CN113332427B - Fe 2 O 3 @ Pt multifunctional nano-particle and preparation method and application thereof - Google Patents

Fe 2 O 3 @ Pt multifunctional nano-particle and preparation method and application thereof Download PDF

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CN113332427B
CN113332427B CN202110523547.XA CN202110523547A CN113332427B CN 113332427 B CN113332427 B CN 113332427B CN 202110523547 A CN202110523547 A CN 202110523547A CN 113332427 B CN113332427 B CN 113332427B
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CN113332427A (en
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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 Fe 2 O 3 The @ Pt multifunctional nano-particle and the preparation method and the application thereof are disclosed, and the preparation method comprises the following steps: FeCl is added 3 ·6H 2 O, NaCl and NaH 2 PO 4 Adding into ultrapure water, stirring and dissolving to obtain Fe 2 O 3 A precursor solution; subjecting said Fe to 2 O 3 Adding the precursor solution into a hydrothermal reaction kettle for reaction, and centrifugally washing after the reaction to obtain Fe 2 O 3 A solution; h is to be 2 PtCl 6 Adding the Fe into the water solution 2 O 3 Stirring the solution to obtain a first solution; reacting NaBH 4 Dropwise adding the solution into the first solution, stopping stirring after dropwise adding, and centrifugally washing to obtain Fe 2 O 3 @ Pt solution; mixing Fe 2 O 3 Adding the @ Pt solution into a strain bottle, adding methoxypolyethylene glycol mercapto (mPEG-SH), ultrasonically treating, stirring at room temperature, and centrifugally washing to obtain Fe 2 O 3 @ Pt multifunctional nanoparticles. Can effectively solve the problems of less types of the sound-sensitive agents and low sound power efficiency.

Description

Fe 2 O 3 @ 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 Fe 2 O 3 The @ 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 sound therapy, which induce the nano material to generate Reactive Oxygen Species (ROS) by introducing an external field to induce oxidative stress inside tumor cells so as to kill 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. The SDT activates the acoustic sensitizer specifically accumulated at the tumor site to generate enough ROS through ROS generated by bubble rupture induced by cavitation effect or through mechanisms such as pyrolysis or sonoluminescence, and the like, so as to cause 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, thus causing less tumor accumulation and limiting the sound power 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 removed 2 Conversion to toxic 1 O 2 . 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, the method can be used for producing a composite materialOxygen consumption during SDT exacerbates 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 Fe 2 O 3 The @ Pt multifunctional nano-particles, and the preparation method and the application thereof solve the problems of few types of the acoustic sensitizers and low acoustic power efficiency in the related technology.
According to a first aspect of embodiments herein, there is provided Fe 2 O 3 A preparation method of @ Pt multifunctional nano-particles comprises the following steps:
FeCl 3 ·6H 2 O, NaCl and NaH 2 PO 4 Adding into ultrapure water, stirring and dissolving to obtain Fe 2 O 3 A precursor solution;
subjecting said Fe to 2 O 3 Adding the precursor solution into a hydrothermal reaction kettle for reaction, and centrifugally washing after the reaction to obtain Fe 2 O 3 A solution;
will H 2 PtCl 6 Adding the Fe into the water solution 2 O 3 Stirring the solution to obtain a first solution;
reacting NaBH 4 Dropwise adding the solution into the first solution, stopping stirring after dropwise adding, and centrifugally washing to obtain Fe 2 O 3 @ Pt solution;
mixing Fe 2 O 3 Adding the @ Pt solution into a strain bottle, adding methoxypolyethylene glycol mercapto (mPEG-SH), ultrasonically treating, stirring at room temperature, and centrifugally washing to obtain Fe 2 O 3 @ Pt multifunctional nanoparticles.
Preferably, the Fe 2 O 3 In a precursor solution, FeCl 3 ·6H 2 O concentration of 0.02M, NaCl concentration of 1-2mM, NaH 2 PO 4 The 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 H 2 PtCl 6 The concentration of the aqueous solution is 20-120 mg/mL.
Preferably, said H 2 PtCl 6 An aqueous solution with said Fe 2 O 3 The volume ratio of the solution was 3: 125.
Preferably, the NaBH 4 The concentration of the solution is 0.1-0.2M, NaBH 4 Solution with Fe 2 O 3 The volume ratio of the solution was 1: 10.
Preferably, said Fe 2 O 3 @ Pt of Fe 2 O 3 Has 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 aspect 2 O 3 @ Pt multifunctional nanoparticles.
According to a third aspect of embodiments of the present application, there is provided Fe as described in the second aspect 2 O 3 The 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 adopts Pt and Fe 2 O 3 Heterojunction 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 Fe 2 O 3 Pt nanoparticles with the size of 4-10nm are successfully grown on the surface. Fe of the present invention 2 O 3 In the @ Pt multifunctional nanoparticles, Fe 2 O 3 The nanoparticles absorb suitable energy under ultrasonic activation, so that electrons in a valence band in a semiconductor are transited to a conduction band, and then are driven under the law of lowest energyWith lower electron from Fe 2 O 3 Migrate to Pt, are captured by Pt nanoparticles on the surface and are adsorbed with O on the surface 2 Reduction reaction occurs to generate toxicity 1 O 2 . At the same time, Pt can also be combined with excessive H in the tumor 2 O 2 Reacting to produce O in sufficient quantity 2 It provides reactant for SDT process, improves acoustic dynamic property, and kills tumor cells. The loading of PEG-SH is to improve the stability of the particles in vivo. Such a design verifies the semiconductor Fe 2 O 3 The 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 dispersibility 2 O 3 Pt 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 art 2 O 3 An acoustic dynamic therapeutic means of nanoparticles. The present invention fills this gap. The preparation method is simple, has good dispersion stability and has a wide application prospect.
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 application 2 O 3 The electron microscope pictures (a) and (b) of the nanoparticles are scanning electron micrographs and transmission electron micrographs.
FIG. 2 shows H at different concentrations 2 PtCl 6 Fe synthesized by 2 O 3 @ 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 nano-particles in the present application example, which contains three elements of Fe, O and Pt.
FIG. 5 shows Fe in the examples of the present application 2 O 3 XRD patterns of nanoparticles and FP nanoparticles.
FIG. 6 shows Fe in the examples of the present application 2 O 3 Particle 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 application 2 O 2 The 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 Fe 2 O 3 (c) FP nanoparticles, (d) FP + H 2 O 2 And (e) is the percent degradation of DPBF by different materials.
FIG. 11 shows Fe in the examples of the present application 2 O 3 And 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 application 2 O 3 And the ac impedance spectrum of the FP nanoparticles.
FIG. 13 shows the cytotoxicity (with/without ultrasound) of Fe2O3 and FP nanoparticles after 24h culture in the present application example, wherein (a) is normoxic and (b) is hypoxic.
FIG. 14 shows ROS levels in different groups of the present examples, (a) shows ROS fluorescence photographs, and (b) shows flow cytometer ROS level measurements.
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 application 2 Concentration 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 only and are not to be construed as limiting the scope of the invention, as the following non-limiting examples and modifications may be made by those skilled in the art in light of the foregoing disclosure. 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
Fe 2 O 3 The preparation method of the @ Pt multifunctional nano-particles can comprise the following steps:
step (1), FeCl 3 ·6H 2 O, NaCl and NaH 2 PO 4 Adding into ultrapure water, stirring and dissolving to obtain Fe 2 O 3 A precursor solution;
specifically, 0.02M FeCl was weighed 3 ·6H 2 O (142.8mg), 1.1mM NaCl (2.5mg) and 0.05mM NaH 2 PO 4 (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 Fe 2 O 3 Adding the precursor solution into a hydrothermal reaction kettle for reaction, and centrifugally washing after the reaction to obtain Fe 2 O 3 A 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 Fe 2 O 3 And (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) of reacting H 2 PtCl 6 Adding the Fe into the water solution 2 O 3 Stirring the solution to obtain a first solution; reacting NaBH 4 Dropwise adding the solution into the first solution, stopping stirring after dropwise adding, and centrifugally washing to obtain Fe 2 O 3 @ Pt solution;
specifically, Pt nanoparticles were grown by reacting H 2 PtCl 6 Mixing and stirring for a certain time, and reducing in situ. By mixing the synthesized Fe 2 O 3 With a source of platinum H 2 PtCl 6 And mixing to realize the in-situ growth of Pt. Re-dissolved Fe 2 O 3 After diluting to 50mL to a concentration of 200. mu.g/mL, 100. mu.L of 100mg/mL H was added 2 PtCl 6 After stirring at room temperature for 20min, 1mL of 0.1M NaBH prepared in advance was added 4 The solution was added dropwise to the previous solution, centrifuged, and then dispersed again in the aqueous solution.
Step (4), adding Fe 2 O 3 Adding the @ Pt solution into a strain bottle, adding methoxypolyethylene glycol mercapto (mPEG-SH), performing ultrasonic treatment, stirring at room temperature, and performing centrifugal washing to obtain Fe 2 O 3 @ Pt multifunctional nanoparticles.
Specifically, mPEG-SH is loaded by adding a certain amount of mPEG-SH into FP solution with the 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 Fe 2 O 3 @ 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
Fe 2 O 3 The preparation method of the @ Pt multifunctional nano-particles can comprise the following steps:
step (1) of subjecting FeCl 3 ·6H 2 O, NaCl and NaH 2 PO 4 Adding into ultrapure water, stirring and dissolving to obtain Fe 2 O 3 A precursor solution;
specifically, 0.02M FeCl was weighed 3 ·6H 2 O (142.8mg), 1mM NaCl (2.5mg) and 0.05mM NaH 2 PO 4 (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 Fe 2 O 3 Adding the precursor solution into a hydrothermal reaction kettle for reaction, and centrifugally washing after the reaction to obtain Fe 2 O 3 A solution;
specifically, the obtained solution is transferred to a hydrothermal reaction kettle with the volume of 50mL, sealed, placed in an oven at the temperature of 220 ℃ for reaction for 5 hours, naturally cooled to room temperature, and then centrifugally washed for 3-4 times. Washing to obtain Fe 2 O 3 And (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 H 2 PtCl 6 Adding the Fe into the water solution 2 O 3 Stirring the solution to obtain a first solution; reacting NaBH 4 The solution is dropwise addedAdding into the first solution, stopping stirring after dropwise adding, and centrifugally washing to obtain Fe 2 O 3 @ Pt solution;
specifically, Pt nanoparticles were grown by mixing H 2 PtCl 6 Mixing and stirring for a certain time, and reducing in situ. By mixing the synthesized Fe 2 O 3 With a source of platinum H 2 PtCl 6 And mixing to realize the in-situ growth of Pt. Re-dissolved Fe 2 O 3 After diluting to 50mL to a concentration of 200. mu.g/mL, 100. mu.L of 100mg/mL H was added 2 PtCl 6 After stirring at room temperature for 20min, 1mL of 0.1M NaBH prepared in advance was added 4 The solution was added dropwise to the previous solution, centrifuged, and then dispersed again in the aqueous solution.
Step (4), adding Fe 2 O 3 Adding the @ Pt solution into a strain bottle, adding methoxypolyethylene glycol mercapto (mPEG-SH), ultrasonically treating, stirring at room temperature, and centrifugally washing to obtain Fe 2 O 3 @ Pt multifunctional nanoparticles.
Specifically, mPEG-SH is loaded by adding a certain amount of mPEG-SH into FP solution with the 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 Fe 2 O 3 @ 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 rotation speed of the centrifuge was 12000rpm, and washing was performed with ultrapure water.
Example 3
Fe 2 O 3 The preparation method of the @ Pt multifunctional nano-particles can comprise the following steps:
step (1), FeCl 3 ·6H 2 O, NaCl and NaH 2 PO 4 Adding into ultrapure water, stirring and dissolving to obtain Fe 2 O 3 A precursor solution;
specifically, 0.02M FeCl was weighed 3 ·6H 2 O (142.8mg), 2mM NaCl (2.5mg) and 1mM NaH 2 PO 4 (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 Fe 2 O 3 Adding the precursor solution into a hydrothermal reaction kettle for reaction, and centrifugally washing after the reaction to obtain Fe 2 O 3 A 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 Fe 2 O 3 And (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 the washed product is redispersed in ultrapure water.
Step (3), adding H 2 PtCl 6 Adding the Fe into the water solution 2 O 3 Stirring the solution to obtain a first solution; reacting NaBH 4 Dropwise adding the solution into the first solution, stopping stirring after dropwise adding, and centrifugally washing to obtain Fe 2 O 3 @ Pt solution;
specifically, Pt nanoparticles were grown by mixing H 2 PtCl 6 Mixing and stirring for a certain time, and reducing in situ. By mixing the synthesized Fe 2 O 3 With a source of platinum H 2 PtCl 6 And mixing to realize the in-situ growth of Pt. Re-dissolved Fe 2 O 3 After diluting to 50mL to a concentration of 200. mu.g/mL, 100. mu.L of 100mg/mL H was added 2 PtCl 6 After stirring at room temperature for 20min, 1mL of 0.1M NaBH prepared in advance was added 4 The solution was added dropwise to the previous solution, centrifuged, and then dispersed again in the aqueous solution.
Step (4), adding Fe 2 O 3 Adding the @ Pt solution into a strain bottle, adding methoxypolyethylene glycol mercapto (mPEG-SH), ultrasonically treating, stirring at room temperature, and centrifugally washing to obtain Fe 2 O 3 @ 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 Fe 2 O 3 @ 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) 2 PtCl 6 And 1mL of 0.2M NaBH prepared beforehand 4 And (3) solution.
Example 5
This example differs from example 1 in that 100. mu.L of 300mg/mL H was added in step (3) 2 PtCl 6 And 1mL of 0.2M NaBH prepared beforehand 4 And (3) solution.
Example 6
This example differs from example 1 in that 100. mu.L of 20mg/mL H was added in step (3) 2 PtCl 6 And 1mL of 0.1M NaBH prepared beforehand 4 And (3) solution.
Example 7
This example differs from example 1 in that the amount of mPEG-SH added in step (4) is 50 mg.
Fe 2 O 3 Prepared by an improved one-step hydrothermal method, Pt nano particles are randomly distributed in Fe by an in-situ growth method 2 O 3 The surface of the nanoparticles. In FIG. 1, (a) and (b) are each Fe 2 O 3 SEM and TEM images of nanoparticles, it can be seen that Fe 2 O 3 Is regular polyhedron with uniform size of about 80-90nm and surface ratioIs smoother.
FIG. 2 shows H at different concentrations 2 PtCl 6 Fe synthesized by 2 O 3 @ 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) 2 O 3 The 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 Fe 2 O 3 SEM and TEM images of @ Pt nanoparticles, it can be seen that Pt nanoparticles are in Fe 2 O 3 The 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 seen 2 O 3 Typical lattice fringes. Wherein the lattice spacings of 0.227nm and 0.141nm correspond to the (111) crystal plane of Pt and hematite alpha-Fe, respectively 2 O 3 The (125) crystal plane of (c). The dotted lines in FIG. 4 clearly show Pt sodium and Fe 2 O 3 The 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 Fe 2 O 3 And XRD pattern of FP nanoparticles, from which it can be seen that its crystalline phase is hematite alpha-Fe 2 O 3 Phase (JCPDS 33-0664), and the crystallization condition is good, which can be confirmed from the 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 Fe 2 O 3 And the particle size distribution curve of FP nanoparticles. With loading of the Pt nanoparticles, the particle size of the nanoparticles showed an increase from 177.6nm to 222.0nm, which again indicated the success of in situ growth of Pt nanoparticles, andand because of the enhanced permeability and retention effect (EPR effect), a suitable particle size favors 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 Fe 2 O 3 Is typically trivalent Fe 3+ And (4) peak.
The loading of mPEG-SH is mainly to improve Fe 2 O 3 Stability of @ Pt nanoparticles by S atom and Fe in mPEG-SH 2 O 3 The 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 is mPEG-SH, FP and stabilized Fe 2 O 3 FTIR spectra for @ Pt nanoparticles. It can be seen that 1470cm in the stabilized FP spectrum -1 Corresponds to the-CH in mPEG-SH 2 Bending vibration of mPEG-SH, which accounts for successful loading of mPEG-SH.
Example 8
This example provides a Fe alloy prepared in the above example 2 O 3 The application of the @ Pt multifunctional nano-particles in preparing oxygen-sensitized acoustic dynamic therapeutic preparations for tumors.
Prepared Fe 2 O 3 The @ Pt multifunctional nano particles are centrifuged and re-dispersed in an aqueous solution system, and a corresponding therapeutic preparation is obtained after sterilization. In Fe 2 O 3 In the @ Pt nanoparticle, Fe 2 O 3 The nano particles can absorb the energy of ultrasonic waves and generate activated electrons to convert O into 2 Is converted into 1 O 2 Thereby killing the tumor cells. The Pt nanoparticles may be combined with Fe 2 O 3 The 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 part 2 O 2 Reaction to form O 2 The 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 method 2 O 3 The 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 Fe 2 O 3 In @ Pt nanoparticles, Fe 2 O 3 The nano particles can absorb the energy of ultrasonic waves and generate activated electrons to convert O into 2 Is converted into 1 O 2 Thereby 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 is known for its peroxidase mimic activity and can catalyze H 2 O 2 Decomposition to O 2 Thereby relieving the hypoxic state of the tumor site. Recorded in H by dissolved oxygen meter 2 O 2 And FP nanoparticles 2 Changes 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 concentrations 2 O 2 The 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 H 2 O 2 And Fe 2 O 3 Nanoparticles plus 1mM H 2 O 2 Change of the dissolution solution in the solution of (1).
FIG. 9 shows FP nanoparticles at different H 2 O 2 Oxygen concentration profile at concentration. As can be seen from the figure, FP nanoparticles can produce O rapidly and efficiently 2 And O is 2 Generation speed of (1) and H 2 O 2 Is concerned with. And Fe 2 O 3 The nanoparticles do not have peroxidase-like activity. This means FP nano-scaleThe particles can provide more oxygen source for the sonodynamic process, thereby inducing 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 dark 2 ) And then, detecting the absorbance change under different irradiation time by using an ultraviolet-visible spectrum. Meanwhile, Fe caused by ultrasonic irradiation is researched 2 O 3 ，FP+H 2 O 2 (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, Fe 2 O 3 FP nanoparticles, FP + H 2 O 2 Degradation curve of DPBF under ultrasound. 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 investigated 2 O 3 And mix H 2 O 2 The 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, Control, Fe 2 O 3 FP nanoparticles and FP + H 2 O 2 The 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 catalyst 2 O 3 Better acoustic-dynamic efficiency, and with H 2 O 2 The 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 studySolid UV-Vis Spectroscopy was used to calculate Fe 2 O 3 And band gap of FP nanoparticles.
In FIG. 11, (a) is Fe 2 O 3 And solid diffuse reflectance 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 Fe 2 O 3 The 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, which confirms the role of the co-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 Fe 2 O 3 And charge transfer capability and carrier separation efficiency of FP nanoparticles. FIG. 12 shows EIS Nyquist plot for FP nanoparticles vs. Fe 2 O 3 Smaller half circle, illustrating FP nanoparticles vs Fe 2 O 3 Higher electron-hole separation efficiency, indicating that the presence of the catalytic Pt nanoparticles can trap the generated electrons and facilitate electron and hole separation. The mechanism is as follows: first, Fe 2 O 3 As n-type semiconductor with bulk Fe 2 O 3 (-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 Fe 2 O 3 This hypothesis is supported by the fact that the work function (5.4eV) is lower than that of the noble metal Pt (5.65 eV). Thus, Fe 2 O 3 The 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 energy 2 O 3 Transfer 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 Fe 2 O 3 Rapidly 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 driveReduction of dissolved molecular oxygen present in the environment by catalytic excess of H 2 O 2 Generation of active oxygen 1 O 2 And 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) 2 O 3 And 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 conditions 2 30s), the survival rate of 4T1 cells is obviously reduced along with the increase of the concentration of FP nano particles, and Fe 2 O 3 Exhibiting a weaker acoustic-dynamic effect. This depends to a large extent on the Pt and Fe 2 O 3 A 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 Fe 2 O 3 Losing 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 culture 3 ]Cl 2 (RDPP) detection of intracellular oxygen levels, the fluorescence of which may be measured by O 2 And (4) quenching. As shown in FIG. 16, intact cells are due to lower O 2 The 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. The fluorescence intensity of FP nanoparticles with US-treated cells appeared to be stronger than cells without US due to O during sonodynamic 2 Is converted into 1 O 2 Thereby, the effect is achieved. All these phenomena are small, FP nanoparticles can improve hypoxic tumor microenvironment through peroxidase-like activity of Pt, and due to Pt and Fe 2 O 3 The 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 present disclosure. 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. Fe 2 O 3 A preparation method of the @ Pt multifunctional nano-particles is characterized by comprising the following steps:
FeCl is added 3 ·6H 2 O, NaCl and NaH 2 PO 4 Adding into ultrapure water, stirring and dissolving to obtain Fe 2 O 3 A precursor solution;
subjecting said Fe to 2 O 3 Adding the precursor solution into a hydrothermal reaction kettle for reaction, and centrifugally washing after the reaction to obtain Fe 2 O 3 A solution;
h is to be 2 PtCl 6 Adding the Fe into the water solution 2 O 3 Stirring the solution to obtain a first solution;
reacting NaBH 4 Dropwise adding the solution into the first solution, stopping stirring after dropwise adding, and centrifugally washing to obtain Fe 2 O 3 @ Pt solution;
mixing Fe 2 O 3 Adding the @ Pt solution into a strain bottle, adding methoxypolyethylene glycol mercapto (mPEG-SH), ultrasonically treating, stirring at room temperature, and centrifugally washing to obtain Fe 2 O 3 @ Pt multifunctional nanoparticles.
2. The method of claim 1, wherein the Fe is 2 O 3 In a precursor solution, FeCl 3 ·6H 2 O concentration of 0.02M, NaCl concentration of 1-2mM, NaH 2 PO 4 The 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 is 2 PtCl 6 The concentration of the aqueous solution is 20-500 mg/mL.
5. The method of claim 1, wherein the H is 2 PtCl 6 Aqueous solution with said Fe 2 O 3 The volume ratio of the solution was 3: 125.
6. The method of claim 1, wherein the NaBH is prepared by 4 The concentration of the solution is 0.1-0.2M, NaBH 4 Solution with Fe 2 O 3 The volume ratio of the solution was 1: 10.
7. The method according to claim 1, wherein the Fe is 2 O 3 Fe in @ Pt 2 O 3 The particle size range of the Pt nanoparticles is 80-90nm, Pt nanoparticles are uniformly loaded on the surface, and the particle size range of the Pt nanoparticles is 4-10 nm.
8. Fe prepared by the method of any one of claims 1 to 7 2 O 3 @ Pt multifunctional nanoparticles.
9. Fe of claim 8 2 O 3 The application of the @ Pt multifunctional nano-particles in preparing the oxygen-sensitized sonodynamic therapy preparation for the tumors.
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