CN112170832A - Raman probe and preparation method and application thereof - Google Patents

Raman probe and preparation method and application thereof Download PDF

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CN112170832A
CN112170832A CN202010947728.0A CN202010947728A CN112170832A CN 112170832 A CN112170832 A CN 112170832A CN 202010947728 A CN202010947728 A CN 202010947728A CN 112170832 A CN112170832 A CN 112170832A
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叶坚
李进
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Shanghai Jiaotong University
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Abstract

The invention relates to a Raman probe and a preparation method and application thereof. The preparation method of the Raman probe comprises the following steps: adding metal nanoparticles into a first solution, and performing centrifugal dispersion to obtain a metal nanoparticle solution, wherein the first solution comprises a first surfactant and deionized water; adding the metal nanoparticle solution into the first Raman molecule solution, and centrifugally washingAfter washing, modified nanoparticles are obtained, wherein the modified nanoparticles are nanoparticles with the first Raman molecule modified on the outer surface of the metal nanoparticles, and the Raman signal of the Raman molecule is 1800-2800cm‑1(ii) a Adding the modified nanoparticles into a second solution, wherein the second solution comprises a second surfactant, a metal ion compound and a reducing agent, and vibrating and stirring to enable the modified nanoparticles to be wrapped by a metal shell layer. The Raman probe, the preparation method and the application thereof have the advantages of high signal-to-noise ratio, high stability and good Raman signal repeatability.

Description

Raman probe and preparation method and application thereof
Technical Field
The invention relates to the field of nanotechnology, in particular to a Raman probe and a preparation method and application thereof.
Background
Raman spectroscopy is a type of fingerprint spectrum that characterizes molecular vibrations. The metal nanoparticles (or the metal rough surface) generate a plasmon resonance phenomenon under the action of incident light, so that the raman spectrum of molecules adsorbed on the surface of the metal nanoparticles (or the metal rough surface) is greatly enhanced, which is called as a Surface Enhanced Raman Scattering (SERS) effect. In recent years, anchoring raman reporter molecules to the surface of metal nanoparticles (i.e., SERS substrates) has received increasing attention as enhanced raman probes. Different Raman reporter molecules are marked on the metal nano particles, so that enhanced Raman probes with different signals can be obtained, and the application of multi-index molecular detection and biological imaging is expected to be realized
The spectral signals of the traditional Raman reporter molecules are multiple peaks and are easy to overlap with each other; and is in the fingerprint area. Because biological samples such as cells contain a large amount of components such as protein, phospholipid and the like, multiple Raman peaks of the substances are also positioned in the area, so that signals of the reporter molecules coincide with signals of biological endogenous components, background noise is generated, and the detection and imaging of high signal-to-noise ratio and multiple indexes in the biological samples are not facilitated.
Generally, detection accuracy is improved by modifying raman molecules, for example, by designing and synthesizing alkynyl-containing raman dye molecules and using phenylboronic acid-modified gold nano-dimeric probes, high-accuracy detection of sialic acid in cancer cells and tissues is realized. In addition, the traditional probe adsorbs Raman signal molecules on the surface of the gold nanoparticle, so that the enhancement effect is general, the Raman signal repeatability is poor, and the stability is poor.
Disclosure of Invention
Therefore, it is necessary to provide a raman probe, a preparation method and an application thereof for improving the signal-to-noise ratio and the repeatability of the raman signal.
A preparation method of a Raman probe comprises the following steps:
adding metal nanoparticles into a first solution, and performing centrifugal dispersion to obtain a metal nanoparticle solution, wherein the first solution comprises a first surfactant and deionized water;
adding the metal nanoparticle solution into a first Raman molecule solution, centrifuging and washing to obtain modified nanoparticles, wherein the modified nanoparticles are nanoparticles modified with the first Raman molecule on the outer surface of the metal nanoparticles, and the Raman signal of the Raman molecule is 1800-2800cm-1；
And adding the modified nano particles into a second solution, wherein the second solution comprises a second surfactant, a metal ion compound and a reducing agent, and vibrating and stirring to enable the modified nano particles to be wrapped with a metal shell layer, so as to obtain the Raman probe.
The preparation method of the Raman probe comprises the steps of adding metal nanoparticles into a first solution, carrying out centrifugal dispersion to obtain a metal nanoparticle solution, then adding the metal nanoparticle solution into a first Raman molecule solution, carrying out centrifugal washing to obtain modified nanoparticles, wherein the modified nanoparticles are nanoparticles with the first Raman molecule modified on the outer surface of the metal nanoparticles, and the Raman signal of the first Raman molecule is 1800-2800 cm--1In this way, the first raman molecule is embedded in the internal gap of the metal nanoparticle, so that the modified nanoparticle is added into the second solution through the strong plasmon coupling effect of the nano-gap structure, the second solution comprises the second surfactant, the metal ion compound and the reducing agent, the modified nanoparticle is wrapped by the metal shell after being vibrated and stirred, and the raman probe is obtained, namely, the first raman molecule is positioned in the gap formed by the metal nanoparticle and the metal shell, and the raman signal of the first raman molecule is 1800-2800 cm--1The characteristic signal is positioned in the Raman silent area, so that the background noise is greatly reduced, and the signal to noise ratio is further improved, so that the Raman probe has high signal to noise ratio, high stability and good Raman signal repeatability.
In one embodiment, in the step of adding the metal nanoparticle solution to the first raman molecule solution, and centrifugally washing to obtain modified nanoparticles: before centrifugal washing, the metal nanoparticle solution and the first Raman molecule solution are vibrated for 2-20 minutes.
In one embodiment, after the step of adding the modified nanoparticles into a second solution, where the second solution includes a second surfactant, a metal ion compound and a reducing agent, and shaking and stirring the solution to wrap a metal shell around the modified nanoparticles, the method further includes the steps of:
and oscillating and mixing the Raman probe and polydopamine, mesoporous silica or a mercapto compound to coat a polydopamine layer, a mesoporous silica layer or a mercapto compound layer outside the Raman probe.
In one embodiment, after the step of adding the modified nanoparticles into a second solution, where the second solution includes a second surfactant, a metal ion compound and a reducing agent, and shaking and stirring the solution to wrap a metal shell around the modified nanoparticles, the method further includes the steps of:
and adding the Raman probe into a second Raman molecule solution, and after centrifugal washing, modifying the second Raman molecule on the outer surface of the Raman probe.
In one embodiment, the first surfactant and the second surfactant are each selected from one or more of cetyl ammonium chloride, cetyl ammonium bromide, polyvinylpyrrolidone.
In one embodiment, the reducing agent is selected from one or more of ascorbic acid, hydroxylamine hydrochloride and formaldehyde.
A Raman probe comprises a metal nano-core, a first Raman signal layer and a first metal shell layer which are sequentially wrapped, wherein a gap is formed between the metal nano-core and the first metal shell layer, and the first Raman signal layer is positioned in the gap; the first Raman signalThe layer comprises a first Raman molecule having a Raman signal of 1800--1。
The Raman probe comprises a metal nano-core, a first Raman signal layer and a first metal shell layer which are sequentially wrapped, a gap is formed between the metal nano-core and the first metal shell layer, the first Raman signal layer is positioned in the gap, the first Raman signal layer comprises a first Raman molecule, and the Raman signal of the first Raman molecule is 1800-2800 cm--1The characteristic signal is positioned in the Raman silencing area, so that background noise is greatly reduced, and the signal-to-noise ratio is improved.
In one embodiment, the first raman molecule comprises a sulfur-containing compound with an alkynyl group or a deuterium atom.
In one embodiment, the Raman signal detection device further comprises a second Raman signal layer and a second metal shell layer which are sequentially wrapped outside the first metal shell layer.
The Raman probe is applied to the fields of biomedical imaging, biomedical detection, anti-counterfeiting or cryptography.
Drawings
FIG. 1 is a Raman spectrum of a Raman probe obtained in example 1;
FIG. 2 is a transmission electron microscope photograph of a Raman probe obtained in example 1;
FIG. 3 is a Raman spectrum of the Raman probe obtained in example 2;
FIG. 4 is a transmission electron microscope photograph of a Raman probe obtained in example 2;
FIG. 5 is a Raman spectrum of the Raman probe obtained in example 3;
FIG. 6 is a transmission electron microscope photograph of a Raman probe obtained in example 3;
FIG. 7 is a Raman spectrum of the Raman probe obtained in example 4;
FIG. 8 is a transmission electron microscope photograph of a Raman probe obtained in example 4;
FIG. 9 is a graph showing UV-VIS absorption spectra of the Raman probe obtained in example 1 and the Raman probe obtained in comparative example 1;
FIG. 10 is a Raman spectrum of the Raman probe obtained in example 1 and the Raman probe obtained in comparative example 1;
fig. 11 is a raman spectrum of the raman probe obtained in example 1 and the raman probe obtained in comparative example 2.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The preparation method of the raman probe of an embodiment includes the steps of:
s1: and adding the metal nanoparticles into the first solution, and performing centrifugal dispersion to obtain a metal nanoparticle solution, wherein the first solution comprises a first surfactant and deionized water.
Specifically, the metal nanoparticles may be gold nanoparticles or the like, and the particle diameter thereof may be 5 to 40 nm. The first surfactant may be one or more selected from cetyl ammonium chloride, cetyl ammonium bromide, and polyvinylpyrrolidone, and in this embodiment, the first surfactant is cetyl ammonium chloride. The concentration of the first solution is 0.01-0.05mL/L, and the volume of the first solution can be 0.5-3 mL. The parameters of the centrifugal dispersion were: the temperature is 4 ℃, the centrifugation speed is 10000-.
The preparation method of the metal nano-core particle may be a sodium citrate thermal reduction method, a seed growth method, a polyvinylpyrrolidone protection reduction method, or an ultraviolet light initiated reduction method, and the like, which is not limited herein.
S2: and adding the metal nanoparticle solution into the first Raman molecule solution, and centrifugally washing to obtain the modified nanoparticles. Wherein the modified nanoparticles are metal nanoparticles, the outer surfaces of which are modified with first Raman moleculesThe metal nanoparticle is coated with a first Raman molecule layer, wherein the Raman signal of the first Raman molecule is 1800-2800cm-1。
The Raman signal of the first Raman molecule is 1800-2800cm-1The background noise of imaging or detection is greatly reduced, and the signal-to-noise ratio is high. And adding the metal nanoparticle solution into the first Raman molecule solution, and centrifuging and washing to enable the first Raman molecule to be embedded in the nanometer gap of the metal nanoparticle, so that the background noise is reduced, and simultaneously, the Raman signal of the probe in a silent region is improved, which is due to the strong plasmon coupling effect of the nanometer gap structure. Wherein, the centrifugal technological parameters can be as follows: the temperature is 4 ℃, the centrifugation speed is 10000-. The number of washes may be 3, the washes being primarily to wash away excess first raman molecules.
Further, the first raman molecule comprises a sulfur-containing compound having an alkynyl group or a sulfur-containing compound having a deuterium atom, and further, the first raman molecule is selected from one or more of S- (4-ethynylphenyl) acetoacetate, S- (4- ((trimethylsilyl) ethynyl) phenyl) acetoacetate, 4' -thiobisthiophenol, and 2-mercapto-4, 5,6,7-d 4-benzimidazole.
In one embodiment, before the centrifugal washing, the metal nanoparticle solution and the first raman molecule solution are oscillated for 2-20 minutes at a frequency of 100-.
S3: and adding the modified nano particles into a second solution, wherein the second solution comprises a second surfactant, a metal ion compound and a reducing agent, and vibrating and stirring to enable the modified nano particles to be wrapped with a metal shell layer, so as to obtain the Raman probe.
Specifically, the process parameters of the shaking stirring are as follows: the oscillation time is 2-20 minutes, and the oscillation frequency is 100-300 rpm/min. The second solution is a reaction solution for forming a metal shell layer, the second surfactant can be one or more selected from cetyl ammonium chloride, cetyl ammonium bromide and polyvinylpyrrolidone, and the metal ion compound solution is one or more selected from chloroauric acid solution, silver nitrate solution, copper chloride solution, copper sulfate solution and chloroplatinic acid solution. The selection of the metal ion compound solution is related to the metal in the formed metal shell layer, and the corresponding metal ion compound solution may be selected.
In one embodiment, the reducing agent is selected from one or more of ascorbic acid, hydroxylamine hydrochloride, formaldehyde. The second surfactant plays a stabilizing role, and under the action of oscillation, the metal ion compound solution reacts with the reducing agent to form a metal shell layer. When the shell layer is a gold shell layer, the metal ion compound solution reacted with the reducing agent is a chloroauric acid solution; when the shell layer is a silver shell layer, the metal ion compound solution reacted with the reducing agent is a silver nitrate solution; when the shell layer is a copper shell layer, the metal ion compound solution reacted with the reducing agent is a copper chloride solution and/or a copper sulfate solution; when the shell layer is a platinum shell layer, the metal ion compound solution reacted with the reducing agent is a chloroplatinic acid solution.
After the metal shell layer is formed by means of vibration stirring, a gap is formed between the metal nanoparticle (namely the metal nano core) and the metal shell layer, a core-shell structure is formed among the metal nanoparticle, the first Raman molecule layer and the metal shell layer, the first Raman molecule layer grows in the gap, the Raman signal is enhanced by the strong plasmon coupling effect of the gap structure, and the sensitivity is improved.
The preparation method of the Raman probe comprises the steps of adding metal nanoparticles into a first solution, carrying out centrifugal dispersion to obtain a metal nanoparticle solution, adding the metal nanoparticle solution into a first Raman molecule solution, and carrying out centrifugal washingObtaining modified nanoparticles, wherein the modified nanoparticles are nanoparticles formed by modifying the outer surface of the metal nanoparticles with the first Raman molecule, and the Raman signal of the first Raman molecule is 1800-2800cm-1In this way, the first raman molecule is embedded in the internal gap of the metal nanoparticle, so that the modified nanoparticle is added into the second solution through the strong plasmon coupling effect of the nano-gap structure, the second solution comprises the second surfactant, the metal ion compound and the reducing agent, the modified nanoparticle is wrapped by the metal shell after being vibrated and stirred, and the raman probe is obtained, namely, the first raman molecule is positioned in the gap formed by the metal nanoparticle and the metal shell, and the raman signal of the first raman molecule is 1800-2800 cm--1The characteristic signal is positioned in the Raman silent area, so that the background noise is greatly reduced, and the signal to noise ratio is further improved, so that the Raman probe has high signal to noise ratio, high stability and good Raman signal repeatability.
In an embodiment, after step S3, the method further includes step S4: and oscillating and mixing the Raman probe and polydopamine, mesoporous silica or a mercapto compound to coat the polydopamine layer, the mesoporous silica layer or the mercapto compound layer outside the Raman probe. Therefore, the poly-dopamine layer, the mesoporous silica layer or the mercapto compound layer and the metal shell layer generate electrostatic adsorption or chemical covalent binding, and the Raman probe is more stable. Wherein, the oscillation process parameters are as follows: at normal temperature, the rotation speed is 5000-.
In one embodiment, after step S3, the method further includes step S40: and adding the Raman probe into the second Raman molecule solution, and after centrifugal washing, modifying the outer surface of the Raman probe with a second Raman molecule. Wherein the Raman signal of the second Raman molecule is 1800-2800cm-1。
The Raman signal of the second Raman molecule is 1800-2800cm-1The background noise of imaging or detection is greatly reduced, and the signal-to-noise ratio is high. Adding the Raman probe into a second Raman molecule solution, and centrifugally washing to enable the second Raman probe to beThe Raman molecules are embedded in the outer surface of the Raman probe, so that the background noise is reduced, and simultaneously, the Raman signal of the probe in a silent region is improved, which is caused by the strong plasmon coupling effect of the nano gap structure. Wherein, the centrifugal technological parameters can be as follows: the temperature is 4 ℃, the centrifugation speed is 10000-. The number of washes may be 3, the washes being primarily to wash away excess second raman molecules.
Further, the second raman molecule comprises a sulfur-containing compound with an alkynyl group or a sulfur-containing compound with a deuterium atom, and further, the second raman molecule is selected from one or more of S- (4-ethynylphenyl) acetoacetate, S- (4- ((trimethylsilyl) ethynyl) phenyl) acetoacetate, 4' -thiobisthiophenol, and 2-mercapto-4, 5,6,7-d 4-benzimidazole.
After step S40, the method further includes step S50: and adding the Raman probe with the outer surface modified with the second Raman molecule into a second solution, wherein the second solution comprises a second surfactant, a metal ion compound and a reducing agent, and vibrating and stirring to enable the outer surface to be wrapped with a second metal shell layer. It should be noted that the second solution and the process parameters are as described in step S3, and are not described herein again.
Further, the mesoporous silica, the mercapto compound, or the high molecular compound capable of generating electrostatic adsorption or chemical covalent bonding with the shell layer is coated outside the nanoparticle in which the second raman signal molecule is modified in the gap of the second layer obtained in step S50, thereby further improving the stability of the nanoparticle. And a multilayer core-shell structure is adopted, so that the signal-to-noise ratio is further improved.
The raman probe of an embodiment includes a metal nano-core, a first raman signal layer, and a first metal shell layer, which are sequentially wrapped, where a gap is formed between the metal nano-core and the first metal shell layer, that is, a gap is formed between the core shells, and the first raman signal layer is located in the gap. The first Raman signal layer comprises a first Raman molecule having a Raman signal of 1800--1。
The Raman probe comprises a metal nano-core, a metal nano-core and a metal nano-core,A first Raman signal layer and a first metal shell layer, wherein a gap is arranged between the metal nano-core and the first metal shell layer, the first Raman signal layer is positioned in the gap and comprises a first Raman molecule, and the Raman signal of the first Raman molecule is 1800-2800 cm--1The characteristic signal is positioned in the Raman silencing area, so that background noise is greatly reduced, and the signal-to-noise ratio is improved.
The principle that the first Raman signal layer is positioned in the gap between the metal nano-core and the first metal shell layer to improve the signal-to-noise ratio is as follows: firstly, a large number of electromagnetic field enhancement and chemical enhancement hot spots are provided by sub-nanometer gaps between the metal nanometer core and the metal shell (core-shell for short). Secondly, the charge transfer effect at the molecular junction between the core and shell will produce strong chemical enhancement and appropriate electromagnetic enhancement. The strong chemical enhancement is mainly due to the transfer of electrons from the high-energy orbitals of the molecules to the metal layer (including the nano-core and shell layer) and then from the metal layer to the low-energy orbitals of the molecules. The electromagnetic field enhancement is mainly local electromagnetic field enhancement caused by surface plasma resonance, and the chemical enhancement is mainly electron resonance generated by charge transfer of metal and adsorbed molecules under the action of incident light.
The first raman molecular layer of the raman probe of the embodiment is located between the core shells, and compared with a core shell structure formed by the metal nano core and the metal shell layer, the first raman molecular layer is equivalent to a gap between the core shells, and the size of the first raman molecular layer is in a nanometer level, so that a large number of electromagnetic field enhancement and chemical enhancement hot spots are provided, the raman signal of the raman probe is improved, and the signal to noise ratio is improved.
In one embodiment, the first raman molecule is embedded on the metal nanoparticle, thereby forming a gap under the action of the first raman molecule. The first Raman signal molecules in the gap are adsorbed to the metal shell layer through acting force. Further, the first raman molecule comprises a sulfur-containing compound with an alkynyl group, and further, the first raman molecule is selected from one or more of S- (4-ethynylphenyl) acetoacetate, S- (4- ((trimethylsilyl) ethynyl) phenyl) acetoacetate, 4' -thiobisthiophenol, and 2-mercapto-4, 5,6,7-d 4-benzimidazole.
In one embodiment, the metal nanoparticle is a gold nanoparticle or a silver nanoparticle, and the first metal shell layer is a gold shell layer, a silver shell layer, a copper shell layer, or a platinum shell layer.
The thicknesses of the metal nanocore, the first raman molecular layer, and the first metal shell layer may be all 5 to 50 nm.
In one embodiment, the raman probe further comprises a second raman signal layer and a second metal shell layer sequentially wrapped around the first metal shell layer. The second raman molecule comprises a sulfur-containing compound with an alkynyl group, and further the second raman molecule is selected from one or more of S- (4-ethynylphenyl) acetoacetate, S- (4- ((trimethylsilyl) ethynyl) phenyl) acetoacetate, 4' -thiobisthiophenol, 2-mercapto-4, 5,6,7-d 4-benzimidazole. The second metal shell layer is a gold shell layer, a silver shell layer, a copper shell layer or a platinum shell layer. The first raman molecule and the second raman molecule may have the same structure or different structures; the first metal shell layer and the second metal shell layer may be the same or different.
The Raman probe is applied to the fields of biomedical imaging, biomedical detection, anti-counterfeiting or cryptography. The biomedical detection comprises DNA detection, RNA detection, exosome detection, antigen-antibody detection, a tumor detection kit, a tumor treatment kit, a tumor detection and treatment integrated kit, tumor drugs and the like.
The application of the Raman probe can improve the detection precision and sensitivity and can also improve the imaging speed.
Use in vivo (mouse) imaging and ex vivo tissue imaging is exemplified.
An imaging method of a raman probe of an embodiment includes the steps of:
uniformly dispersing the Raman probe of any embodiment in physiological saline or PBS (phosphate buffer solution) with the pH value of 7.4 to obtain 0.01-50nmol/L Raman probe solution;
locally injecting a raman probe solution dispersed by ultrasonic into the body of a test animal;
and after 0.5-24h of injection, performing Raman imaging on the interested part of the test animal by using a Raman spectrometer, and analyzing the imaging result. In the Raman imaging process, the integral time of each pixel point is 0.7-10000 ms. Further, the integration time of each pixel point may be 10-1000 ms.
A method of imaging a raman probe of another embodiment includes the steps of:
uniformly dispersing the Raman probe of any embodiment in physiological saline or PBS (phosphate buffer solution) with the pH value of 7.4 to obtain 0.01-50nmol/L Raman probe solution;
and (3) incubating the isolated tissue or the isolated organ and the Raman probe solution subjected to ultrasonic dispersion for 10-60 minutes, performing Raman imaging on the isolated tissue or the isolated organ by using a Raman spectrometer, and analyzing the imaging result.
In the Raman imaging process, the integral time of each pixel point is 0.7-10000 ms. Further, the integration time of each pixel point may be 10-1000 ms.
A method of imaging a raman probe of another embodiment includes the steps of:
uniformly dispersing the Raman probe of any embodiment in physiological saline or PBS (phosphate buffer solution) with the pH value of 7.4 to obtain 0.01-50nmol/L Raman probe solution;
locally injecting an ultrasonically dispersed raman probe solution into a dead human or animal body;
and after 0.5-24h of injection, performing Raman imaging on the interested part by using a Raman spectrometer, and analyzing the imaging result. In the Raman imaging process, the integral time of each pixel point is 0.7-10000 ms. Further, the integration time of each pixel point may be 10-1000 ms.
According to the Raman probe and the preparation method and application thereof, the Raman signal of the Raman probe is improved through the gap structure, and the Raman signal of the Raman molecule is positioned in the silent area, so that the background noise is reduced, the signal to noise ratio is improved, and the detection sensitivity is further improved, and compared with the common probes such as a nano gold ball and a nano gold rod, the Raman enhancement performance is improved by 4-5 orders of magnitude. The Raman probe has a core-shell structure, and all layers are adsorbed or covalently acted, so that the structural stability and the light stability are high, and low photo-thermal damage is realized under non-resonance excitation. Therefore, the Raman probe can be suitable for molecular markers with different Raman signals, is simple to prepare, and can realize multi-index molecular detection and ultra-fast reading biomedical Raman imaging. It should be noted that by changing the types of the first raman molecule and the second raman molecule, a multicolor raman probe with a high signal-to-noise ratio can be obtained.
The following is a description with reference to specific examples, in which all the starting materials are commercially available.
Example 1
Adding 400uL of gold nano-core particles with the concentration of 1nmol/L into 1mL of hexadecyl ammonium chloride solution with the concentration of 0.02mol/L, wherein the gold nano-core particles are prepared by adopting a seed growth method, the particle size of the gold nano-core particles is 25nm, centrifugally separating, and re-dispersing in 400uL of hexadecyl ammonium chloride solution with the concentration of 0.02mol/L to obtain the gold nano-core taking hexadecyl ammonium chloride as a stabilizer. Wherein, the parameters of centrifugal dispersion are as follows: the temperature is 4 ℃, the centrifugation speed is 10000rpm/min, and the centrifugation time is 5 minutes;
adding 20uL of 4,4 '-thiobisthiophenol solution with the concentration of 10mmol/L into the obtained gold nano-core taking the hexadecyl ammonium chloride as the stabilizing agent, mixing and oscillating for 10 minutes, centrifuging and washing, re-dispersing in 200uL of hexadecyl ammonium chloride solution with the concentration of 0.1mol/L, repeating for three times to obtain the nano-particles of which the outer surfaces are modified with a layer of 4,4' -thiobisthiophenol as a signal molecular layer; wherein the oscillation frequency is 150rpm/min, and the centrifugal dispersion parameters are as follows: the temperature is 4 ℃, the centrifugation speed is 8000rpm/min, and the centrifugation time is 5 minutes;
adding the obtained gold nanoparticles with the layer of 4,4' -thiobisthiophenol modified on the outer surface of the gold nanoparticle into a growth solution, mixing the growth solution with 4mL of 0.05mol/L hexadecyl ammonium chloride solution, 200uL of 4.86mmol/L chloroauric acid solution and 120uL of 40mmol/L ascorbic acid solution, and oscillating and stirring to wrap a gold shell layer outside the 4,4' -thiobisthiophenol layer to obtain the Raman probe taking the 4,4' -thiobisthiophenol as Raman signal molecules in a Raman signal layer.
The raman spectrum and transmission electron microscope image of the raman probe obtained in example 1 are shown in fig. 1 and 2, and the particle diameter is about 60 nm.
Example 2
Adding 400uL of gold nano-core particles with the concentration of 1nmol/L into 1mL of hexadecyl ammonium chloride solution with the concentration of 0.02mol/L, wherein the gold nano-core particles are prepared by adopting a seed growth method, the particle size of the gold nano-core particles is 25nm, centrifugally separating, and re-dispersing in 400uL of hexadecyl ammonium chloride solution with the concentration of 0.02mol/L to obtain the gold nano-core taking hexadecyl ammonium chloride as a stabilizer. Wherein, the parameters of centrifugal dispersion are as follows: the temperature is 4 ℃, the centrifugation speed is 10000rpm/min, and the centrifugation time is 5 minutes;
adding 20uL of S- (4- ((trimethylsilyl) ethynyl) phenyl) acetoacetate solution with the concentration of 10mmol/L into the obtained gold nano-core with the hexadecyl ammonium chloride as a stabilizing agent, mixing and oscillating for 10 minutes, centrifuging and washing, re-dispersing in 200uL of hexadecyl ammonium chloride solution with the concentration of 0.1mol/L, and repeating for three times to obtain the nano-particles with the S- (4- ((trimethylsilyl) ethynyl) phenyl) acetoacetate modified on the outer surface of the gold nano-core as a signal molecular layer; wherein the oscillation frequency is 150rpm/min, and the centrifugal dispersion parameters are as follows: the temperature is 4 ℃, the centrifugation speed is 8000rpm/min, and the centrifugation time is 5 minutes;
adding the obtained gold nanoparticles with a layer of S- (4- ((trimethylsilyl) ethynyl) phenyl) acetoacetic acid modified on the outer surface of the gold nanoparticle into a growth solution, mixing the growth solution with 4mL of 0.05mol/L hexadecyl ammonium chloride solution, 200uL of 4.86mmol/L chloroauric acid solution and 120uL of 40mmol/L ascorbic acid solution, and stirring in an oscillating way to ensure that a gold shell layer is wrapped outside the S- (4- ((trimethylsilyl) ethynyl) phenyl) acetoacetic acid layer, thereby obtaining the Raman probe taking S- (4- ((trimethylsilyl) ethynyl) phenyl) acetoacetic acid as Raman signal molecules in the Raman signal layer.
Fig. 3 and 4 show a raman spectrum and a transmission electron microscope image of the raman probe obtained in example 2.
Example 3
Adding 400uL of gold nano-core particles with the concentration of 1nmol/L into 1mL of hexadecyl ammonium chloride solution with the concentration of 0.02mol/L, wherein the gold nano-core particles are prepared by adopting a seed growth method, the particle size of the gold nano-core particles is 25nm, centrifugally separating, and re-dispersing in 400uL of hexadecyl ammonium chloride solution with the concentration of 0.02mol/L to obtain gold nano-cores with hexadecyl ammonium chloride as a stabilizer; wherein, the parameters of centrifugal dispersion are as follows: the temperature is 4 ℃, the centrifugation speed is 10000rpm/min, and the centrifugation time is 5 minutes;
adding 20uL of S- (4-ethynylphenyl) acetoacetate solution with the concentration of 10mmol/L into the obtained gold nano-core with the hexadecyl ammonium chloride as a stabilizing agent, mixing and oscillating for 10 minutes, centrifuging and washing, re-dispersing in 200uL of hexadecyl ammonium chloride solution with the concentration of 0.1mol/L, and repeating for three times to obtain the nano-particles with the outer surface of the gold nano-core modified with a layer of S- (4-ethynylphenyl) acetoacetate as a signal molecular layer; wherein the oscillation frequency is 150rpm/min, and the centrifugal dispersion parameters are as follows: the temperature is 4 ℃, the centrifugation speed is 8000rpm/min, and the centrifugation time is 5 minutes;
adding the obtained gold nanoparticles with the S- (4-ethynylphenyl) acetoacetic acid layer modified on the outer surface of the gold nanoparticle into a growth solution, mixing the growth solution with 4mL of 0.05mol/L hexadecyl ammonium chloride solution, 200uL of 4.86mmol/L chloroauric acid solution and 120uL of 40mmol/L ascorbic acid solution, and oscillating and stirring to ensure that the S- (4-ethynylphenyl) acetoacetic acid layer is wrapped with a gold shell layer, thereby obtaining the Raman probe with the S- (4-ethynylphenyl) acetoacetic acid as Raman signal molecules in the Raman signal layer.
Fig. 5 and 6 show a raman spectrum and a transmission electron microscope image of the raman probe obtained in example 3.
Example 4
Adding 400uL of gold nano-core particles with the concentration of 1nmol/L into 1mL of hexadecyl ammonium chloride solution with the concentration of 0.02mol/L, wherein the gold nano-core particles are prepared by adopting a seed growth method, the particle size of the gold nano-core particles is 25nm, centrifugally separating, and re-dispersing in 400uL of hexadecyl ammonium chloride solution with the concentration of 0.02mol/L to obtain gold nano-cores with hexadecyl ammonium chloride as a stabilizer; wherein, the parameters of centrifugal dispersion are as follows: the temperature is 4 ℃, the centrifugation speed is 10000rpm/min, and the centrifugation time is 5 minutes;
adding 20uL of 2-mercapto-4, 5,6,7-d 4-benzimidazole solution with the concentration of 10mmol/L into the obtained gold nano-core taking the hexadecyl ammonium chloride as the stabilizing agent, mixing and oscillating for 10 minutes, centrifuging and washing, re-dispersing in 200uL of hexadecyl ammonium chloride solution with the concentration of 0.1mol/L, and repeating for three times to obtain the nano-particles of which the outer surface of the gold nano-core is modified with a layer of 2-mercapto-4, 5,6,7-d 4-benzimidazole as a signal molecular layer; wherein the oscillation frequency is 150rpm/min, and the centrifugal dispersion parameters are as follows: the temperature is 4 ℃, the centrifugation speed is 8000rpm/min, and the centrifugation time is 5 minutes;
adding the obtained gold nanoparticles with the layer of 2-mercapto-4, 5,6,7-d 4-benzimidazole modified on the outer surface of the gold nanoparticle into a growth solution, mixing the growth solution with 4mL of 0.05mol/L hexadecyl ammonium chloride solution, 200uL of 4.86mmol/L chloroauric acid solution and 120uL of 40mmol/L ascorbic acid solution, oscillating and stirring to wrap a gold shell layer outside the 2-mercapto-4, 5,6,7-d 4-benzimidazole layer, and obtaining the Raman probe taking the 2-mercapto-4, 5,6,7-d 4-benzimidazole as Raman signal molecules in a Raman signal layer.
Fig. 7 and 8 show a raman spectrum and a transmission electron microscope image of the raman probe obtained in example 4.
Example 5
Adding 5mL0.4nmol/L of the Raman probe prepared in the example 1, wherein the particle size of the Raman probe is 60nm, into 5mL0.1mol/L of hexadecyl ammonium chloride solution, centrifugally separating and re-dispersing the Raman probe into the 5mL0.001mol/L of hexadecyl ammonium chloride solution, and adding 30 mu L of 0.1mol/L of NaOH solution to adjust the pH value of the solution to 10 to obtain a pH value modified nanoparticle solution; wherein, the parameters of centrifugal dispersion are as follows: the temperature is 4 ℃, the centrifugation speed is 8000rpm/min, and the centrifugation time is 5 minutes;
adding a methanol solution containing 5% tetraethyl orthosilicate into the pH value modified nanoparticle solution for three times, adding 50 mul of the methanol solution containing 5% tetraethyl orthosilicate each time, and continuing stirring for reaction for 15 hours to obtain a Raman probe solution coated with a mesoporous silica layer, wherein the thickness of the mesoporous silica layer is 12 nm;
and centrifuging the Raman probe solution wrapped with the mesoporous silica layer, dispersing the solution in ethanol, adding 6 solid ammonium nitrate particles for ultrasonic treatment, repeatedly washing for 3 times, and centrifugally dispersing the solution in ethanol to remove the hexadecyl ammonium chloride to obtain the treated Raman probe, namely the Raman probe with the outer layer structure of mesoporous silica.
Comparative example 1
Adding 400uL of gold nano-core particles (the particle size is 25nm) with the concentration of 1 nmol/prepared by adopting a seed growth method into 1mL of 0.02mol/L hexadecyl ammonium chloride solution, and centrifugally separating and re-dispersing the gold nano-core particles in the 400uL of 0.02mol/L hexadecyl ammonium chloride solution to obtain gold nano-cores with hexadecyl ammonium chloride as a stabilizer; wherein, the parameters of centrifugal dispersion are as follows: the temperature is 4 ℃, the centrifugation speed is 8000rpm/min, and the centrifugation time is 5 minutes;
adding 20uL of 4,4 '-thiobisthiophenol solution with the concentration of 10mmol/L into the obtained gold nano-core taking the hexadecyl ammonium chloride as the stabilizing agent, mixing and oscillating for 10 minutes, centrifuging and washing, re-dispersing in 200uL of hexadecyl ammonium chloride solution with the concentration of 0.1mol/L, repeating for three times to obtain the nano-particles of which the outer surfaces are modified with a layer of 4,4' -thiobisthiophenol as a signal molecular layer; wherein the oscillation frequency is 150rpm/min, and the centrifugal dispersion parameters are as follows: the temperature is 4 ℃, the centrifugation speed is 8000-10000rpm/min, and the centrifugation time is 5 minutes.
As can be seen from fig. 9 and 10, the difference in morphology between the raman probe obtained in comparative example 1 and the raman probe obtained in example 1 is that the raman probe mainly obtained in comparative example 1 has only the nano-core and the first raman signal layer of the raman probe obtained in example 1. This topographical difference exhibited a large difference in raman intensity, as shown in fig. 10. Under the condition of uniform test acquisition time, the raman signal intensity of the raman probe obtained in example 1 is very significantly greater than that of the raman probe obtained in comparative example 1.
Comparative example 2
Adding 400uL of gold nano-core particles with the concentration of 1nmol/L into 1mL of hexadecyl ammonium chloride solution with the concentration of 0.02mol/L, wherein the gold nano-core particles are prepared by adopting a seed growth method, the particle size of the gold nano-core particles is 25nm, centrifugally separating, and re-dispersing in 400uL of hexadecyl ammonium chloride solution with the concentration of 0.02mol/L to obtain the gold nano-core taking hexadecyl ammonium chloride as a stabilizer. Wherein, the parameters of centrifugal dispersion are as follows: the temperature is 4 ℃, the centrifugation speed is 10000rpm/min, and the centrifugation time is 5 minutes;
adding 20uL of 1, 4-benzenedithiol ethanol solution with the concentration of 10mmol/L into the obtained gold nano-core taking the hexadecyl ammonium chloride as the stabilizing agent, mixing and oscillating for 10 minutes, centrifuging and washing, re-dispersing in 200uL of hexadecyl ammonium chloride solution with the concentration of 0.1mol/L, repeating for three times to obtain the nano-particles of which the outer surfaces are modified with a layer of 1, 4-benzenedithiol serving as a signal molecular layer; wherein the oscillation frequency is 150rpm/min, and the centrifugal dispersion parameters are as follows: the temperature is 4 ℃, the centrifugation speed is 8000rpm/min, and the centrifugation time is 5 minutes;
adding the obtained gold nanoparticles with the layer of 1, 4-benzenedithiol modified on the outer surface of the gold nanoparticle into a growth solution, mixing the growth solution with 4mL of 0.05mol/L hexadecyl ammonium chloride solution, 200uL of 4.86mmol/L chloroauric acid solution and 120uL of 40mmol/L ascorbic acid solution, oscillating and stirring to enable the 1, 4-benzenedithiol layer to wrap a gold shell layer, and obtaining the Raman probe with the 1, 4-benzenedithiol as Raman signal molecules in the Raman signal layer.
The raman spectrum of the raman probe obtained in comparative example 2 is shown in fig. 11. As can be seen from FIG. 11, Raman signal components containing 1, 4-benzenedithiolThe Raman probe of the probe is 1800-2800cm-1There is no raman signal.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (10)

1. A preparation method of a Raman probe is characterized by comprising the following steps:
adding metal nanoparticles into a first solution, and performing centrifugal dispersion to obtain a metal nanoparticle solution, wherein the first solution comprises a first surfactant and deionized water;
adding the metal nanoparticle solution into a first Raman molecule solution, centrifuging and washing to obtain modified nanoparticles, wherein the modified nanoparticles are nanoparticles modified with the first Raman molecule on the outer surface of the metal nanoparticles, and the Raman signal of the Raman molecule is 1800-2800cm-1；
And adding the modified nano particles into a second solution, wherein the second solution comprises a second surfactant, a metal ion compound and a reducing agent, and vibrating and stirring to enable the modified nano particles to be wrapped with a metal shell layer, so as to obtain the Raman probe.
2. A method for preparing a raman probe according to claim 1, wherein in the step of adding the metal nanoparticle solution to the first raman molecule solution, and centrifugally washing to obtain modified nanoparticles: before centrifugal washing, the metal nanoparticle solution and the first Raman molecule solution are vibrated for 2-20 minutes.
3. The method for preparing a raman probe according to claim 1, wherein after the step of adding the modified nanoparticles into a second solution, the second solution comprising a second surfactant, a metal ion compound and a reducing agent, shaking and stirring to coat a metal shell layer on the modified nanoparticles, thereby obtaining the raman probe, the method further comprises the steps of:
and oscillating and mixing the Raman probe and polydopamine, mesoporous silica or a mercapto compound to coat a polydopamine layer, a mesoporous silica layer or a mercapto compound layer outside the Raman probe.
4. The method for preparing a raman probe according to claim 1, wherein after the step of adding the modified nanoparticles into a second solution, the second solution comprising a second surfactant, a metal ion compound and a reducing agent, shaking and stirring to coat a metal shell layer on the modified nanoparticles, thereby obtaining the raman probe, the method further comprises the steps of:
and adding the Raman probe into a second Raman molecule solution, and after centrifugal washing, modifying the second Raman molecule on the outer surface of the Raman probe.
5. A method for preparing Raman probe according to any one of claims 1-4, wherein said first surfactant and said second surfactant are each selected from one or more of cetyl ammonium chloride, cetyl ammonium bromide, and polyvinylpyrrolidone.
6. A method for preparing Raman probe according to any one of claims 1 to 4, wherein said reducing agent is one or more selected from ascorbic acid, hydroxylamine hydrochloride and formaldehyde.
7. A Raman probe is characterized by comprising a metal nano-core, a first Raman signal layer and a first metal shell layer which are sequentially wrapped, wherein a gap is formed between the metal nano-core and the first metal shell layer, and the first Raman signal layer is positioned in the gap; the first Raman signal layer comprises Raman molecules with Raman signal of 1800--1。
8. A Raman probe according to claim 7 wherein said first Raman molecule comprises a sulfur-containing compound having an alkynyl group or a deuterium atom.
9. The raman probe of claim 7, further comprising a second raman signal layer and a second metal shell layer sequentially wrapped around the first metal shell layer.
10. Use of a raman probe according to any one of claims 7 to 9 in the fields of biomedical imaging, biomedical detection, anti-counterfeiting or cryptography.
CN202010947728.0A 2020-09-10 2020-09-10 Raman probe and preparation method and application thereof Pending CN112170832A (en)

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