CN112494666A - T1-T2 dual-activation magnetic resonance imaging contrast agent and preparation method and application thereof - Google Patents
T1-T2 dual-activation magnetic resonance imaging contrast agent and preparation method and application thereof Download PDFInfo
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- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
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- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
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- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/183—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an inorganic material or being composed of an inorganic material entrapping the MRI-active nucleus, e.g. silica core doped with a MRI-active nucleus
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- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
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- A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
- A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
- A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
- A61K49/1851—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
- A61K49/1857—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. PLGA
Abstract
The invention provides a T1-T2 dual-activation magnetic resonance imaging contrast agent, and a preparation method and application thereof. The T1-T2 double-activation magnetic resonance imaging contrast agent has a core-shell structure and sequentially comprises T2 contrast agent nanoparticles, a silicon dioxide layer, a T1 contrast agent layer and a modification layer from inside to outside, wherein the T2 contrast agent nanoparticles are superparamagnetic iron oxide nanoparticles. The T1-T2 dual-activation magnetic resonance imaging contrast agent is in a T1 and T2 contrast agent signal dual-quenching state in normal tissues around a tumor in vivo, and can realize simultaneous activation of T1 and T2 contrast agent signals at the tumor part, so that the tumor part and the surrounding normal tissues present obvious MRI signal difference, and the contrast agent has targeting effect on tumor cells, thereby realizing high-quality imaging of the tumor part.
Description
Technical Field
The invention belongs to the technical field of material science and biomedicine, and relates to a T1-T2 dual-activation magnetic resonance imaging contrast agent, and a preparation method and application thereof.
Background
Magnetic Resonance Imaging (MRI) has the advantages of high resolution, no ionizing radiation damage, multi-parameter and multi-sequence Imaging, and the like, and has become one of the most powerful detection means in modern clinical diagnosis. To highlight differences between tissues, particularly between normal and diseased regions, contrast agents are often used to improve imaging contrast. According to the principle of action, MRI contrast agents can be divided into longitudinal relaxation contrast agents (T1 contrast agents) and transverse relaxation contrast agents (T2 contrast agents), T1 contrast agents primarily accelerate T1 relaxation and produce "bright" contrast in T1-weighted images, and T2 contrast agents primarily increase T2 relaxation rate and produce "dark" contrast effects.
In recent years, the development of MRI contrast agents has greatly promoted the application of MRI to the field of tumor diagnosis, and Glutathione (GSH), Matrix Metalloproteinase (MMP), pH, and the like are different from those of normal tissues in a tumor microenvironment.
Choi et al (Choi J S, Kim S, Yoo D, et al, distance-dependent magnetic resonance tuning as a top MRI sensing platform for biological targets [ J ] Nature Materials,2017,16(5): 537) 542.) report a magnetic nanoprobe based on distance modulation, where T1 activation is mainly modulated by the distance between T1 positive contrast agent (Gd-DTPA) and T2 positive contrast agent (SPIO), and the T1 signal of the nanoprobe is quenched when the distance between the two is shortened; whereas in the tumor microenvironment (MMP-2), the distance between the two increases and the T1 signal is activated. But has the disadvantage of poor amplification of the activation response.
Wang et al (Wang Z, Xue X, Lu H, et al. two-way magnetic resonance imaging for non-invasive and quantitative biological imaging [ J ]. Nature Nanotechnology,2020,15(6):1-9.) constructed a GSH sensitive dendrimer encapsulated T1 contrast agent (porphyrin chelated manganese) and T2 positive contrast agent (SPIO) nanoprobe (ratio 20:1) to further enhance MRI signal activation amplification at the imaged site. However, T1 contrast medium is highly toxic and has a GSH response pattern, which is inferior to the pH response pattern in sensitivity and specificity.
CN105188772A discloses a T1-T2 dual-mode magnetic resonance imaging contrast agent based on metal oxide nanoparticles, which is a nanoparticle having a core and a porous shell structure, the core being manganese oxide, the porous shell being an iron oxide layer doped with manganese ions derived from manganese oxide, and the MRI contrast agent can be used not only as a T1 contrast agent, but also as a T2 contrast agent, enhancing the imaging contrast. But the sensitivity and specificity are poor.
In summary, an MRI contrast agent which can effectively enhance MRI signals and has high sensitivity and specificity is provided, which is of great significance to the MRI field.
Disclosure of Invention
Aiming at the defects and practical requirements of the prior art, the invention provides a T1-T2 dual-activation magnetic resonance imaging contrast agent, a preparation method and an application thereof, the T1-T2 dual-activation magnetic resonance imaging contrast agent has pH responsiveness and tumor targeting property, can be enriched at a tumor part, and can simultaneously activate T1 and T2 signals under the acidic condition of a tumor microenvironment, so that high-quality imaging of the tumor part is realized.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides a T1-T2 dual-activation magnetic resonance imaging contrast agent, wherein the T1-T2 dual-activation magnetic resonance imaging contrast agent has a core-shell structure, and sequentially comprises T2 contrast agent nanoparticles, a silicon dioxide layer, a T1 contrast agent layer and a modification layer from inside to outside, and the T2 contrast agent nanoparticles are superparamagnetic iron oxide nanoparticles.
In the T1-T2 dual-activation magnetic resonance imaging contrast agent, superparamagnetic iron oxide nanoparticles are a good MRI T2 contrast agent and have a high T2 relaxation rate; the silica and the T1 contrast agent sequentially coated on the superparamagnetic iron oxide nanoparticle can realize double quenching of signals of the T1 contrast agent and the T2 contrast agent, and have specific response capability of a tumor microenvironment, namely when the magnetic resonance contrast agent is in an acid environment near a tumor, the T1 contrast agent can form free ions, so that the free ions are separated from the T2 contrast agent, and the signals of the T1 contrast agent and the T2 contrast agent are simultaneously activated; the modifying layer can enable the magnetic resonance contrast agent to have tumor targeting, so the T1-T2 dual-activation magnetic resonance imaging contrast agent is in a T1 and T2 contrast agent signal dual-quenching state in normal tissues around a tumor in vivo, and T1 and T2 contrast agent signals can be simultaneously activated at the tumor part, so that the tumor part and the surrounding normal tissues present obvious MRI signal difference, and high-quality imaging of the tumor part is realized.
Preferably, the superparamagnetic iron oxide nanoparticles have a particle size of 8 to 20nm, including but not limited to 9nm, 10nm, 11nm, 13nm, 15nm, 18nm or 19 nm.
In the invention, the superparamagnetic iron oxide nanoparticles with the particle size of 8-20 nm have good superparamagnetic property and are suitable for being used as a T2 contrast agent, when the particle size is less than 8nm, the signal intensity of the T2 contrast agent is influenced, and when the particle size is more than 20nm, the next modification and in-vivo application are influenced.
Preferably, the thickness of the silicon dioxide layer is 4-12 nm, including but not limited to 5nm, 6nm, 7nm, 8nm, 10nm or 11 nm.
According to the invention, the thickness of the silicon dioxide layer is controlled to be 4-12 nm, namely, the distance between the T1 contrast agent and the T2 contrast agent is 4-12 nm, the signal double quenching of the T1 contrast agent and the T2 contrast agent can be effectively realized, when the thickness is less than 4nm, the load capacity of the T1 contrast agent is reduced, the signal intensity of the T1 contrast agent is influenced, and when the thickness is more than 12nm, the distance between the T1 contrast agent and the T2 contrast agent is larger, and the signal double quenching effect of the T1 contrast agent and the T2 contrast agent is influenced.
Preferably, the mass ratio of the T2 contrast agent nanoparticles to the T1 contrast agent layer is 1 (5-30), including but not limited to 1:6, 1:7, 1:8, 1:10, 1:15, 1:18, 1:20, 1:25, 1:26, 1:27 or 1: 28.
Preferably, the T1 contrast agent layer includes manganese oxide and/or gadolinium oxide.
Preferably, the modifying layer comprises polyethylene glycol-phenylboronic acid.
In the invention, the phenylboronic acid molecule in the polyethylene glycol-phenylboronic acid can be specifically combined with Cis-diol (Cis-diol) on sialic acid on the surface of a tumor cell to form a boronic acid ester bond, so that the T1-T2 dual-activation magnetic resonance contrast agent has tumor targeting property.
Preferably, the molecular weight of the polyethylene glycol is 2000-10000, including but not limited to 2200, 2500, 2800, 3600, 4500, 5500, 6000, 7000, 8000, 9000, 9500 or 9800.
According to the invention, the molecular weight of polyethylene glycol is controlled to be 2000-10000, so that the biocompatibility of the T1-T2 dual-activation magnetic resonance contrast agent can be effectively improved, the blood circulation time of the dual-activation magnetic resonance contrast agent in a living body is prolonged, the enrichment amount of the T1-T2 dual-activation magnetic resonance contrast agent in a tumor part is increased, and the imaging effect is improved.
In a second aspect, the present invention provides a method for preparing a T1-T2 dual-activation magnetic resonance imaging contrast agent as set forth in the first aspect, the method comprising:
and sequentially carrying out coating silicon dioxide treatment, coating T1 contrast agent treatment and modification treatment on the superparamagnetic iron oxide nanoparticles to obtain the T1-T2 double-activation magnetic resonance imaging contrast agent.
Preferably, the silica coating treatment comprises:
adding superparamagnetic iron oxide nanoparticles, polyoxyethylene (5) nonylphenyl ether, ammonia water and tetraethyl silicate into a solvent in sequence, and reacting to obtain superparamagnetic iron oxide nanoparticles coated with silicon dioxide.
Preferably, the ratio of the solvent, the superparamagnetic iron oxide nanoparticles, the polyoxyethylene (5) nonylphenyl ether, the ammonia water and the tetraethyl silicate is (2-10) mL, (0.5-2.5) mg, (0.2-1) g, (50-200) μ L, (2-20) μ L, including but not limited to 3mL, 0.6mg, 0.3g, 52 μ L, 4 μ L, 3mL, 0.8mg, 0.4g, 60 μ L, 8 μ L, 5mL, 1.5mg, 0.5g, 100 μ L, 15 μ L, 7mL, 2mg, 0.7g, 150 μ L, 17 μ L or 9mL, 2.4mg, 0.9g, 190 μ L, 19 μ L.
Preferably, the solvent comprises cyclohexane and/or n-hexane.
Preferably, the superparamagnetic iron oxide nanoparticles comprise oleic acid-modified superparamagnetic iron oxide nanoparticles.
Preferably, the reaction time is 2-48 h, including but not limited to 3h, 6h, 10h, 15h, 20h, 30h, 35h, 40h, 45h or 48 h.
Preferably, the treatment with the T1 contrast agent comprises adding an oxidant and a metal salt into the superparamagnetic iron oxide nanoparticle coated with the silicon dioxide to react to obtain the superparamagnetic iron oxide nanoparticle coated with the silicon dioxide and the T1 contrast agent layer.
Preferably, the ratio of the superparamagnetic iron oxide nanoparticle coated with silicon dioxide, the oxidant and the metal salt is 1mL (200-600) mu g, including but not limited to 1mL 210 mu g 310 mu g, 1mL 250 mu g 350 mu g, 1mL 300 mu g 400 mu g, 1mL 350 mu g 450 mu g, 1mL 500 mu g 600 mu g, 1mL 550 mu g 800 mu g or 1mL 580 mu g 950 mu g.
Preferably, the oxidizing agent comprises potassium permanganate.
Preferably, the metal salt comprises a manganese salt and/or a gadolinium salt.
Preferably, the manganese salt comprises any one of manganese sulfate, manganese nitrate, manganese chloride or manganese acetate or a combination of at least two of them, with typical but non-limiting combinations including a combination of manganese sulfate and manganese nitrate, a combination of manganese nitrate and manganese chloride, a combination of manganese chloride and manganese acetate or a combination of manganese chloride and manganese sulfate.
Preferably, the gadolinium salt comprises any one of gadolinium sulfate, gadolinium nitrate, gadolinium chloride or gadolinium acetate or a combination of at least two of them, with typical but non-limiting combinations including a combination of gadolinium sulfate and gadolinium nitrate, a combination of gadolinium nitrate and gadolinium chloride, a combination of gadolinium chloride and gadolinium acetate or a combination of gadolinium nitrate and gadolinium acetate.
Preferably, the reaction time is 1-4 h, including but not limited to 1.5h, 2h, 2.5h, 3h or 3.5 h.
Preferably, the modification treatment comprises adding amino-polyethylene glycol-phenylboronic acid into superparamagnetic iron oxide nanoparticles coated with silicon dioxide and a T1 contrast agent, and carrying out reaction to obtain the T1-T2 dual-activation magnetic resonance imaging contrast agent.
Preferably, the ratio of the superparamagnetic iron oxide nanoparticle coated with the silicon dioxide and the T1 contrast agent to the amino-polyethylene glycol-phenylboronic acid is 1mL (1-4) mg, including but not limited to 1mL:2mg, 1mL:2.5mg, 1mL:3mg or 1mL:3.5 mg.
Preferably, the reaction time is 6-48 h, including but not limited to 8h, 10h, 12h, 20h, 25h, 30h, 35h, 38h, 40h, 42h or 46 h.
As a preferred technical scheme, the preparation method of the T1-T2 dual-activation magnetic resonance imaging contrast agent comprises the following steps:
(1) adding superparamagnetic iron oxide nanoparticles modified by oleic acid into a solvent, carrying out ultrasonic treatment for 5-10 min, adding polyoxyethylene (5) nonylphenyl ether and ammonia water, carrying out ultrasonic treatment for 3-10 min, and adding tetraethyl silicate, wherein the ratio of the superparamagnetic iron oxide nanoparticles, the solvent, polyoxyethylene (5) nonylphenyl ether, the ammonia water and the tetraethyl silicate is (0.5-2.5) mg, (2-10) mL, (0.2-1) g, (50-200) microliter, (2-20) microliter, carrying out stirring reaction for 2-48 h, centrifuging, collecting precipitates, washing with ethanol and water for 2-4 times respectively, and redissolving in a water phase;
(2) adding potassium permanganate into the product obtained in the step (1), stirring for 5-20 min, and continuously adding metal salt, wherein the proportion of the product obtained in the step (1), the potassium permanganate and the metal salt is 1mL (200-600) mu g (300-1000) mu g, stirring for reaction for 1-4 h, centrifuging, collecting precipitate, washing for 2-4 times, and redissolving in a water phase;
(3) and (3) adding amino-polyethylene glycol-phenylboronic acid into the product obtained in the step (2), wherein the proportion of the product obtained in the step (2) to the amino-polyethylene glycol-phenylboronic acid is 1mL (1-4) mg, stirring for 6-48 h, centrifuging, collecting precipitates, and redissolving the precipitates in a water phase to obtain the magnetic resonance contrast agent.
In a third aspect, the present invention provides a contrast agent composition comprising a T1-T2 dual-activation magnetic resonance contrast agent as described in the first aspect.
Preferably, the contrast agent composition further comprises a pharmaceutically acceptable adjuvant.
In a fourth aspect, the invention provides the use of the T1-T2 dual-activation magnetic resonance contrast agent or the contrast agent composition of the third aspect in the preparation of a magnetic resonance imaging agent.
Compared with the prior art, the invention has the following beneficial effects:
(1) the T1-T2 dual-activation magnetic resonance imaging contrast agent is in a T1 and T2 contrast agent signal dual-quenching state in normal tissues around a tumor in vivo, and can realize simultaneous activation of T1 and T2 contrast agent signals at the tumor part, so that the tumor part and the surrounding normal tissues present obvious MRI signal difference, and the contrast agent has targeting effect on tumor cells, thereby realizing high-quality imaging of the tumor part;
(2) in the invention, the thickness of the silicon dioxide layer is controlled to be 4-12 nm, namely, the distance between the T1 contrast agent and the T2 contrast agent is 4-12 nm, so that the signal double quenching of the T1 contrast agent and the T2 contrast agent can be effectively realized;
(3) the T1-T2 dual-activation magnetic resonance contrast agent has a pH response mechanism, can simultaneously realize signal activation of T1 and T2 contrast agents under an acidic condition, and has an activation effect which is enhanced along with the increase of acidity; can be enriched at the tumor site and can obviously enhance the signal intensity of T1 and T2 contrast agents at the tumor site.
Drawings
FIG. 1 is a process diagram of example 1 for the preparation of T1-T2 dual-activation magnetic resonance contrast agents, SPIO is oleic acid modified superparamagnetic iron oxide, TEOS is tetraethyl silicate, SPIO @ SiO2Is oleic acid modified superparamagnetic iron oxide coated with silicon dioxide, SSM is oleic acid modified superparamagnetic iron oxide coated with silicon dioxide and manganese oxide, PBA-PEG-NH2The magnetic resonance imaging contrast agent is amino-polyethylene glycol-phenylboronic acid, the SSM-PEG-PBA is T1-T2 double-activation magnetic resonance imaging contrast agent, and the superparamagnetic iron oxide nanoparticle, the silicon dioxide layer, the manganese oxide layer and the polyethylene glycol-phenylboronic acid which are modified by oleic acid are sequentially arranged from inside to outside;
FIG. 2 is a transmission electron micrograph of a T1-T2 double-activated magnetic resonance contrast agent (silica layer thickness 4 nm);
FIG. 3 is a transmission electron micrograph of a T1-T2 double-activated magnetic resonance contrast agent (silica layer thickness 8 nm);
FIG. 4 is a transmission electron micrograph of a T1-T2 double-activated magnetic resonance contrast agent (silica layer thickness 12 nm);
FIG. 5 is a transmission electron micrograph of a T1-T2 double-activated magnetic resonance contrast agent (silica layer thickness 32 nm);
FIG. 6 is an elemental analysis chart of a T1-T2 dual-activation magnetic resonance contrast agent, in which Fe shows only Fe, Si shows only Si, Mn shows only Mn, and Merge shows the above three elements simultaneously;
FIG. 7 is a graph of T1 and T2 contrast agent signal intensities for T1-T2 dual-activation magnetic resonance contrast agents under different pH conditions;
FIG. 8 is a graph of signal intensity of T1 and T2 contrast agents for T1-T2 dual-activation magnetic resonance contrast agents with different thicknesses of silica layers, A is a T1 weighted graph and a T2 weighted graph for T1-T2 dual-activation magnetic resonance contrast agents with different thicknesses of silica layers, B is a T2 relaxation time inverse graph for T1-T2 dual-activation magnetic resonance contrast agents with different thicknesses of silica layers, and C is a T1 relaxation time inverse graph for T1-T2 dual-activation magnetic resonance contrast agents with different thicknesses of silica layers;
FIG. 9 is a graph of a semi-quantitative analysis of cellular uptake, NH in the non-targeting group2PEG (Phenylboronic acid-free targeting molecule) -modified contrast agents, targeting group being NH2-PEG-PBA (phenylboronic acid-containing targeting molecule) modified contrast agents;
fig. 10 is a graph of MRI imaging effect in vivo in mice before and after tail vein injection of T1-T2 dual-activation magnetic resonance contrast agent, a is a graph of MRI T1 weighted imaging and T2 weighted imaging in vivo in mice before and after tail vein injection of T1-T2 dual-activation magnetic resonance contrast agent, B is a graph of inverse relaxation time of MRI T1 in vivo in mice before and after tail vein injection of T1-T2 dual-activation magnetic resonance contrast agent, and C is a graph of inverse relaxation time of MRI T2 in vivo in mice before and after tail vein injection of T1-T2 dual-activation magnetic resonance contrast agent.
Detailed Description
To further illustrate the technical means adopted by the present invention and the effects thereof, the present invention is further described below with reference to the embodiments and the accompanying drawings. It is to be understood that the specific embodiments described herein are merely illustrative of the invention and are not limiting of the invention.
The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or apparatus used are conventional products commercially available from normal sources, not indicated by the manufacturer.
In the examples of the present invention, superparamagnetic iron oxide nanoparticles (10nm) modified with oleic acid were purchased from Zhongke thunder (Beijing) science and technology Co., Ltd, and amino-polyethylene glycol (molecular weight: 5000) -phenylboronic acid was purchased from Xianruixi Biotechnology Co., Ltd.
Example 1
The embodiment provides a T1-T2 dual-activation magnetic resonance imaging contrast agent, the T1-T2 dual-activation magnetic resonance contrast agent takes superparamagnetic iron oxide nanoparticles modified by oleic acid as an inner core, a silicon dioxide layer and a manganese oxide layer are sequentially coated from inside to outside, polyethylene glycol-phenylboronic acid is modified on the outermost layer, and the thickness of the silicon dioxide layer is 4 nm. The preparation process of the T1-T2 dual-activation magnetic resonance imaging contrast agent is shown in figure 1, and specifically comprises the following steps:
(1) adding 1mg of oleic acid modified superparamagnetic iron oxide nanoparticles into 5mL of cyclohexane, carrying out ultrasonic treatment for 5min, adding 0.5g of polyoxyethylene (5) nonylphenyl ether and 50 mu L of ammonia water, carrying out ultrasonic treatment for 10min, adding 5 mu L of tetraethyl silicate, carrying out stirring reaction for 2h, centrifuging, collecting precipitates, washing with ethanol and water for 3 times respectively, and redissolving in 1mL of water phase;
(2) adding 200 mu g of potassium permanganate into 1mL of the product obtained in the step (1), stirring for 10min, continuously adding 300 mu g of manganese sulfate, stirring for reacting for 2h, centrifuging, collecting precipitate, washing for 3 times, and redissolving in 1mL of water phase;
(3) and (3) adding 1mL of the product obtained in the step (2) into 2mg of amino-polyethylene glycol-phenylboronic acid, stirring for 24h, centrifuging, collecting precipitate, and re-dissolving in 1mL of water phase to obtain the T1-T2 dual-activation magnetic resonance contrast agent.
Example 2
The embodiment provides a T1-T2 dual-activation magnetic resonance imaging contrast agent, the T1-T2 dual-activation magnetic resonance contrast agent takes superparamagnetic iron oxide nanoparticles modified by oleic acid as an inner core, a silicon dioxide layer and a manganese oxide layer are sequentially coated from inside to outside, polyethylene glycol-phenylboronic acid is modified on the outermost layer, and the thickness of the silicon dioxide layer is 8 nm. The preparation process of the magnetic resonance imaging contrast agent comprises the following steps:
(1) adding 1mg of oleic acid modified superparamagnetic iron oxide nanoparticles into 5mL of cyclohexane, carrying out ultrasonic treatment for 5min, adding 0.5g of polyoxyethylene (5) nonylphenyl ether and 50 mu L of ammonia water, carrying out ultrasonic treatment for 10min, adding 2 mu L of tetraethyl silicate, carrying out stirring reaction for 12h, centrifuging, collecting precipitates, washing with ethanol and water for 3 times respectively, and redissolving in 1mL of water phase;
(2) adding 400 mu g of potassium permanganate into 1mL of the product obtained in the step (1), stirring for 10min, continuously adding 600 mu g of manganese sulfate, stirring for reacting for 2h, centrifuging, collecting precipitate, washing for 3 times, and redissolving in a water phase;
(3) and (3) adding 1mL of the product obtained in the step (2) into 2mg of amino-polyethylene glycol-phenylboronic acid, stirring for 24h, centrifuging, collecting precipitate, and redissolving in an aqueous phase to obtain the T1-T2 dual-activation magnetic resonance contrast agent.
Example 3
The embodiment provides a T1-T2 dual-activation magnetic resonance imaging contrast agent, the T1-T2 dual-activation magnetic resonance contrast agent takes superparamagnetic iron oxide nanoparticles modified by oleic acid as an inner core, a silicon dioxide layer and a manganese oxide layer are sequentially coated from inside to outside, polyethylene glycol-phenylboronic acid is modified on the outermost layer, and the thickness of the silicon dioxide layer is 12 nm. The preparation process of the T1-T2 dual-activation magnetic resonance imaging contrast agent comprises the following steps:
(1) adding 1mg of oleic acid modified superparamagnetic iron oxide nanoparticles into 5mL of cyclohexane, carrying out ultrasonic treatment for 5min, adding 0.5g of polyoxyethylene (5) nonylphenyl ether and 50 mu L of ammonia water, carrying out ultrasonic treatment for 10min, adding 2 mu L of tetraethyl silicate, carrying out stirring reaction for 24h, centrifuging, collecting precipitates, washing with ethanol and water for 3 times respectively, and redissolving in 1mL of water phase;
(2) adding 600 mu g of potassium permanganate into 1mL of the product obtained in the step (1), stirring for 10min, continuously adding 900 mu g of manganese sulfate, stirring for reacting for 2h, centrifuging, collecting precipitate, washing for 3 times, and redissolving in 1mL of water phase;
(3) and (3) adding 1mL of the product obtained in the step (2) into 2mg of amino-polyethylene glycol-phenylboronic acid, stirring for 24h, centrifuging, collecting precipitate, and redissolving in an aqueous phase to obtain the T1-T2 dual-activation magnetic resonance contrast agent.
Example 4
The embodiment provides a T1-T2 dual-activation magnetic resonance imaging contrast agent, the T1-T2 dual-activation magnetic resonance contrast agent takes superparamagnetic iron oxide nanoparticles modified by oleic acid as an inner core, a silicon dioxide layer and a manganese oxide layer are sequentially coated from inside to outside, polyethylene glycol-phenylboronic acid is modified on the outermost layer, and the thickness of the silicon dioxide layer is 32 nm. The preparation process of the T1-T2 dual-activation magnetic resonance imaging contrast agent comprises the following steps:
(1) adding 1mg of oleic acid modified superparamagnetic iron oxide nanoparticles into 5mL of cyclohexane, carrying out ultrasonic treatment for 5min, adding 0.5g of polyoxyethylene (5) nonylphenyl ether and 50 mu L of ammonia water, carrying out ultrasonic treatment for 10min, adding 4 mu L of tetraethyl silicate, carrying out stirring reaction for 48h, centrifuging, collecting precipitates, washing with ethanol and water for 3 times respectively, and redissolving in 1mL of water phase;
(2) adding 600 mu g of potassium permanganate into 1mL of the product obtained in the step (1), stirring for 10min, continuously adding 900 mu g of manganese sulfate, stirring for reacting for 2h, centrifuging, collecting precipitate, washing for 3 times, and redissolving in 1mL of water phase;
(3) and (3) adding 1mL of the product obtained in the step (2) into 2mg of amino-polyethylene glycol-phenylboronic acid, stirring for 24 hours, centrifuging, collecting precipitate, and redissolving in a water phase to obtain the magnetic resonance contrast agent.
Test example 1
This experimental example examined the thickness of the silica layer of the T1-T2 dual-activation magnetic resonance contrast agent prepared in examples 1 to 4 using a transmission electron microscope.
0.5mg/mL of the T1-T2 dual-activation magnetic resonance contrast agent samples prepared in examples 1-4 were prepared, 1. mu.L of the prepared samples were dropped onto a copper mesh for TEM test with a pipette, and observed and detected with a Transmission Electron Microscope (TEM) after the solution was naturally volatilized.
As shown in FIGS. 2 to 5, the thicknesses of the silica layers of the T1-T2 dual-activation magnetic resonance contrast agents prepared in examples 1 to 4 were 4nm, 8nm, 12nm and 32nm, respectively.
Test example 2
Elemental analysis was performed using the example of T1-T2 dual-activation magnetic resonance contrast agent prepared in example 1.
0.5mg/mL of the T1-T2 dual-activation magnetic resonance contrast agent samples prepared in examples 1-4 were prepared, 1. mu.L of the prepared samples were dropped onto a copper mesh for TEM test with a pipette, and elemental scanning analysis was performed using a high-resolution transmission electron microscope (HRTEM) after the solution was naturally volatilized.
The result is shown in fig. 6, in the T1-T2 dual-activation magnetic resonance contrast agent of the present invention, silicon dioxide and T1 contrast agent manganese oxide are sequentially and uniformly coated on T2 contrast agent superparamagnetic iron oxide nanoparticles.
Test example 3
The pH responsiveness of the T1-T2 dual-activation magnetic resonance contrast agent of the present invention was analyzed by taking, as an example, the T1-T2 dual-activation magnetic resonance contrast agent prepared in example 1.
0.1mg of the T1-T2 dual-activation magnetic resonance contrast agent prepared in example 1 was added to 1mL of a pre-prepared aqueous solution with pH values of 7.4, 6.0, 5.0 and 4.0, respectively, and incubated overnight, followed by testing with a 3.0T magnetic resonance scanner, which resulted in T1-weighted imaging T1W and T2-weighted imaging T2W at different pH values.
As shown in fig. 7, the T1-T2 dual-activation magnetic resonance contrast agent of the present invention has good pH responsiveness, is in a state of dual quenching of T1 and T2 signals in a neutral environment, and can simultaneously achieve T1 and T2 signal activation in an acidic environment, and the activation effect thereof increases with the increase of acidity, and by calculating the inverse difference of the relaxation time of T1 and T2 signals at pH 5 and pH 7, respectively, and then adding, it can be calculated that the activation amplification of T1 and T2 signals at pH 5 is up to 12.
Test example 4
The effect of the thickness of the silica layer in the T1-T2 dual-activation magnetic resonance contrast agent on the T1 and T2 contrast agent signals was investigated.
Different thicknesses of the T1-T2 dual-activation magnetic resonance contrast agents prepared in examples 1-4 were prepared into 0.1mg/mL solutions (solvent is water), and tested by a 3.0T magnetic resonance scanner to obtain T1 weighted imaging T1W and T2 weighted imaging T2W.
As a result, as shown in fig. 8, as the thickness of the silica layer increases, the distance between T2 and T1 contrast agents also increases, the T1 signal is always in a quenching state, and for the T2 signal, the distance between T2 and T1 contrast agents increases, the T2 signal gradually increases, and when the distance is greater than 12nm and increases to 32nm, the T2 signal has almost no quenching effect, and when the distance is less than 4nm, the silica layer is too thin to attach a sufficient amount of T1 contrast agents, which is not practical, so that the thickness of the silica layer is controlled to be 4-12 nm, and the T1 and T2 can be simultaneously quenched and the T1 contrast agent loading amount can be simultaneously maintained.
Test example 5
Taking the T1-T2 dual-activation magnetic resonance contrast agent prepared in example 1 as an example, the tumor targeting of the T1-T2 dual-activation magnetic resonance contrast agent is studied.
The experimental process comprises the following steps: incubating 4T1 tumor cells with a culture dish special for laser confocal culture, and adding a non-target group (NH) into one group when the number of cells reaches more than half2PEG-modified T1-T2 dual-activation magnetic resonance contrast agent), and the other group is added with a targeting group (T1-T2 dual-activation magnetic resonance contrast agent prepared in example 1, namely NH)2PEG-PBA modified T1-T2 double-activation magnetic resonance contrast agent), marking the two molecules by fluorescent molecules, respectively incubating for 0.5h, 1h, 2h and 4h, washing for three times by PBS, then carrying out cell nucleus staining, detecting the condition of the contrast agent taken by cells by a laser confocal microscope, and counting the average fluorescence intensity
The result is shown in fig. 9, the fluorescence intensity of the targeted group is significantly higher than that of the non-targeted group, which indicates that the T1-T2 dual-activation magnetic resonance contrast agent of the present invention has good active targeting of tumor cells.
Test example 6
The imaging effect of the T1-T2 dual-activation magnetic resonance contrast agent was tested by taking the T1-T2 dual-activation magnetic resonance contrast agent prepared in example 1 as an example.
Experimental mice were anesthetized before and after injection by injecting T1-T2 double-activation magnetic resonance contrast agent prepared in example 1 at a dose of 10mg/kg via tail vein, and scanned with a 3.0T magnetic resonance scanner to obtain T1-weighted images and T2-weighted images of their images.
As shown in fig. 10, by injecting the T1-T2 dual-activation magnetic resonance contrast agent through tail vein, the dual activation of T1 and T2 signals can be simultaneously realized at the tumor site in the mouse body, the T1 and T2 signals of the tumor site are significantly improved, and the purpose of high-definition imaging is realized.
In conclusion, the T1-T2 dual-activation magnetic resonance contrast agent has a pH response mechanism, can simultaneously realize signal activation of T1 and T2 contrast agents under an acidic condition, and the activation effect is enhanced along with the increase of acidity; can be enriched at the tumor site and significantly enhance the T1 and T2 contrast agent signals at the tumor site.
The applicant states that the present invention is illustrated in detail by the above examples, but the present invention is not limited to the above detailed methods, i.e. it is not meant that the present invention must rely on the above detailed methods for its implementation. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (10)
1. A T1-T2 dual-activation magnetic resonance imaging contrast agent is characterized in that the T1-T2 dual-activation magnetic resonance imaging contrast agent has a core-shell structure and sequentially comprises T2 contrast agent nanoparticles, a silicon dioxide layer, a T1 contrast agent layer and a modification layer from inside to outside;
the T2 contrast agent nanoparticle is a superparamagnetic iron oxide nanoparticle.
2. The T1-T2 dual-activation magnetic resonance imaging contrast agent as claimed in claim 1, wherein the superparamagnetic iron oxide nanoparticles have a particle size of 8-20 nm;
preferably, the thickness of the silicon dioxide layer is 4-12 nm;
preferably, the mass ratio of the T2 contrast agent nanoparticles to the T1 contrast agent layer is 1 (5-30).
3. The T1-T2 dual-activation magnetic resonance imaging contrast agent of claim 1 or 2, wherein the T1 contrast agent layer comprises manganese oxide and/or gadolinium oxide;
preferably, the modifying layer comprises polyethylene glycol-phenylboronic acid;
preferably, the molecular weight of the polyethylene glycol is 2000-10000.
4. A method of preparing a T1-T2 dual-activation magnetic resonance imaging contrast agent as claimed in any one of claims 1 to 3, the method comprising:
and sequentially carrying out coating silicon dioxide treatment, coating T1 contrast agent treatment and modification treatment on the superparamagnetic iron oxide nanoparticles to obtain the T1-T2 double-activation magnetic resonance imaging contrast agent.
5. The method of claim 4, wherein the coating silica treatment comprises:
adding superparamagnetic iron oxide nanoparticles, polyoxyethylene (5) nonylphenyl ether, ammonia water and tetraethyl silicate into a solvent in sequence, and reacting to obtain superparamagnetic iron oxide nanoparticles coated with silicon dioxide;
preferably, the proportion of the solvent, the superparamagnetic iron oxide nanoparticles, the polyoxyethylene (5) nonylphenyl ether, the ammonia water and the tetraethyl silicate is (2-10) mL, (0.5-2.5) mg, (0.2-1) g, (50-200) mu L, (2-20) mu L;
preferably, the solvent comprises cyclohexane and/or n-hexane;
preferably, the superparamagnetic iron oxide nanoparticles comprise oleic acid-modified superparamagnetic iron oxide nanoparticles;
preferably, the reaction time is 2-48 h.
6. The preparation method according to claim 4 or 5, wherein the T1 contrast agent coating treatment comprises adding an oxidant and a metal salt into the superparamagnetic iron oxide nanoparticle coated with silica, and carrying out a reaction to obtain superparamagnetic iron oxide nanoparticles coated with silica and a T1 contrast agent;
preferably, the proportion of the superparamagnetic iron oxide nanoparticle coated with the silicon dioxide, the oxidant and the metal salt is 1mL (200-600) mu g (300-1000);
preferably, the oxidizing agent comprises potassium permanganate;
preferably, the metal salt comprises a manganese salt and/or a gadolinium salt;
preferably, the manganese salt comprises any one of manganese sulfate, manganese nitrate, manganese chloride or manganese acetate or a combination of at least two of the manganese sulfate, the manganese nitrate, the manganese chloride or the manganese acetate;
preferably, the gadolinium salt comprises any one of gadolinium sulfate, gadolinium nitrate, gadolinium chloride or gadolinium acetate or a combination of at least two of the foregoing;
preferably, the reaction time is 1-4 h.
7. The preparation method according to any one of claims 4 to 6, wherein the modification treatment comprises adding amino-polyethylene glycol-phenylboronic acid to superparamagnetic iron oxide nanoparticles coated with silica and a T1 contrast agent, and carrying out a reaction to obtain the T1-T2 dual-activation magnetic resonance imaging contrast agent;
preferably, the proportion of the superparamagnetic iron oxide nanoparticles coated with the silicon dioxide and the T1 contrast agent to the amino-polyethylene glycol-phenylboronic acid is 1mL (1-4) mg;
preferably, the reaction time is 6-48 h.
8. The method of any one of claims 4 to 7, comprising the steps of:
(1) adding superparamagnetic iron oxide nanoparticles modified by oleic acid into a solvent, carrying out ultrasonic treatment for 5-10 min, adding polyoxyethylene (5) nonylphenyl ether and ammonia water, carrying out ultrasonic treatment for 3-10 min, and adding tetraethyl silicate, wherein the ratio of the superparamagnetic iron oxide nanoparticles, the solvent, polyoxyethylene (5) nonylphenyl ether, the ammonia water and the tetraethyl silicate is (0.5-2.5) mg, (2-10) mL, (0.2-1) g, (50-200) microliter, (2-20) microliter, carrying out stirring reaction for 2-48 h, centrifuging, collecting precipitates, washing with ethanol and water for 2-4 times respectively, and redissolving in a water phase;
(2) adding potassium permanganate into the product obtained in the step (1), stirring for 5-20 min, and continuously adding metal salt, wherein the proportion of the product obtained in the step (1), the potassium permanganate and the metal salt is 1mL (200-600) mu g (300-1000) mu g, stirring for reaction for 1-4 h, centrifuging, collecting precipitate, washing for 2-4 times, and redissolving in a water phase;
(3) and (3) adding amino-polyethylene glycol-phenylboronic acid into the product obtained in the step (2), wherein the proportion of the product obtained in the step (2) to the amino-polyethylene glycol-phenylboronic acid is 1mL (1-4) mg, stirring for 6-48 h, centrifuging, collecting precipitates, and redissolving the precipitates in a water phase to obtain the magnetic resonance contrast agent.
9. A contrast agent composition comprising the T1-T2 dual-activation magnetic resonance contrast agent of any one of claims 1 to 3;
preferably, the contrast agent composition further comprises a pharmaceutically acceptable adjuvant.
10. Use of the T1-T2 dual-activation magnetic resonance contrast agent of any one of claims 1-3 or the contrast agent composition of claim 9 for the preparation of a magnetic resonance imaging agent.
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