CN112891566A - Nano material, preparation method thereof and contrast agent containing nano material - Google Patents
Nano material, preparation method thereof and contrast agent containing nano material Download PDFInfo
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- CN112891566A CN112891566A CN201911230151.5A CN201911230151A CN112891566A CN 112891566 A CN112891566 A CN 112891566A CN 201911230151 A CN201911230151 A CN 201911230151A CN 112891566 A CN112891566 A CN 112891566A
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- 239000002086 nanomaterial Substances 0.000 title claims abstract description 47
- 239000002872 contrast media Substances 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000002105 nanoparticle Substances 0.000 claims abstract description 105
- 230000005291 magnetic effect Effects 0.000 claims abstract description 25
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229910052751 metal Inorganic materials 0.000 claims abstract description 19
- 239000002184 metal Substances 0.000 claims abstract description 19
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229960004889 salicylic acid Drugs 0.000 claims abstract description 12
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- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 11
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- GVGUFUZHNYFZLC-UHFFFAOYSA-N dodecyl benzenesulfonate;sodium Chemical compound [Na].CCCCCCCCCCCCOS(=O)(=O)C1=CC=CC=C1 GVGUFUZHNYFZLC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
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- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 claims description 2
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- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 2
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- DGOFDXKSKYTBGX-UHFFFAOYSA-L 2-carboxyphenolate;nickel(2+) Chemical compound [Ni+2].OC1=CC=CC=C1C([O-])=O.OC1=CC=CC=C1C([O-])=O DGOFDXKSKYTBGX-UHFFFAOYSA-L 0.000 description 1
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- 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
- 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
- A61K49/1866—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 the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid
- A61K49/1869—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 the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid coated or functionalised with a protein being an albumin, e.g. HSA, BSA, ovalbumin
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- A—HUMAN NECESSITIES
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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
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
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- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- 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
- 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
- A61K49/1863—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 a polysaccharide or derivative thereof, e.g. chitosan, chitin, cellulose, pectin, starch
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Abstract
A nanomaterial is disclosed, the nanomaterial comprising nanoparticles; the nano particles are magnetic metal complexes, and the ligands of the magnetic metal complexes are salicylic acid. The application also discloses a preparation method of the nano material and a contrast agent comprising the nano material. The nano material has excellent relaxation performance and excellent biological safety when being used in a contrast agent.
Description
Technical Field
The invention relates to a nano material, a preparation method thereof and a contrast agent containing the nano material, belonging to the technical field of nano materials.
Background
Magnetic resonance techniques are currently a common technique used for early diagnosis of cancer. Magnetic Resonance Imaging (MRI) technology is one of the commonly used techniques for early diagnosis of cancer. Compared with electron Computed Tomography (CT), Positron Emission Tomography (PET) and ultrasound imaging (US), MRI has the advantages of high tissue resolution, high spatial resolution, no hard artifacts, no radioactive damage, and the like. However, MRI often requires the use of contrast agents to improve diagnostic capabilities. For example, gadolinium-based contrast agents are one common paramagnetic contrast agent.
However, the imaging effect of the currently used gadolinium-based contrast agent is not very ideal, for example, the relaxation rate of Gd-DTPA (wherein DTPA is diethylenetriaminepentaacetic acid) is low, generally about 4, which causes less difference from normal tissue imaging, and poor sensitivity and accuracy. Further, gadolinium ions released from gadolinium-based contrast agents have adverse effects on human tissues or organs.
Disclosure of Invention
The present invention can solve the above-described problems, and provides a nanomaterial with high relaxation rate and high biosafety. In particular, in one aspect, the present invention provides a nanomaterial characterized in that,
the nanomaterial comprises nanoparticles;
the nano particles are magnetic metal complexes, and the ligands of the magnetic metal complexes are salicylic acid.
As one of the embodiments, "nanoparticles" refers to gadolinium salicylate nanoparticles.
Optionally, the nanoparticles have a particle size of 1-500 nm.
Optionally, the nanoparticles have a particle size of 1-200 nm.
Preferably, the nanoparticles have a particle size of 50-150nm, preferably 60-130 nm.
In a preferred embodiment of the nanomaterial of the present invention, the magnetic metal is selected from: gd. At least one of Dy, Mn, Fe and Ni.
In the present invention, the magnetic metal complex of the nanoparticle is a coordination compound composed of a metal cation and a salicylate, for example, the nanoparticle is composed of gadolinium ions (Gd)3+) Together with the salicylate radical, form a coordination compound.
In a preferred embodiment of the nanomaterial of the present invention, the surface of the nanomaterial is modified with a macromolecular material having good biocompatibility.
Preferably, the macromolecular material is at least one selected from proteins, oligopeptides, polysaccharides, polyether polymers and polyester polymers.
Preferably, the macromolecular material is selected from at least one of animal serum albumin and chitosan.
Preferably, the macromolecular material is selected from animal serum albumin or chitosan activated thiol.
In the present invention, chitosan is chitosan obtained by deacetylation of chitin widely existing in nature, and has a chemical name of polyglucosamine (1-4) -2-amino-B-D glucose, such as chitosan from Sigma.
In the present invention, the material embedding the nanoparticles is in particular animal serum albumin of high biocompatibility, such as Bovine Serum Albumin (BSA). In this case, preferably, the animal serum albumin is a reduced animal serum albumin, such as reduced bovine serum albumin (rBSA).
The invention uses macromolecule material to embed the nanometer particles, and the obtained embedded nanometer material can realize long circulation and has little toxicity to human body when being used as MRI contrast agent. In fact, for macromolecular materials, biodegradable non-toxic natural macromolecules (e.g. polypeptides with a molecular weight below 10,000Da) or synthetic macromolecules (e.g. PEG-PLGA with a molecular weight of 10-100Kda) can be used in the present invention, and besides the above macromolecular materials, at least one of proteins, oligopeptides, polysaccharides, polyethers or polyesters, preferably animal serum albumin, can be used as macromolecular material.
In a preferred embodiment of the nanomaterial of the present invention, the salicylate is derived from salicylic acid or a derivative thereof.
In a preferred embodiment of the nanomaterial of the present invention, the salicylate is derived from at least one of salicylic acid, a metal salicylate.
In a preferred embodiment of the nanomaterial of the present invention, the salicylate is derived from sodium salicylate.
In a preferred embodiment of the nanomaterial of the present invention, the magnetic metal cation is derived from at least one of metal chloride, magnetic metal oxide and magnetic metal fluoride.
In a preferred embodiment of the nanomaterial of the present invention, the magnetic metal cations are derived from metal chlorides.
In a preferred embodiment of the nanomaterial of the present invention, the molecular weight of the nanoparticle is in the range of 2,000-7,000.
In another aspect, the present invention provides a method for preparing a nanomaterial of the present invention, the method comprising:
and reacting the solution containing the ligand precursor and the magnetic metal source to obtain the nano particles, namely the nano material.
In a preferred embodiment of the method of the invention, said nanoparticles are obtained in a manner comprising: and reacting the solution containing the ligand precursor and the magnetic metal source to obtain the nano-particle.
In a preferred embodiment of the method of the present invention, the ligand precursor comprises at least one of salicylic acid, a metal salt of salicylic acid;
the magnetic metal source comprises at least one of a magnetic metal chloride, a magnetic metal oxide, and a magnetic metal fluoride;
the reaction conditions include: the reaction was stirred.
In a preferred embodiment of the process of the invention, the reaction is carried out under sealed conditions.
In a preferred embodiment of the method of the present invention, the preparation method further comprises:
and reacting raw materials containing the macromolecular material and the nano particles to obtain the nano material.
In a preferred embodiment of the process of the invention, the reaction conditions comprise: the reaction was stirred.
In a preferred embodiment of the process of the invention, the process comprises: and adding the macromolecular material into a solution containing the nano particles and an activating agent, and stirring for reaction to obtain the nano material.
In a preferred embodiment of the process of the invention, the preparation process comprises:
(S1) stirring the mixture containing salicylic acid and/or salicylate under a sealed condition to react to obtain nanoparticles; dispersing the nanoparticles to obtain a nanoparticle dispersion liquid;
(S2) reacting the mixture containing the reducing agent and the macromolecular material to obtain a reduced macromolecular material;
(S3) adding an activator to the dispersion of nanoparticles described in the step (S1), and then adding the reduced macromolecular material described in the step (2), and reacting to obtain the nanomaterial.
In a preferred embodiment of the process of the invention, the reducing agent comprises NaBH4、SnCl2、H2C2O4、KBH4And sodium citrate.
In a preferred embodiment of the method of the invention, the macromolecular material is selected from at least one of animal serum albumin, chitosan.
In a preferred embodiment of the process according to the invention, the activator is selected from at least one of EDC, NHS, DDC.
In a preferred embodiment of the process of the invention, the preparation process comprises:
(a1) stirring a mixture containing salicylic acid and/or salicylate under a sealed condition for reaction to obtain nanoparticles;
(a2) dispersing the nano particles into a solution containing a macromolecular material, adjusting the pH value to acidity, then adding a solution containing a surfactant, and reacting to obtain the nano material.
In a preferred embodiment of the method of the invention, the macromolecular material is selected from at least one of bovine serum albumin, chitosan.
In a preferred embodiment of the process of the present invention, the surfactant is selected from at least one of sodium tripolyphosphate and sodium dodecylbenzene sulfonate.
In the present invention, or in the method of the present invention, the nanoparticles are monodisperse, have a normal distribution of particle size and a uniform shape and size.
When used as a contrast medium, the contrast medium is generally used by intravenous injection, and the particle diameter cannot be too large, and therefore the particle diameter of the nanoparticle of the present invention is preferably 200nm or less. However, the particle size cannot be too small to achieve entrapment, and the particle size of the nanospheres is further preferably 50-150nm, more preferably 60-130 nm.
In a preferred embodiment of the process according to the invention, the nanoparticles obtained are reacted with macromolecular material and subsequently dialyzed to obtain embedded nanoparticles. Unreacted materials can be removed by dialysis. Preferably, dialysis is performed for 2 to 7 days, preferably 3 to 5 days. The dialysate is deionized water.
In the method of the present invention, preferably, the macromolecular material is first reduced with a reducing agent to give a reduced macromolecular material before reacting with the nanoparticles. Preferably, the reducing agent is selected from sodium borohydride.
In yet another aspect, the present invention provides a contrast agent comprising at least one of the nanomaterials of the invention, the nanomaterials prepared according to the methods of the invention.
In the present invention, the contrast agent may be various medical contrast agents, such as a Magnetic Resonance Imaging (MRI) contrast agent, an electron Computed Tomography (CT) contrast agent, or a Positron Emission Tomography (PET) contrast agent.
Preferably, the contrast agent is a magnetic resonance imaging contrast agent, in particular a magnetic resonance imaging T1A contrast agent.
Compared with the prior art, the invention has the beneficial effects that:
the embedded nano-particles of the invention have excellent relaxation property and high r when used as contrast agents1And extremely low r2/r1。
Drawings
FIG. 1 is a transmission electron micrograph of gadolinium salicylate nanoparticles prepared in example 1;
FIG. 2 is a transmission electron micrograph of gadolinium salicylate nanoparticles (GdSalNPs-rBSA) coated with rBSA in example 1;
FIG. 3 is a DLS particle size distribution plot of gadolinium salicylate nanoparticles obtained in example 1 and gadolinium salicylate nanoparticles encapsulating rBSA;
FIG. 4 is a Zeta potential diagram of gadolinium salicylate nanoparticles obtained in example 1 and gadolinium salicylate nanoparticles coated with rBSA;
FIG. 5 is a longitudinal relaxation diagram of gadolinium salicylate nanoparticles obtained in example 1 and gadolinium salicylate nanoparticles coated with rBSA; wherein (a) and (b) are three parallel samples of gadolinium salicylate nanoparticles respectively at a field strength of 1.5T1Relaxation Rate (1/T)1，s-1) Or with T2Relaxation Rate (1/T)2，s-1) A plot of gadolinium ion concentration as a function of gadolinium; (c) (d) three parallel samples, each of gadolinium salicylate nanoparticles comprising rBSA at a field strength of 1.5T1Relaxation Rate (1/T)1，s-1) Or with T2Relaxation Rate (1/T)2，s-1) A plot of gadolinium ion concentration as a function of gadolinium;
FIG. 6 is a schematic illustration of in vivo imaging of gadolinium salicylate nanoparticles obtained in example 1 or gadolinium salicylate nanoparticles coated with rBSA; wherein, a and b are respectively the effect graphs of the gadolinium salicylate nano-particles or the gadolinium salicylate nano-particles wrapping rBSA on the magnetic resonance imaging of the tumor parts of the nude mice with 4T1 tumor at different time points.
Detailed Description
The present application will be described in detail with reference to examples, but the present application is not limited to these examples.
In the present application, unless otherwise specified, the reactions mentioned are all carried out at normal temperature and pressure.
The raw materials, equipment and catalysts in the examples of the present application were all purchased from commercial sources unless otherwise specified.
Bovine serum albumin in the examples was purchased from Shanghai Aladdin.
Example 1
(1) Preparation of gadolinium salicylate nanoparticles
Mixing 8mL Nasal and 8mL GDdCl3Into 20mL glass bottles, respectively. The glass vial was sealed with a lid and magnetically stirred at 40 ℃ for 2 hours. After the stirring is completed. The resulting solution was centrifuged, the supernatant removed and the precipitate redispersed in 16ml of purified water. The washing was repeated three times and the precipitate was redispersed in 16ml of pure water. Then obtaining monodisperse gadolinium salicylate nano particles, and finally storing the obtained gadolinium salicylate solution at low temperature (0-4 ℃).
(2) Preparation of sulfydryl-activated bovine serum albumin and embedding of sulfydryl-activated bovine serum albumin in gadolinium salicylate nanoparticles
260 μ L NaBH4Adding the solution into 20.0mL of bovine serum albumin solution, and magnetically stirring the solution for 1h at room temperature to obtain the solution, namely the reduced bovine serum albumin. 50 μ LEDC and 250 μ LNHS were added to 5.0mL gadolinium salicylate solution, magnetically stirred under ice bath conditions at 0 deg.C, then 15mL reduced bovine serum albumin was added. The reaction was magnetically stirred at room temperature for 2 hours. The obtained gadolinium salicylate nanoparticles containing reduced bovine serum albumin were dialyzed for 3 days, pure water was replaced every day, and unreacted EDC and NHS were removed. Thus obtaining the gadolinium salicylate nano particles embedded with the reduced bovine serum albumin.
Example 2
Gd in step (1) of example 13+Change to Dy3+、Mn2+、Fe3+The preparation of thiol-activated bovine serum albumin and the embedding of the thiol-activated bovine serum albumin into the MRI contrast agent were the same as in example 1, and thus reduced bovine serum albumin-embedded dysprosium salicylate nanoparticles, reduced bovine serum albumin-embedded manganese salicylate nanoparticles, and reduced bovine serum albumin-embedded iron salicylate nanoparticles were obtained.
Example 3
Gd in step (1) of example 13+Changed into Ni2+The other steps are the same as the example 1, and the nickel salicylate nanometer particles embedded with the reduced bovine serum albumin can be prepared.
Example 4
The thiol-activated bovine serum albumin (rBSA) of example 1 was changed to chitosan (CSN, available from Sigma, type 50g, particle size 50-100nm) and the embedded nanomaterials were prepared as follows:
preparing 0.2% (w/v) chitosan solution with 1% (w/v) acetic acid as solvent, dispersing 1.5mg of gadolinium salicylate nano-particles (GdSalNPs) prepared in example 1 into 0.5ml of chitosan solution to obtain the solution, and adjusting the pH value of the solution to 4.7-4.8 by using sodium hydroxide; preparing 0.3% (w/v) of sodium Tripolyphosphate (TPP) aqueous solution; and under the magnetic stirring at 40 ℃, adding 0.1mL of TPP solution into 0.5mL of the chitosan solution to prepare the ion-crosslinked embedded nanospheres embedded with the chitosan, thereby obtaining the embedded nano material GdSal-CSN.
Performance testing and characterization
The morphology and the performance of the embedded nano-materials obtained in the examples 1 to 4 are characterized.
The gadolinium salicylate nanoparticles (GdSalNPs) prepared in example 1 and the embedded nanoparticle example (GdSalNPs-rBSA) are used as examples to illustrate the appearance and performance characterization results. The corresponding products obtained in the other examples have similar properties.
FIG. 1 is a transmission electron micrograph of coordination compound nanoparticles (GdSalNPs) formed by salicylate and gadolinium ions prepared in example 1.
In the present invention, the transmission electron microscope was JEM-2100, available from Japan Electron Ltd under the experimental conditions of 200 kV.
It can be seen from fig. 1 that gadolinium salicylate nanoparticles have a circular shape and a particle size of less than 100nm, which indicates that the nanoparticles are not metabolized by the kidney too early due to too small a particle size, and thus, long circulation in vivo is achieved.
FIG. 2 is a transmission electron micrograph of gadolinium salicylate nanoparticles (GdSalNPs-rBSA) coated with rBSA in example 1. The adhesion of nanoparticles to each other is observed in fig. 2, which is probably caused by the protein encapsulated on the surface of nanospheres, and this indirectly becomes evidence of the successful encapsulation of protein rBSA on the surface of nanoparticles.
Fig. 3 is a DLS particle size distribution diagram of gadolinium salicylate nanoparticles obtained in example 1 and gadolinium salicylate nanoparticles coated with bsa. FIG. 3 shows that the particle sizes of the gadolinium salicylate nanoparticles obtained in example 1 and gadolinium salicylate nanoparticles wrapping rBSA are distributed between 50-150nm, and the particle size range is favorable for long-time retention of the nanoparticles at tumor sites and is favorable for enhancing in vivo imaging effect. The particle size of the gadolinium salicylate nano-particles wrapping the rBSA is larger than that of the gadolinium salicylate nano-particles, which indicates that the rBSA successfully wraps the gadolinium salicylate nano-particles.
FIG. 4 shows the optimum r obtained in example 11Zeta potential diagrams of gadolinium salicylate nanoparticles with relaxivity and gadolinium salicylate nanoparticles coated with rBSA. Fig. 4 shows that the gadolinium salicylate nanoparticles obtained in example 1 and the gadolinium salicylate nanoparticles wrapping rBSA are both negatively charged, and the negatively charged nanoparticles have a smaller chance of forming protein corona precipitates in vivo, so that the long circulation of the nanoparticles in vivo is facilitated, and the imaging effect at the tumor site is enhanced.
FIGS. 5-6 were obtained using a 1.5T NMR spectrometer model Magnetom Avanto, available from Siemens, Germany.
Fig. 5 is a longitudinal relaxation diagram of gadolinium salicylate nanoparticles obtained in example 1 and gadolinium salicylate nanoparticles coated with rBSA. FIG. 5 shows that the relaxivity of gadolinium salicylate nanoparticles and gadolinium salicylate nanoparticles coated with rBSA is better (B)01.5T). For MRI in vitro relaxation studies, samples were configured with deionized water as test samples at different Gd concentrations (0, 25, 50, 100, 200, 400, and 800 μ M). Group scans of the sample tubes with volume coils using a clinical MRI scanner (1.5T, Magnetom Avanto, Siemens, Germany) to obtain T1And T2Value, whereby the longitudinal direction (r) can be calculated1) And the transverse direction (r)2) Relaxation time (1/T)1And 1/T2) Slope as a function of various Gd concentrations as relaxation rate. Among them, a, b, c and d show that the relaxivity of the gadolinium salicylate nanoparticles and the gadolinium salicylate nanoparticles containing rBSA is significantly higher than that of the commercially available gadolinium-based contrast agent; and the relaxivity of gadolinium salicylate nanoparticles comprising rBSA to gadolinium salicylate nanoparticlesHigher; the relaxation rate of gadolinium salicylate nanoparticles comprising rBSA is 4-5 times that of commercially available gadolinium-based contrast agents [ chem. Rev 2019,119, 957-1057-]The relaxation test conditions of the commercially available gadolinium-based contrast agent in this document are consistent with the relaxation test conditions of gadolinium salicylate nanoparticles obtained in example 1 of the present application and gadolinium salicylate nanoparticles coated with rBSA.
Fig. 6 is a schematic illustration of in vivo imaging of gadolinium salicylate nanoparticles prepared in example 1 or gadolinium salicylate nanoparticles coated with rBSA. The results show that gadolinium salicylate nanoparticles and gadolinium salicylate nanoparticles coated with rBSA achieve the strongest MRI signals at 12 hours after injection respectively. The point in time at which the MRI signal is strongest depends on the size of the particle size of the contrast agent. The particle diameter of the gadolinium salicylate nano particle wrapping rBSA is 124.7nm (d)h) The particle diameter of the gadolinium salicylate nano particle is 54.8nm (d)h). In addition, the MRI signal at 12 hours after injection of the rksa-coated gadolinium salicylate nanoparticles was much stronger than the MRI signal at 12 hours after injection of the gadolinium salicylate nanoparticles.
Although the present application has been described with reference to a few embodiments, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the application as defined by the appended claims.
Claims (10)
1. A nano-material is characterized in that,
the nanomaterial comprises nanoparticles;
the nano particles are magnetic metal complexes, and the ligands of the magnetic metal complexes are salicylic acid.
2. Nanomaterial according to claim 1, characterized in that the magnetic metal is chosen from: gd. At least one of Dy, Mn, Fe and Ni;
preferably, the surface of the nano material is modified with a macromolecular material with good biocompatibility;
preferably, the macromolecular material is selected from at least one of protein, oligopeptide, polysaccharide, polyether polymer and polyester polymer;
preferably, the particle size of the nanoparticles is 1-500 nm;
preferably, the macromolecular material is selected from at least one of animal serum albumin and chitosan.
3. The method for preparing nanomaterials of any one of claims 1 or 2, wherein the method comprises:
and reacting the solution containing the ligand precursor and the magnetic metal source to obtain the nano particles, namely the nano material.
4. The production method according to claim 1, wherein the ligand precursor includes at least one of salicylic acid, a metal salicylate;
the magnetic metal source comprises at least one of a magnetic metal chloride, a magnetic metal oxide, and a magnetic metal fluoride;
the reaction conditions include: stirring and reacting;
preferably, the reaction is carried out under sealed conditions;
preferably, the method further comprises the following steps:
reacting raw materials containing macromolecular materials and the nano particles to obtain the nano materials;
preferably, the reaction conditions include: the reaction was stirred.
5. The method of manufacturing according to claim 4, wherein the method comprises: and adding the macromolecular material into a solution containing the nano particles and an activating agent, and stirring for reaction to obtain the nano material.
6. The method of manufacturing according to claim 5, comprising:
(S1) stirring the mixture containing salicylic acid and/or salicylate under a sealed condition to react to obtain nanoparticles; dispersing the nanoparticles to obtain a nanoparticle dispersion liquid;
(S2) reacting the mixture containing the reducing agent and the macromolecular material to obtain a reduced macromolecular material;
(S3) adding an activator to the dispersion of nanoparticles described in the step (S1), and then adding the reduced macromolecular material described in the step (2), and reacting to obtain the nanomaterial.
7. The method of claim 6, wherein the reducing agent comprises NaBH4、SnCl2、H2C2O4、KBH4And sodium citrate;
the macromolecular material is selected from animal serum albumin;
the activator is selected from at least one of EDC, NHS and DDC;
preferably, the preparation method comprises:
(a1) stirring a mixture containing salicylic acid and/or salicylate under a sealed condition for reaction to obtain nanoparticles;
(a2) dispersing the nano particles into a solution containing a macromolecular material, adjusting the pH value to acidity, then adding a solution containing a surfactant, and reacting to obtain the nano material.
8. The method of claim 7, wherein the macromolecular material is selected from the group consisting of chitosan;
the surfactant is at least one selected from sodium tripolyphosphate and sodium dodecyl benzene sulfonate.
9. A contrast agent comprising at least one nanomaterial according to any one of claims 1 or 2 and a nanomaterial prepared by a method according to any one of claims 3 to 8.
10. The contrast agent according to claim 9, wherein the contrast agent is a magnetic resonance imaging contrast agent.
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