FIG. 16 shows O in different groups in the examples of the present application2Concentration fluorescence photograph.
Detailed Description
Reference will now be made in detail to the exemplary embodiments, examples of which are illustrated in the accompanying drawings. When the following description refers to the accompanying drawings, like numbers in different drawings represent the same or similar elements unless otherwise indicated. The embodiments described in the following exemplary embodiments do not represent all embodiments consistent with the present application. Rather, they are merely examples of apparatus and methods consistent with certain aspects of the present application, as detailed in the appended claims.
The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used in this application and the appended claims, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It should also be understood that the term "and/or" as used herein refers to and encompasses any and all possible combinations of one or more of the associated listed items.
The invention is further described with reference to the following figures and specific examples.
It is to be understood that the following examples are illustrative of the present invention and are not to be construed as limiting the scope of the invention, and that certain insubstantial modifications and adaptations of the invention by those skilled in the art in light of the foregoing description are intended to be included within the scope of the invention. The specific process parameters and the like of the following examples are also merely examples of suitable ranges, i.e., those skilled in the art can select the appropriate ranges through the description herein, and are not limited to the specific values exemplified below.
Example 1
Fe2O3The preparation method of the @ Pt multifunctional nano-particles can comprise the following steps:
step (1), FeCl3·6H2O, NaCl and NaH2PO4Adding into ultrapure water, stirring and dissolving to obtain Fe2O3A precursor solution;
specifically, 0.02M FeCl was weighed3·6H2O (142.8mg), 1.1mM NaCl (2.5mg) and 0.05mM NaH2PO4(0.179mg) in 30mL of ultrapure water, and stirred at room temperature for 10min to give a uniform, clear and transparent solution.
Step (2) of subjecting the Fe2O3Adding the precursor solution into a hydrothermal reaction kettle for reaction, and centrifugally washing after the reaction to obtain Fe2O3A solution;
specifically, the obtained solution is transferred to a 50mL hydrothermal reaction kettle, sealed, placed in a 220 ℃ oven for reaction for 5 hours, naturally cooled to room temperature, and centrifugally washed for 3-4 times. Washing to obtain Fe2O3And (3) nanoparticles. After the reaction is finished, the solid-liquid separation is carried out by using high-speed centrifugation at 12000rpm for 10min, and then washing is carried out for 3-4 times. The washing mode is that ethanol and ultrapure water are mixed according to the ratio of 1:1, and redispersing the washed product in ultrapure water.
Step (3), adding H2PtCl6Adding the Fe into the water solution2O3Stirring the solution to obtain a first solution; reacting NaBH4Dropwise adding the solution into the first solution, stopping stirring after dropwise adding, and centrifugally washing to obtain Fe2O3@ Pt solution;
specifically, Pt nanoparticles were grown by mixing H2PtCl6Mixing and stirring for a certain time, and reducing in situ. By mixing the synthesized Fe2O3With a source of platinum H2PtCl6And mixing to realize the in-situ growth of Pt. Re-dissolved Fe2O3After diluting to 50mL to a concentration of 200. mu.g/mL, 100. mu.L of 100mg/mL H was added2PtCl6After stirring at room temperature for 20min, 1mL of 0.1M NaBH prepared in advance was added4The solution was added dropwise to the previous solution, centrifuged, and then dispersed again in the aqueous solution.
Step (4), adding Fe2O3Adding the @ Pt solution into a strain bottle, adding methoxypolyethylene glycol mercapto (mPEG-SH), ultrasonically treating, stirring at room temperature, and centrifugally washing to obtain Fe2O3@ Pt multifunctional nanoparticles.
Specifically, mPEG-SH is loaded by adding a certain amount of mPEG-SH into FP solution with a redispersed volume of 5mL, adding 40mg of mPEG-SH, stirring for a certain time at room temperature, and performing ultrasonic treatment for 3-4 times.
By adding 40mg of mPEG-SH to the prepared Fe2O3@ Pt nanoparticle aqueous solution, after stirring for a certain time and sonication for 3-4 times, centrifugally washed, and then dispersed again in the aqueous solution. Wherein the centrifugal speed is 12000rpm, and the washing is carried out by ultrapure water. Stirring for 2 days, and ultrasonic frequency is 1-2 times per day, and each ultrasonic time is 10 min. After the stirring, the mixture was centrifuged, washed and redissolved in ultrapure water. The centrifugation was carried out at 12000rpm, and the resultant was washed with ultrapure water.
Example 2
Fe2O3The preparation method of the @ Pt multifunctional nano-particles can comprise the following steps:
step (1), FeCl3·6H2O, NaCl and NaH2PO4Adding into ultrapure water, stirring and dissolving to obtain Fe2O3A precursor solution;
specifically, 0.02M FeCl was weighed3·6H2O (142.8mg), 1mMNaCl (2.5mg) and 0.05mM NaH2PO4(0.179mg) in 30mL of ultrapure water, and stirred at room temperature for 10min to give a uniform, clear and transparent solution.
Step (2) of subjecting the Fe2O3Adding the precursor solution into a hydrothermal reaction kettle for reaction, and centrifugally washing after the reaction to obtain Fe2O3A solution;
specifically, the obtained solution is transferred to a 50mL hydrothermal reaction kettle, sealed, placed in a 220 ℃ oven for reaction for 5 hours, naturally cooled to room temperature, and centrifugally washed for 3-4 times. Washing to obtain Fe2O3And (3) nanoparticles. After the reaction is finished, the solid-liquid separation is carried out by using high-speed centrifugation at 12000rpm for 10min, and then washing is carried out for 3-4 times. The washing mode is that ethanol and ultrapure water are mixed according to the ratio of 1:1, and redispersing the washed product in ultrapure water.
Step (3), adding H2PtCl6Adding the Fe into the water solution2O3Stirring the solution to obtain a first solution; reacting NaBH4Dropwise adding the solution into the first solution, stopping stirring after dropwise adding, and centrifugally washing to obtain Fe2O3@ Pt solution;
specifically, Pt nanoparticles were grown by mixing H2PtCl6Mixing and stirring for a certain time, and reducing in situ. By mixing the synthesized Fe2O3With a source of platinum H2PtCl6And mixing to realize the in-situ growth of Pt. Re-dissolved Fe2O3After diluting to 50mL to a concentration of 200. mu.g/mL, 100. mu.L of 100mg/mL H was added2PtCl6After stirring at room temperature for 20min, 1mL of 0.1M NaBH prepared in advance was added4The solution was added dropwise to the previous solution, centrifuged, and then dispersed again in the aqueous solution.
Step (4), adding Fe2O3Adding the @ Pt solution into a strain bottle, adding methoxypolyethylene glycol mercapto (mPEG-SH), ultrasonically treating, stirring at room temperature, and centrifugally washing to obtain Fe2O3@ Pt multifunctional nanoparticles.
Specifically, mPEG-SH is loaded by adding a certain amount of mPEG-SH into FP solution with a redispersed volume of 5mL, adding 40mg of mPEG-SH, stirring for a certain time at room temperature, and performing ultrasonic treatment for 3-4 times.
By adding 40mg of mPEG-SH to the prepared Fe2O3@ Pt nanoparticle aqueous solution, after stirring for a certain time and sonication for 3-4 times, centrifugally washed, and then dispersed again in the aqueous solution. Wherein the centrifugal speed is 12000rpm, and the washing is carried out by ultrapure water. Stirring for 2 days, and ultrasonic frequency is 1-2 times per day, and each ultrasonic time is 10 min. After the stirring, the mixture was centrifuged, washed and redissolved in ultrapure water. The centrifugation was carried out at 12000rpm, and the resultant was washed with ultrapure water.
Example 3
Fe2O3The preparation method of the @ Pt multifunctional nano-particles can comprise the following steps:
step (1), FeCl3·6H2O, NaCl and NaH2PO4Adding into ultrapure water, stirring and dissolving to obtain Fe2O3A precursor solution;
specifically, 0.02M FeCl was weighed3·6H2O (142.8mg), 2mM NaCl (2.5mg) and 1mM NaH2PO4(0.179mg) in 30mL of ultrapure water, and stirred at room temperature for 10min to give a uniform, clear and transparent solution.
Step (2) of subjecting the Fe2O3Adding the precursor solution into a hydrothermal reaction kettle for reaction, and centrifugally washing after the reaction to obtain Fe2O3A solution;
specifically, the obtained solution is transferred to a 50mL hydrothermal reaction kettle, sealed, placed in a 220 ℃ oven for reaction for 10 hours, naturally cooled to room temperature, and centrifugally washed for 3-4 times. Washing to obtain Fe2O3And (3) nanoparticles. After the reaction is finished, the solid-liquid separation is carried out by using high-speed centrifugation at 12000rpm for 10min, and then washing is carried out for 3-4 times. The washing mode is that ethanol and ultrapure water are mixed according to the ratio of 1:1, and redispersing the washed product in ultrapure water.
Step (3), adding H2PtCl6Adding the Fe into the water solution2O3Stirring the solution to obtain a first solution; reacting NaBH4Dropwise adding the solution into the first solution, stopping stirring after dropwise adding, and centrifugally washing to obtain Fe2O3@ Pt solution;
specifically, Pt nanoparticles were grown by mixing H2PtCl6Mixing and stirring for a certain time, and reducing in situ. By mixing the synthesized Fe2O3With a source of platinum H2PtCl6And mixing to realize the in-situ growth of Pt. Re-dissolved Fe2O3After diluting to 50mL to a concentration of 200. mu.g/mL, 100. mu.L of 100mg/mL H was added2PtCl6After stirring at room temperature for 20min, 1mL of 0.1M NaBH prepared in advance was added4The solution was added dropwise to the previous solution, centrifuged, and then dispersed again in the aqueous solution.
Step (4), adding Fe2O3Adding the @ Pt solution into a strain bottle, adding methoxypolyethylene glycol mercapto (mPEG-SH), ultrasonically treating, stirring at room temperature, and centrifugally washing to obtain Fe2O3@ Pt multifunctional nanoparticles.
Specifically, mPEG-SH is loaded by adding a certain amount of mPEG-SH into FP solution with a redispersed volume of 5mL, adding 40mg of mPEG-SH, stirring for a certain time at room temperature, and performing ultrasonic treatment for 3-4 times.
By adding 40mg of mPEG-SH to the prepared Fe2O3@ Pt nanoparticle aqueous solution, after stirring for a certain time and sonication for 3-4 times, centrifugally washed, and then dispersed again in the aqueous solution. Wherein the centrifugal speed is 12000rpm, and the washing is carried out by ultrapure water. Stirring for 2 days, and ultrasonic frequency is 1-2 times per day, and each ultrasonic time is 10 min. After the stirring, the mixture was centrifuged, washed and redissolved in ultrapure water. The centrifugation was carried out at 12000rpm, and the resultant was washed with ultrapure water.
Example 4
This example differs from example 1 in that 100. mu.L of 500mg/mL H was added in step (3)2PtCl6And 1mL of 0.2M NaBH prepared beforehand4And (3) solution.
Example 5
This example differs from example 1 in that 100. mu.L of 300mg/mL H was added in step (3)2PtCl6And 1mL of 0.2M NaBH prepared beforehand4And (3) solution.
Example 6
This example differs from example 1 in that 100. mu.L of 20mg/mL H was added in step (3)2PtCl6And 1mL of 0.1M NaBH prepared beforehand4And (3) solution.
Example 7
This example differs from example 1 in that the amount of mPEG-SH added in step (4) is 50 mg.
Fe2O3Prepared by an improved one-step hydrothermal method, Pt nano particles are randomly distributed in Fe by an in-situ growth method2O3The surface of the nanoparticles. In FIG. 1, (a) and (b) are each Fe2O3SEM and TEM images of nanoparticles, it can be seen that Fe2O3Is regular polyhedron, has uniform size of about 80-90nm, and smooth surface.
FIG. 2 shows H at different concentrations2PtCl6Fe synthesized by2O3@ Pt nanoparticles, where the concentrations (a-d) in FIG. 2 were 500 (example 4), 300 (example 5), 100 (example 1), 20mg/mL (example 6), respectively, it can be seen that Pt nanoparticles nucleate alone (a-b in FIG. 2) at higher concentrations of H2PtCl6 and grow in Fe at lower concentrations (d in FIG. 2)2O3The Pt nanoparticles on the surface were less and had an effect on the subsequent oxygen production performance, so 100mg/mL was chosen here as the final concentration.
In FIG. 3, (a) and (b) are Fe2O3SEM and TEM images of @ Pt nanoparticles, it can be seen that Pt nanoparticles are in Fe2O3The surface distribution is good, and the size is relatively uniform and is about 4-10 nm. There were no separately nucleated Pt nanoparticles. The uniformity of growth can be seen in the SEM images. FIG. 3 (c) is an HRTEM image of FP nanoparticles, where clear Pt nanoparticles and Fe can be seen2O3Is typical ofAnd (4) lattice fringes. Wherein the lattice spacings of 0.227nm and 0.141nm correspond to the (111) crystal plane of Pt and hematite alpha-Fe, respectively2O3The (125) crystal plane of (c). The dotted lines in FIG. 4 clearly show Pt sodium and Fe2O3The interface of the nanoparticles illustrates the successful construction of the heterojunction. From fig. 5, the elemental contents and distribution of Fe, O and Pt can be seen, demonstrating successful loading and uniform distribution of Pt.
FIG. 5 shows Fe2O3And XRD pattern of FP nanoparticles, from which it can be seen that its crystalline phase is hematite alpha-Fe2O3Phase (JCPDS 33-0664), and good crystallization, which is demonstrated by results of HRTEM and Mapping. While peaks at Pt (111) and Pt (200) appeared at 39.8 ° and 46.2 °, due to the small diameter of Pt nanoparticles, although in a crystalline state, the peaks of XRD were broadened according to Scherrer's formula. FIG. 6 shows Fe2O3And the particle size distribution curve of FP nanoparticles. With the loading of Pt nanoparticles, the particle size of the nanoparticles showed an increase from 177.6nm to 222.0nm, which again indicates the success of in situ growth of Pt nanoparticles, and due to the enhanced permeability and retention effect (EPR effect), a suitable particle size favours the accumulation of particles at the tumor.
FIG. 7 is X-ray photoelectron spectroscopy (XPS) of FP nanoparticles for detecting the valence of Fe element on the FP surface, and it can be seen that Fe2O3Is typically trivalent Fe3+Peak(s).
The loading of mPEG-SH is mainly to improve Fe2O3Stability of the @ Pt nanoparticles by S atom and Fe in mPEG-SH2O3The affinity of the Pt atoms on the surface of @ Pt realizes loading through covalent connection, and the loaded nanoparticles are well dispersed in different dispersants. FIG. 8 shows mPEG-SH, FP and stabilized Fe2O3FTIR spectra of @ Pt nanoparticles. It can be seen that 1470cm in the stabilized FP spectrum-1Corresponds to the-CH in mPEG-SH2Bending vibration of mPEG-SH, which accounts for successful loading of mPEG-SH.
Example 8
The present embodiment provides aFe prepared in the above examples2O3The application of the @ Pt multifunctional nano-particles in preparing the oxygen-sensitized sonodynamic therapy preparation for the tumors.
Prepared Fe2O3The @ Pt multifunctional nano particles are centrifuged and re-dispersed in an aqueous solution system, and a corresponding therapeutic preparation is obtained after sterilization. In Fe2O3In the @ Pt nanoparticle, Fe2O3The nano particles can absorb the energy of ultrasonic waves and generate activated electrons to convert O into2Is converted into1O2Thereby killing the tumor cells. The Pt nanoparticles may be combined with Fe2O3The heterogeneous structure is formed to inhibit the recombination of electrons and holes excited by ultrasound, and on the other hand, the heterogeneous structure can be combined with excessive H at the tumor part2O2Reaction to form O2The method promotes the generation of toxic singlet oxygen in the acoustic dynamic process, realizes strong tumor killing effect, and aims to achieve better tumor treatment effect and solve the problems of less types of acoustic sensitizers and low acoustic dynamic efficiency in the related technology.
The following examples perform performance characterization of the FP nanoparticles in example 1.
Example 9
Fe prepared by the method2O3The application of the @ Pt multifunctional nano-particles in preparing an oxygen-sensitized sonodynamic therapy preparation for tumors comprises the following steps: alleviating tumor hypoxia and treating the application of the acoustic power. In Fe2O3In the @ Pt nanoparticle, Fe2O3The nano particles can absorb the energy of ultrasonic waves and generate activated electrons to convert O into2Is converted into1O2Thereby killing the tumor cells. The Pt nano particles can form a heterostructure with Fe2O3 to inhibit the compounding of electrons and holes excited by ultrasonic waves on one hand, and can react with excessive H2O2 at a tumor part to generate O2 on the other hand, so that the generation of toxic singlet oxygen in the acoustic power process is promoted, a strong tumor killing effect is realized, a better tumor treatment effect is achieved, and the problems of less types of acoustic sensitizers and low acoustic power efficiency in the related technology are solved. Noble metal Pt with its peroxidase mimic activityIt is known to catalyze H2O2Decomposition to O2Thereby relieving the hypoxic state of the tumor site. Recorded in H by dissolved oxygen meter2O2And FP nanoparticles2Changes in concentration, the peroxidase mimetic properties of FP nanoparticles were studied. The FP nano-particles are prepared into 50 mu g/mL aqueous solution, placed in a 20mL strain bottle, and added with H with different concentrations2O2The final concentration was 200. mu.M, 500. mu.M, and 1 mM. The dissolved oxygen concentration was measured every 10 seconds. At the same time test H2O2And Fe2O3Nanoparticles plus 1mM H2O2Change of the dissolution solution in the solution of (1).
FIG. 9 shows FP nanoparticles at different H2O2Oxygen concentration profile at concentration. As can be seen from the figure, FP nanoparticles can produce O rapidly and efficiently2And O is2Generation speed of (1) and H2O2Is concerned with. And Fe2O3The nanoparticles do not have peroxidase-like activity. This means that the FP nanoparticles can provide more oxygen source for the sonodynamic process, leading to higher sonodynamic performance.
Example 10
The typical ROS detection reagent DPBF was used to detect ROS generation from ultrasonically irradiated FP nanoparticles. The probe DPBF can react with ROS generated by the sonosensitizer FP nanoparticles and degrade, so that the characteristic absorption peak of the DPBF at the wavelength of 415nm is reduced. mu.L of DPBF (2mM) was added to 3mL of the hydro-alcoholic mixed solution of FP (50. mu.g/mL), and the mixture was exposed to ultrasound (1.0MHZ, 1.0W/cm) in the dark2) And then, detecting the absorbance change under different irradiation time by using an ultraviolet-visible spectrum. Meanwhile, Fe caused by ultrasonic irradiation is researched2O3，FP+H2O2(200. mu.M) ROS-generating properties.
Fig. 10 shows the UV absorption curves of DPBF for different groups. In FIG. 10, (a), (b), (c) and (d) are respectively Control, Fe2O3FP nanoparticles, FP + H2O2Deflexing of DPBF under ultrasoundA wire. As can be seen from (c) in fig. 9, the absorption of DPBF after ultrasonic irradiation of FP nanoparticles is significantly reduced, which indicates the acoustic dynamic effect of FP nanoparticles. To verify the dual role of Pt, including peroxidase-like activity and co-catalyst activity, Fe with the same Fe concentration as FP nanoparticles was also investigated2O3And mix H2O2The acoustic dynamic properties of FP nanoparticles of (a). FIG. 10 (e) shows statistics of DPBF absorption at 415nm for different groups at different times. Found out that, Control, Fe2O3FP nanoparticles and FP + H2O2The percent degradation over 10min was 4.46%, 27.92%, 54.75% and 59.53%, respectively. This indicates that FP nanoparticles exhibit a specific Fe ratio in the presence of the helper catalyst2O3Better acoustic-dynamic efficiency, and with H2O2The mixed FP nanoparticles showed the best acoustodynamic performance due to the increase of the oxygen source.
Example 11
To scientifically determine the reason for FP nanoparticle design, the present study used solid UV-Vis spectroscopy to calculate Fe2O3And band gap of FP nanoparticles.
In FIG. 11, (a) is Fe2O3And solid diffuse reflection spectrum of FP nanoparticles, and (b) in fig. 11 is a conversion curve calculated according to (a) in fig. 11. It can be found that the original Fe2O3The band gap of the heterojunction FP nanoparticles was 1.95eV, and after Pt was deposited on the surface, the band gap of the heterojunction FP nanoparticles dropped to 1.83eV, confirming the role of the helper catalyst Pt as a trap. The reduction in band gap indicates that the hybrid can absorb more energy and generate more reactive holes and electrons, and thus more ROS. At the same time, this study also used Electrochemical Impedance Spectroscopy (EIS) to evaluate Fe2O3And charge transfer capability and carrier separation efficiency of FP nanoparticles. FIG. 12 shows EIS Nyquist plot of FP nanoparticles vs. Fe2O3Smaller half circle, illustrating FP nanoparticles vs Fe2O3Higher electron hole separation efficiency, which indicates that the catalyst is Pt nanoThe presence of the particles can trap the generated electrons and facilitate electron and hole separation. The mechanism is as follows: first, Fe2O3As n-type semiconductor with bulk Fe2O3(-2.2 eV) with a narrow gap of about 1.95eV, it is possible to cause h with absorption of ultrasonic energy+And e-We expect that the Pt region supported on the surface should act as an electron absorber. Semiconductor Fe2O3This hypothesis is supported by the fact that the workfunction of (5.4eV) is lower than that of the noble metal Pt (5.65 eV). Thus, Fe2O3The Fermi level of (A) is higher than that of Pt, and electrons are caused to be separated from Fe based on the principle of minimum energy2O3Transfer to Pt. When the interfaces are in intimate contact, charge can accumulate on the semiconductor, creating a space electric field that can cause the band to bend and form a schottky barrier. In view of the above conditions, the hybrid can promote phonon-induced electrons from Fe2O3Rapidly transferred and then trapped by the Pt domain, thereby suppressing the possibility of electron-hole recombination. Furthermore, we expect that the electrons captured by the Pt domain should be able to drive the reduction of dissolved molecular oxygen present in the environment by catalyzing excess H2O2Generation of active oxygen1O2And then produced.
Example 12
The experiment shows the application of the material in killing tumor cells through the killing effect at the cell level. The cells used were 4T1 mouse breast cancer cells. The mouse breast cancer cells and materials with different concentrations are cultured together, and the cell survival rate is measured after 24 hours under the condition of ultrasonic irradiation. As shown in (a) in FIG. 13 and (b) in FIG. 13, it is clear that Fe is present even at a high concentration (200. mu.g/mL)2O3And FP nanoparticles also showed no significant toxicity to 4T1 cancer cells, suggesting their potential for biological applications. Exposure to US (1.0MHZ, 1.0W/cm) under normoxic conditions230s), the survival rate of 4T1 cells is obviously reduced along with the increase of the concentration of FP nano particles, and Fe2O3Exhibiting a weaker acoustic-dynamic effect. This depends to a large extent on the Pt and Fe2O3A schottky barrier formed in the interface. Upon incubation under hypoxic conditions, which mimic hypoxia, FP nanoparticles have a slightly but not large sonodynamic effect on cells, while Fe2O3Losing its ability to inhibit cell growth due to the excellent peroxidase-like activity of Pt, which provides a sufficient source of oxygen for the cells. Under both normoxic and hypoxic conditions, US alone is not harmful to cells.
Intracellular ROS production in 4T1 cells was determined by oxidation-sensitive probe 2 ', 7' -dichlorofluorescein diacetate (DCFH-DA). The probe can be oxidized to Dichlorofluorescein (DCF) in the presence of ROS, and emits green fluorescence. Fig. 14 is a fluorescence image of intracellular ROS, and it can be seen that cells incubated with pure ultrasound and FP nanoparticles showed no DCF fluorescence, indicating that no ROS were produced in these groups. However, in FP + US treated cells, the cells showed increased fluorescence with DCF, i.e. strong green fluorescence, indicating that FP nanoparticles are able to generate US-induced ROS. This conclusion is also corroborated by the ROS levels measured by the flow cytometer of fig. 10 d.
The killing effect of the material on 4T1 cells was also determined by accurate flow cytometry apoptosis assay in different protocols by Annexin V-fluorescein isothiocyanate (Annexin-FTIC) and PI double staining principles, respectively, to verify the synergistic therapeutic effect (FIG. 15). The results further demonstrate that most cells were killed by FP + US treatment, which indicates that FP nanoparticles under US assistance showed high ultrasound toxicity to cells, while having good biocompatibility in itself.
To further confirm the killing mechanism of FP nanoparticles, a typical oxygen probe [ Ru (dpp) ] was used after cell culture3]Cl2(RDPP) detection of intracellular oxygen levels, the fluorescence of which may be measured by O2And (4) quenching. As shown in FIG. 16, intact cells are due to lower O2The concentration showed strong red fluorescence of RDPP, while the FP nanoparticle group showed weaker fluorescence due to better nanoenzyme activity of Pt. Clearly, platinum on the surface is an effective promoter, increasing the production of intracellular oxygen. Fluorescence of FP nanoparticles with US-treated cellsThe intensity appears to be stronger than cells without US due to O during sonodynamic2Is converted into1O2Thereby, the effect is achieved. All these phenomena are small, FP nanoparticles can improve hypoxic tumor microenvironment through the peroxidase-like activity of Pt, and due to Pt and Fe2O3The Schottky barrier formed between the two electrodes enhances the ultrasonic catalytic capability, so that the ultrasonic wave-sensitive material can be used as a potential sound-sensitive agent.
Other embodiments of the present application will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure disclosed herein. This application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the application and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the application being indicated by the following claims.
It will be understood that the present application is not limited to the precise arrangements described above and shown in the drawings and that various modifications and changes may be made without departing from the scope thereof. The scope of the application is limited only by the appended claims.

Claims (9)

1. Fe2O3A preparation method of the @ Pt multifunctional nano-particles is characterized by comprising the following steps:
FeCl is added3·6H2O, NaCl and NaH2PO4Adding into ultrapure water, stirring and dissolving to obtain Fe2O3A precursor solution;
subjecting said Fe to2O3Adding the precursor solution into a hydrothermal reaction kettle for reaction, and centrifugally washing after the reaction to obtain Fe2O3A solution;
h is to be2PtCl6Adding the Fe into the water solution2O3Stirring the solution to obtain a first solution;
reacting NaBH4Dropwise adding the solution into the first solution, stopping stirring after dropwise adding, and centrifugally washing to obtain Fe2O3@ Pt solution;
mixing Fe2O3Adding the @ Pt solution into a strain bottle, adding methoxypolyethylene glycol mercapto (mPEG-SH), ultrasonically treating, stirring at room temperature, and centrifugally washing to obtain Fe2O3@ Pt multifunctional nanoparticles.
2. The method of claim 1, wherein the Fe is2O3In a precursor solution, FeCl3·6H2O concentration of 0.02M, NaCl concentration of 1-2mM, NaH2PO4The concentration is 0.05-1 mM.
3. The preparation method according to claim 1, wherein the reaction temperature in the hydrothermal reaction kettle is 220 ℃ and the reaction time is 5-10 h.
4. The method of claim 1, wherein the H is2PtCl6The concentration of the aqueous solution is 20-500 mg/mL.
5. The method of claim 1, wherein the H is2PtCl6An aqueous solution with said Fe2O3The volume ratio of the solution was 3: 125.
6. The method of claim 1, wherein the NaBH is prepared by4The concentration of the solution is 0.1-0.2M, NaBH4Solution with Fe2O3The volume ratio of the solution was 1: 10.
7. The method according to claim 1, wherein the Fe is2O3@ Pt of Fe2O3Has a particle size of about 80-90nm, and is uniformly loaded with Pt nanoparticles having a particle size of about 4-10 nm.
8. A product obtained by the production method according to any one of claims 1 to 7Fe2O3@ Pt multifunctional nanoparticles.
9. Fe of claim 82O3The application of the @ Pt multifunctional nano-particles in preparing the oxygen-sensitized sonodynamic therapy preparation for the tumors.
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