CN116925763A - Near infrared long afterglow nano probe for imaging atherosclerosis plaque, and preparation method and application thereof - Google Patents
Near infrared long afterglow nano probe for imaging atherosclerosis plaque, and preparation method and application thereof Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/08—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials
- C09K11/77—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials containing rare earth metals
- C09K11/7708—Vanadates; Chromates; Molybdates; Tungstates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/02—Use of particular materials as binders, particle coatings or suspension media therefor
- C09K11/025—Use of particular materials as binders, particle coatings or suspension media therefor non-luminescent particle coatings or suspension media
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- Chemical & Material Sciences (AREA)
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- Engineering & Computer Science (AREA)
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- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Inorganic Chemistry (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention relates to a near infrared long afterglow nano probe for imaging atherosclerosis plaques, and a preparation method and application thereof. The nano probe has good afterglow luminescence property, and simultaneously selects the osteopontin highly expressed on the surface of foam cells as a potential target point for highly specific identification of the atherosclerosis plaque, so that the nano probe has good atherosclerosis plaque targeting capability, and has high stability, good dispersibility and uniform particle size distribution, and the real-time monitoring of atherosclerosis is realized by a long afterglow imaging technology, so that a new strategy is provided for diagnosis of the atherosclerosis plaque.
Description
Technical Field
The invention belongs to the technical field of biomedical materials, relates to a near-infrared long afterglow nano probe and a preparation method and application thereof, and in particular relates to a near-infrared long afterglow nano probe for imaging atherosclerosis plaques and a preparation method and application thereof.
Background
Atherosclerosis (AS) is an important component of cardiovascular disease, a chronic disease driven by inflammation, which extends through various stages of AS, from the generation of lipid streaks on the arterial wall to the formation of AS plaques. Clinical studies have found that asymptomatic accumulation of AS plaques may lead to sudden onset of fatal cardiovascular disease, including plaque rupture, myocardial infarction, stroke, and even sudden death, and therefore early and accurate detection of AS is critical to reduce the incidence of life-threatening cardiovascular events.
Traditional imaging techniques such AS non-invasive Ultrasound (US), computed Tomography (CT), magnetic Resonance Imaging (MRI), positron Emission Tomography (PET), computed Tomography (CTA), etc., are not effective in assessing the composition of AS plaque, while invasive techniques such AS intravascular ultrasound (IVUS) and Optical Coherence Tomography (OCT) are expensive and can cause vascular accessory damage, greatly limiting the screening and diagnostic applications of vulnerable AS plaque, and furthermore, these methods are not able to distinguish the type of atherosclerotic plaque from molecular levels.
Over the last several decades, molecular diagnostic techniques have become increasingly popular and a variety of imaging probes have been developed for non-invasive observation and detection of AS lesions. The near infrared long afterglow luminescent nanoparticle is a unique optical nano probe, can continuously emit light after the excitation is stopped, emits near infrared light in a tissue transparent window of 650-1350nm, has no background autofluorescence within a few hours after the excitation is stopped, and can realize high-sensitivity biological imaging without autofluorescence, so that the near infrared long afterglow luminescent nanoparticle has advantages in the AS diagnosis field.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a near infrared long afterglow nano probe and a preparation method and application thereof, in particular to a near infrared long afterglow nano probe for imaging atherosclerosis plaques and a preparation method and application thereof. The invention synthesizes a nanometer diagnosis probe based on near infrared long afterglow luminescent nanometer particles, can specifically target AS plaque, realizes high-sensitivity imaging diagnosis of AS plaque, and provides a new method for diagnosis of AS plaque.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a near infrared long persistence nanoprobe for imaging atherosclerotic plaques, the near infrared long persistence nanoprobe comprising mesoporous silica microspheres, a long persistence nanomaterial comprising transition metal loaded in the mesopores of the silica microspheres, and osteopontin antibodies modified on the surfaces of the mesoporous silica microspheres.
The nano probe has good afterglow luminescence property, and simultaneously selects the osteopontin highly expressed on the surface of foam cells AS a potential target point for highly specific identification of the atherosclerosis plaque, so that the nano probe has good atherosclerosis plaque targeting capability, and has high stability, good dispersibility and uniform particle size distribution, and AS real-time monitoring is realized by a long afterglow imaging technology, so that a new strategy is provided for diagnosis of AS plaque.
Preferably, the osteopontin antibody is attached to the surface of the mesoporous silica microsphere by PEG.
The osteopontin antibody is connected to the surface of the mesoporous silica microsphere through PEG, so that the circulation time of the probe in vivo is prolonged, the targeting efficiency of the probe is improved, and the diagnosis of the atherosclerosis plaque can be better realized.
Preferably, the PEG has a number average molecular weight of 2000-8000, e.g. 2000, 3000, 4000, 5000, 6000, 7000, 8000, etc.
Preferably, the transition metal comprises zinc, gallium, tin, chromium and yttrium.
The combination of five specific transition metal ions of zinc, gallium, tin, chromium and yttrium is loaded in the mesopores, so that the obtained nano particles have more excellent near infrared long afterglow performance.
Preferably, the molar ratio of zinc, gallium, tin, chromium and yttrium is (1-2): (1-2): (0.1-1): (0.001-0.01): (0.001-0.01). Wherein the specific point value in (1-2) may be selected from 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, etc.; wherein the specific point value in (0.1-1) may be selected from 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, etc.; the specific point value in (0.001-0.01) can be selected from 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, etc.
Under the specific proportion, the five metals enable the near infrared long afterglow performance of the nano probe to be more excellent.
Preferably, the particle size of the near infrared long persistence nanoprobe is 80 to 250nm, for example 80nm, 100nm, 120nm, 140nm, 150nm, 170nm, 180nm, 200nm, 250nm, etc.
Other specific point values in the numerical ranges are selectable, and will not be described in detail herein.
In a second aspect, the present invention provides a method for preparing a near infrared long persistence nanoprobe for imaging an atherosclerotic plaque according to the first aspect, the method comprising:
(1) Mixing mesoporous silica microspheres with a transition metal ion solution, drying and calcining to obtain near infrared long afterglow nano particles;
(2) Performing amino modification on the near infrared long afterglow nano particles obtained in the step (1) to obtain amino modified near infrared long afterglow nano particles;
(3) Modifying the amino modified near infrared long afterglow nano particles obtained in the step (2) by using PEG to obtain PEG modified near infrared long afterglow nano particles;
(4) And (3) mixing and reacting the PEG modified near infrared long afterglow nano particles obtained in the step (3) with the activated osteopontin antibody to obtain the near infrared long afterglow nano probe.
The invention relates to a nano probe which is a mesoporous silica microsphere with uniform size synthesized based on a template method, a pre-prepared transition metal ion solution is adsorbed in a mesoporous by utilizing the adsorption effect of the mesoporous, near infrared long afterglow nano particles are synthesized under the high temperature condition, then the surfaces of the near infrared long afterglow nano particles are connected with the active ester (NHS) end of PEG through amino groups, and the tail end maleimide group (MAL) of the PEG is connected with a osteopontin antibody, so that a novel bio-safe nano probe for imaging Atherosclerosis (AS) plaque is synthesized.
Preferably, the preparation method of the mesoporous silica microsphere comprises the following steps:
mixing the template agent, the catalyst, the silicon source and the solvent for reaction, and drying and calcining after the reaction is completed to obtain the catalyst.
Specifically, the preparation method of the mesoporous silica microsphere comprises the following steps:
the template agent solution is firstly and uniformly mixed with the catalyst solution and water in an oil bath at 55-65 ℃, then is mixed with cyclohexane and a silicon source, reacts, and is obtained after the reaction is finished, and the mixture is centrifuged, washed, dried and calcined.
Preferably, the templating agent comprises cetyl trimethylammonium chloride (CTAC).
Preferably, the catalyst comprises triethanolamine.
Preferably, the silicon source comprises TEOS (tetraethyl orthosilicate).
Preferably, the total ion concentration in the transition metal ion solution of step (1) is 1.5-2.5mol/L, e.g. 1.5mol/L, 1.6mol/L, 1.7mol/L, 1.8mol/L, 2.0mol/L, 2.2mol/L, 2.3mol/L, 2.4mol/L, 2.5mol/L, etc.; the mass volume ratio of the mesoporous silica microsphere to the transition metal ion solution is 100 (400-800) mg/mu L, such as 100:400 mg/mu L, 100:500 mg/mu L, 100:600 mg/mu L, 100:700 mg/mu L, 100:800 mg/mu L and the like.
Preferably, the transition metal ion solution is a mixed solution of zinc ion salt, gallium ion salt, tin ion salt, chromium ion salt and yttrium ion salt.
Preferably, the transition metal ion solution is a mixed solution of zinc acetate, gallium nitrate, crystalline tin tetrachloride, chromium acetate and yttrium nitrate.
Preferably, the drying in step (1) is performed in a vacuum oven for more than 8 hours, e.g. 8 hours, 9 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, etc.
Preferably, grinding is also performed before the calcining of step (1).
Preferably, the calcination of step (1) is carried out at 800-1000 ℃ (e.g., 800 ℃, 850 ℃,900 ℃, 950 ℃, 1000 ℃ etc.) for 2-4 hours (e.g., 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, etc.).
Other specific point values in the numerical ranges are selectable, and will not be described in detail herein.
Preferably, the amino modification method in step (2) is as follows: the near infrared long persistence nanoparticle is reacted with APTES ((3-aminopropyl) triethoxysilane) at a temperature of 70-90 ℃ (e.g., 70 ℃, 75 ℃, 80 ℃, 85 ℃,90 ℃, etc.) for a time of 18-24 hours (e.g., 18h, 19h, 20h, 22h, 24h, etc.).
Preferably, the mass to volume ratio of the near infrared long persistence nanoparticle to APTES is (0.2-0.8) 1mg/μL, e.g., 0.2:1mg/μL, 0.3:1mg/μL, 0.4:1mg/μL, 0.5:1mg/μL, 0.6:1mg/μL, 0.7:1mg/μL, 0.8:1mg/μL, etc.
Other specific point values in the numerical ranges are selectable, and will not be described in detail herein.
Preferably, the PEG of step (3) is end-group modified to MAL-PEG-NHS (maleimide-polyethylene glycol-active ester) prior to use.
Preferably, the mass ratio of the amino modified near infrared long persistence nanoparticle of step (3) to PEG is 1 (1-4), such as 1:1, 1:2, 1:3, 1:4, etc.
Preferably, the amino-modified near infrared long persistence nanoparticle of step (3) is reacted with PEG at 15-35 ℃ (e.g., 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃ etc.) for 10-36 hours (e.g., 10 hours, 15 hours, 18 hours, 20 hours, 24 hours, 30 hours, 36 hours, etc.).
Other specific point values in the numerical ranges are selectable, and will not be described in detail herein.
Preferably, the osteopontin antibody of step (4) is activated using a reducing agent.
Preferably, the reducing agent comprises TCEP (tris (2-carboxyethyl) phosphine hydrochloride).
Preferably, the mass ratio of the PEG-modified near infrared long persistence nanoparticle of step (4) to the activated osteopontin antibody is (250-1000): 1, e.g., 250:1, 300:1, 400:1, 500:1, 600:1, 700:1, 800:1, 900:1, 1000:1, etc.
Preferably, the reaction of step (4) is carried out at 15-35 ℃ (e.g., 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃ etc.) for 10-18 hours (e.g., 11h, 12h, 13h, 14h, 15h, 16h, 18h, etc.).
Other specific point values in the numerical ranges are selectable, and will not be described in detail herein.
In a third aspect, the present invention provides the use of a near infrared long persistence nanoprobe for imaging atherosclerotic plaques according to the first aspect for the preparation of an atherosclerotic plaque diagnostic agent.
Compared with the prior art, the invention has the following beneficial effects:
the nano probe has good afterglow luminescence property, and simultaneously selects the osteopontin highly expressed on the surface of foam cells AS a potential target point for highly specific identification of the atherosclerosis plaque, so that the nano probe has good atherosclerosis plaque targeting capability, and has high stability, good dispersibility and uniform particle size distribution, and AS real-time monitoring is realized by a long afterglow imaging technology, so that a new strategy is provided for diagnosis of AS plaque.
Drawings
FIG. 1 is a transmission electron microscope image of mesoporous silica microspheres;
FIG. 2 is a transmission electron microscopy image of near infrared long afterglow nanoparticles (mZGS);
FIG. 3 is a graph of the afterglow emission spectra of near infrared long afterglow nanoparticles (mZGS);
FIG. 4 is an afterglow attenuation spectrum of near infrared long afterglow nanoparticles (mZGS);
FIG. 5 is an overview of the aortic arch oil red O staining of mice;
FIG. 6 is a graph of staining of rat aortic arch frozen sections with oil red O and paraffin sections H & E, masson;
fig. 7 is a graph of imaging signals from AS model mice and normal mice.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
Example 1
The mesoporous silica microsphere is prepared in the embodiment, and is specifically as follows:
mesoporous silica microspheres were synthesized using a template method in which CTAC (cetyltrimethylammonium chloride) was used as the template and TEOS (tetraethyl orthosilicate) was used as the silicon source. Uniformly dispersing 0.18g of TEA (triethanolamine) in 5mL of deionized water, transferring to a 100mL round bottom flask, adding 24mL of CTAC solution with mass fraction of 25%, adding 31mL of deionized water, stirring in an oil bath at 60 ℃ for 1h until the mixture is uniformly stirred, slowly adding 20mL of mixed solution of TEOS and cyclohexane (TEOS: cyclohexane=1:4, v/v) along the wall, reacting for 24h, washing with ethanol and deionized water for three times, drying for 8h, and calcining at 550 ℃ to obtain the mesoporous silica microspheres.
Example 2
The near infrared long afterglow nanoparticle (abbreviated as mZGS) is prepared in the embodiment, and is specifically as follows:
preparing a 2M metal ion solution, and weighing a certain amount of zinc nitrate, gallium nitrate, tin chloride, chromium nitrate and yttrium nitrate according to the mole ratio of zinc ions, gallium ions, tin ions, chromium ions and yttrium ions of 1.3:1.4:0.3:0.005:0.003. 100mg of mesoporous silica microspheres prepared in example 1 are weighed and uniformly mixed with 600 mu L of the metal ion solution, and then the mixture is dried in a vacuum drying oven for 12 hours and calcined at 900 ℃ for 3 hours, so as to obtain near infrared long afterglow nano particles (abbreviated as mZGS).
Example 3
The present example prepares amino-modified near infrared long afterglow nanoparticles (abbreviated as mZGS-NH) 2 ) The method is characterized by comprising the following steps:
200mg of the near infrared long persistence nanoparticle (mZGS) prepared in example 2 was added with 80mL of DMF, dispersed by ultrasonic, stirred in an oil bath, slowly added with 500. Mu.L of APTES,after 24 hours of reaction at 80 ℃, centrifugally cleaning to obtain amino modified near infrared long afterglow nano particles (called mZGS-NH for short) 2 )。
Example 4
The preparation method of the PEG modified near infrared long afterglow nanoparticle (called mZGS-PEG for short) comprises the following steps:
10mg of mZGS-NH obtained in example 3 was taken 2 Dispersing in 10mL PBS (10X, 0.1M), adding 20mg MAL-PEG-NHS, stirring gently at 25deg.C for 24h, centrifuging, and washing with 0.01M PBS three times to obtain PEG-modified near infrared long afterglow nanoparticle (abbreviated as mZGS-PEG).
Example 5
The near infrared long afterglow nanoprobe (abbreviated as mZGS-OPN) for imaging the atherosclerosis plaque is prepared in the embodiment, and is specifically as follows:
(1) Activation of OPN Ab: mu.L of OPN Ab (from Abcam, model Ab 218237) was taken, 180. Mu.L of 10 XPBS buffer was added to make up 200. Mu.L, an equal volume of TCEP (tris (2-carboxyethyl) phosphine hydrochloride) solution (10 XPBS dissolved 50 mmol/L) was added, and the mixture was placed on a shaking table and reacted at 25℃for 30min, at which time OPN Ab was in an activated state (disulfide cleavage to thiol) and the antibody with free thiol was ultrafiltered with a 30kD ultrafilter tube at 6000rpm for 5min at 4 ℃.
(2) The mZGS-PEG prepared in example 4 was added into Tris buffer 10000rpm for centrifugal resuspension, and the mixture was stirred with OPN Ab in an activated state in a glass bottle for 18 hours, and the obtained product was subjected to centrifugal resuspension with 1 XPBS to obtain a near infrared long afterglow nanoprobe (abbreviated as mZGS-OPN) for imaging atherosclerotic plaque.
Test example 1
The morphology and particle diameter of the mesoporous silica microsphere prepared in example 1 and the near infrared long afterglow nanoparticle prepared in example 2 were observed by Transmission Electron Microscope (TEM): and diluting the mesoporous silica microspheres and the near infrared long afterglow nano particles with ethanol, and uniformly dispersing by ultrasonic treatment. And (3) dripping the mesoporous silica microsphere and the near infrared long afterglow nanoparticle solution drop 1 on a transmission electron microscope copper net, and observing and photographing under the transmission electron microscope after the ethanol is completely volatilized. The transmission electron microscope diagrams of the mesoporous silica microsphere and the near infrared long afterglow nanoparticle are respectively shown in fig. 1 and 2, and the transmission electron microscope diagrams of fig. 1 and 2 can be seen as follows: the synthesized mesoporous silica microsphere and near infrared long afterglow nanoparticle have uniform particle size distribution and good dispersibility.
Test example 2
Excitation and emission spectrometry measurements were performed on the near infrared long afterglow nanoparticle prepared in example 2 using a spectrometer: a proper amount of mZGS nano particle sample is taken and placed on a sample mounting table of a spectrometer, and is excited by 659nm red light for 5min, the afterglow emission spectrum of the mZGS nano particle is measured, as shown in figure 3, and the afterglow attenuation spectrum of the mZGS nano particle is measured as shown in figure 4. As can be seen from fig. 3 and 4: the near infrared long afterglow nano particle has good afterglow luminescence property, the afterglow emission peak is positioned at 696nm of the biological window, and the afterglow luminescence signal shows slow attenuation.
Test example 3
The application of the nano probe in the diagnosis of the atherosclerosis plaque is explored:
(1) Establishing a mouse atherosclerosis model (AS model):
c57BL/6J ApoE at 8 weeks of age -/- After the mice are adaptively fed for 7 days, carotid artery ligation is given to the mice, and the mice are continuously fed with high-fat feed for 4 weeks to establish an atherosclerosis model. The method comprises the following specific steps: after the mice were anesthetized with 5% chloral hydrate by mass fraction, the mice were fixed on cardboard, cut along the middle of the neck, left common carotid artery, external carotid artery, internal carotid artery and occipital artery were peeled off under a microscope, the external carotid artery, internal carotid artery and occipital artery were ligated with 6-0 non-absorbable suture, while the suprathyroidial artery was opened and the neck incision was sutured.
Taking C57BL/6J ApoE after 4 weeks of surgical ligation and high-fat feed feeding -/- The mice were euthanized with excess chloral hydrate, supine fixed on dissecting plates, the skin of the mice was cut from the middle of the abdomen until the neck, the viscera of the mice were removed, the cervical blood vessels were carefully and passively separated under a microscope and exposed, perivascular tissues were removed, aortic arch tissues were removed, the blood vessels were fixed in 4% paraformaldehyde for more than 24 hours, aortic arch oil red O staining was performed, AS shown in FIG. 5 (normal C57BL/6J mice aortic arch, right image AS AS modelThe aortic arch of the mice); and frozen sections were stained with oil red O and paraffin sections H&E. Masson staining, AS shown in fig. 6 (upper panel is normal C57BL/6J mouse aortic arch section, lower panel is AS model mouse aortic arch section), confirmed successful construction of mouse atherosclerosis model from the results of fig. 5 and 6.
(2) Long persistence luminescent imaging of atherosclerotic plaques in mice:
AS shown in fig. 7, the result of taking AS model mice and normal C57BL/6J mice with similar weights AS experimental groups and control groups, respectively, using a shaver and depilatory cream to remove neck hair of the mice, injecting 200 μl of the nano probe (mZGS-OPN) solution prepared in example 5 with 3mg/mL of tail vein into the two groups of mice, irradiating the mice with 659nm LED red light for 5min, and collecting related imaging signals by a small animal imaging system (a is a control group mouse afterglow imaging signal graph, B is a control group mouse in vitro aortic arch afterglow imaging signal graph, C is an experimental group mouse afterglow imaging signal graph, D is an experimental group mouse in vitro aortic arch afterglow imaging signal graph), is shown in fig. 7: obvious afterglow luminescence signals are observed at the necks of mice in the experimental group, no signals are observed at the necks of mice in the control group, the afterglow signals are mainly concentrated in an aortic arch through in-vitro aortic imaging, and the afterglow signals are consistent with an in-vivo imaging result, so that the synthesized nano probe mZGS-OPN successfully targets the atherosclerosis plaque part, and the diagnosis of atherosclerosis is realized.
The applicant states that the present invention is illustrated by the above examples as a near infrared long persistence nanoprobe for imaging atherosclerotic plaques and a method for preparing the same and application thereof, but the present invention is not limited to the above examples, i.e., it does not mean that the present invention must be practiced depending on the above examples. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Claims (10)
1. The near infrared long afterglow nano probe for imaging the atherosclerosis plaque is characterized by comprising mesoporous silica microspheres, long afterglow nano materials containing transition metal and being loaded in mesoporous silica microspheres, and osteopontin antibodies modified on the surfaces of the mesoporous silica microspheres.
2. The near infrared long persistence nanoprobe for imaging atherosclerotic plaque of claim 1, wherein said osteopontin antibody is attached to mesoporous silica microsphere surface by PEG;
preferably, the PEG has a number average molecular weight of 2000-8000.
3. The near infrared long persistence nanoprobe for imaging atherosclerotic plaques according to claim 1 or 2, wherein said transition metals comprise zinc, gallium, tin, chromium and yttrium;
preferably, the molar ratio of zinc, gallium, tin, chromium and yttrium is (1-2): (1-2): (0.1-1): (0.001-0.01): (0.001-0.01);
preferably, the particle size of the near infrared long afterglow nanoprobe is 80-250nm.
4. A method of preparing a near infrared long persistence nanoprobe for imaging atherosclerotic plaque according to any of claims 1 to 3, comprising:
(1) Mixing mesoporous silica microspheres with a transition metal ion solution, drying and calcining to obtain near infrared long afterglow nano particles;
(2) Performing amino modification on the near infrared long afterglow nano particles obtained in the step (1) to obtain amino modified near infrared long afterglow nano particles;
(3) Modifying the amino modified near infrared long afterglow nano particles obtained in the step (2) by using PEG to obtain PEG modified near infrared long afterglow nano particles;
(4) And (3) mixing and reacting the PEG modified near infrared long afterglow nano particles obtained in the step (3) with the activated osteopontin antibody to obtain the near infrared long afterglow nano probe.
5. The method for preparing a near infrared long persistence nanoprobe for imaging an atherosclerotic plaque according to claim 4, wherein the method for preparing mesoporous silica microspheres comprises:
mixing the template agent, the catalyst, the silicon source and the solvent for reaction, and drying and calcining after the reaction is completed to obtain the catalyst;
preferably, the templating agent comprises cetyltrimethylammonium chloride;
preferably, the catalyst comprises triethanolamine;
preferably, the silicon source comprises TEOS.
6. The method for preparing a near infrared long persistence nanoprobe for imaging atherosclerotic plaque according to claim 4 or 5, wherein the total ion concentration in the transition metal ion solution of step (1) is 1.5-2.5mol/L, and the mass volume ratio of the mesoporous silica microsphere to the transition metal ion solution is 100 (400-800) mg/μl;
preferably, the transition metal ion solution is a mixed solution of zinc ion salt, gallium ion salt, tin ion salt, chromium ion salt and yttrium ion salt;
preferably, the drying in the step (1) is performed in a vacuum drying oven for more than 8 hours;
preferably, grinding is also carried out before the calcination in the step (1);
preferably, the calcination in step (1) is carried out at 800-1000 ℃ for 2-4 hours.
7. The method of preparing near infrared long persistence nanoprobes for imaging atherosclerotic plaque according to any of claims 4 to 6, wherein the amino modification method of step (2) is: reacting near infrared long afterglow nano particles with APTES at 70-90 ℃ for 18-24 hours;
preferably, the mass volume ratio of the near infrared long afterglow nanoparticle to APTES is (0.2-0.8) 1 mg/MuL.
8. The method of preparing near infrared long persistence nanoprobes for atherosclerotic plaque imaging according to any of claims 4-7, wherein the PEG of step (3) is end-group modified to MAL-PEG-NHS prior to use;
preferably, the mass ratio of the amino modified near infrared long afterglow nano particles to PEG in the step (3) is 1 (1-4);
preferably, the amino modified near infrared long afterglow nanoparticle in step (3) is reacted with PEG at 15-35 ℃ for 10-36h.
9. The method of preparing near infrared long persistence nanoprobes for atherosclerotic plaque imaging of any of claims 4-8, wherein the osteopontin antibody of step (4) is activated using a reducing agent;
preferably, the reducing agent comprises TCEP;
preferably, the mass ratio of the PEG modified near infrared long persistence nanoparticle to the activated osteopontin antibody in the step (4) is (250-1000): 1;
preferably, the reaction of step (4) is carried out at 15-35℃for 10-18h.
10. Use of the near infrared long persistence nanoprobe for imaging atherosclerotic plaques according to any of claims 1-3 for the preparation of an atherosclerotic plaque diagnostic agent.
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