CN114540016A - Nanometer material with inorganic metal ion mediated targeting effect on surface and application thereof - Google Patents
Nanometer material with inorganic metal ion mediated targeting effect on surface and application thereof Download PDFInfo
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Abstract
The invention discloses a nano material with a surface inorganic metal ion mediated targeting effect, wherein the surface of the nano material is provided with inorganic metal ions which can be specifically combined with specific receptor proteins on cell membranes, and the targeting property of the nano material is optimized by regulating the content of the surface inorganic metal ions in the nano material and the exposure of the inorganic metal ions on the surface of the nano material, so that the surface ions of the nano material become active sites of the targeting effect and are selectively combined with ion transporters on the surface of the cell membranes, and the ion mediated targeting effect on the surface of the nano material is realized. The invention belongs to the technical field of targeting nanometer, and particularly relates to a nanometer material with a surface inorganic metal ion mediated targeting effect and application thereof.
Description
Technical Field
The invention belongs to the technical field of targeting nanometer, and particularly relates to a nanometer material with a surface inorganic metal ion mediated targeting effect and application thereof.
Background
Due to the advantages of good biological safety, abundant physicochemical properties, large specific surface area, easy surface functionalization and modification and the like, the constructed targeting nanoprobe has wide application prospect in the fields of diagnosis and treatment of tumors, cardiovascular and cerebrovascular diseases and the like. At present, the targeting of the nano material is mainly realized by coupling ligand molecules such as antibodies, polypeptides, nucleic acids and the like with a targeting function on the surface of the nano material, and specifically combining the ligand molecules with specific biological molecules. Therefore, the specificity of the ligand is crucial to the targeting efficiency and the diagnostic effect of the nanoprobe. For this reason, many articles and patents [ Theranostics,2016,6(11):1780.CN202110697471.2, CN202011534812.6, CN202010872013.3 ] all disclose that ligand molecules are modified on the surface of the nanomaterial to improve the targeting efficiency of the ligand-mediated nanoprobe.
Although the targeting effect can be realized by modifying the nano material on the surface of the ligand molecule, the targeting effect mediated by the existing ligand molecule often causes that the targeting binding site of the ligand molecule is difficult to be effectively exposed due to the non-directional coupling technology, and the availability of the ligand molecule in the targeting process is insufficient, thereby influencing the targeting efficiency. In recent years, with the development of the directional coupling technology of ligand molecules, ligand target sites are fully exposed, but the directional coupling technology is complex in process and high in preparation cost, and the popularization and application of the directional coupling technology are limited.
Aiming at the problem of insufficient targeting efficiency in the biomedical application of nano materials, the invention provides a nano material with inorganic metal ion mediated targeting on the surface, which is different from the targeting effect mediated by the existing ligand molecules. The surface metal ion mediated targeting nanomaterial provided by the invention provides a new idea for the design and construction of a high-specificity nanoprobe.
Disclosure of Invention
In order to meet the requirements of biomedical application on targeted nano materials, the invention provides a method for further improving the targeting property of nano particles by regulating the content of inorganic metal ions in the nano materials and the exposure of the inorganic metal ions on the surface, and the method is applied to the fields of magnetic resonance imaging, cell tracing, magnetic particle imaging, targeted drug delivery and the like.
In order to realize the functions, the technical scheme adopted by the invention is as follows: the nanometer material with the surface provided with inorganic metal ions for mediating the targeting effect can be specifically combined with specific receptor proteins on cell membranes so as to realize the targeted enrichment of the nanometer material on specific tissues, and the nanometer material is a nanometer material harmless to human bodies, such as ferrite nanometer particles, quantum dots, up-conversion nanometer materials, noble metal nanometer particles and the like.
Preferably, the inorganic metal ions on the surface of the nano material are at least one of transition metal elements in trace elements contained in a human body, and the mass percentage of the inorganic metal ions in the nano material is 12% -60%.
Preferably, the size of the nano material ranges from 1.5nm to 5.5nm, and the morphology of the nano material is at least one of spherical, cubic, granular, linear and flaky, preferably granular.
Preferably, the nanomaterial is prepared by at least one of a high-temperature thermal decomposition method, a coprecipitation method, a hydrothermal method, or a sol-gel method, and surface modification is performed by a ligand exchange or a ligand addition method to enable the nanomaterial to be dispersed in an aqueous phase.
The invention also provides an application of the surface inorganic metal ion mediated targeting nanomaterial, the nanomaterial is specifically combined with cell expression ion channel protein or metal ion transport protein to realize the targeted enrichment of the nanomaterial on a specific tissue, the degree of the targeted enrichment of the nanomaterial on the specific tissue is regulated by regulating the content of inorganic metal ions in the nanomaterial and the exposure of the surface inorganic metal ions on the surface of the nanomaterial, and the nanomaterial can be applied to the fields of magnetic resonance imaging, cell tracing, magnetic particle imaging, targeted drug delivery and the like; wherein the cell expresses an ion channel protein comprising: at least one of sodium ion channel protein, potassium ion channel protein, calcium ion channel protein, and magnesium ion channel protein; the metal ion transporter includes at least one of a divalent metal ion transporter family and a solute carrier family protein.
Preferably, the cells expressing the ion channel protein or the metal ion transporter comprise normal or diseased somatic cells or tumor cells, and the normal cells comprise at least one of hepatocytes, cholangiocytes, pancreatic cells, colorectal cells, breast cells, kidney cells, stomach cells, thyroid cells, and osteoblasts; the tumor cells comprise at least one of liver cancer cells, bile duct cancer cells, pancreatic cancer cells, colorectal cancer cells, breast cancer cells, kidney cancer cells, stomach cancer cells, thyroid cancer cells and bone tumor cells.
Preferably, the specific tissue is a focal tissue or a normal tissue.
The invention adopts the scheme to obtain the following beneficial effects: according to the nano material with the surface metal ion mediated targeting effect, the degree of targeted enrichment of the nano material on the specific tissue is regulated and controlled by regulating the content of inorganic metal ions in the nano material and the exposure of the surface inorganic metal ions on the surface of the nano material, and the targeting efficiency of the nano material can be improved, so that the nano material can be better applied to the fields of magnetic resonance imaging, cell tracing, magnetic particle imaging, targeted drug delivery and the like.
Drawings
FIG. 1 is a schematic structural diagram of a surface inorganic metal ion-mediated targeting nanomaterial according to some embodiments of the present invention;
FIG. 2 is a flow chart illustrating the preparation of nanoprobes according to some embodiments of the present invention;
FIG. 3 is a transmission electron microscope image of manganese ferrite nanoparticles of example 1 of the present invention;
FIG. 4 is a metal element analysis diagram of manganese ferrite nanoparticles of example 1 of the present invention;
FIG. 5 is a graph showing the size distribution of manganese ferrite nanoparticles of example 1 of the present invention;
FIG. 6 is a photo-micrograph of the super-resolution structure of the specific binding between the manganese ferrite nanoparticles and the SLC39A14 protein on the surface of the hepatocyte in example 1 of the present invention;
FIG. 7 is a graph of manganese ferrite nanoparticles specifically endocytosed with different manganese contents by hepatocytes according to example 2 of the present invention;
FIG. 8 is the quantitative manganese ferrite nanoparticle live hepatocyte specific magnetic resonance imaging in example 3 of the present invention;
fig. 9 is the copper ferrite nanoparticle in vivo bone tissue specific magnetic resonance imaging in example 3 of the present invention.
Wherein 1 is nano-particles, 2 is surface metal ions, A is a precursor, a is liver, and b is gallbladder.
Detailed Description
The technical solutions of the present invention are described clearly and completely below, and it is obvious that the described embodiments are some, not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Fig. 1 is a schematic structural diagram of a nanomaterial with surface metal ion-mediated targeting effect according to some embodiments of the present invention, as shown in fig. 1, the surface of the nanomaterial has inorganic metal ions, and the nanomaterial is a nanomaterial harmless to human body, for example: ferrite nanoparticles, quantum dots, up-conversion nanomaterials, noble metal nanoparticles, and the like; the inorganic metal ion is transition metal element in microelements contained in human body, specifically, the inorganic metal ion can be at least one of iron, zinc, copper, manganese, magnesium, etc.; the nanomaterial can deliver a substance to a target tissue, the substance can be a contrast agent or a drug or the like or a combination thereof, and the target tissue can be a focal tissue (such as a tumor) or a normal tissue; and the surface inorganic metal ions can be combined with specific proteins on the cell surface in the target tissue to realize the targeted enrichment of the nano material to the target tissue.
The cell expresses ion channel proteins including: ion channel proteins, metal ion transporters, ion channel proteins include: at least one of sodium ion channel protein, potassium ion channel protein, calcium ion channel protein (Transent Receptor Potential Vanilloid substrate) and magnesium ion channel protein; metal ion transporters include: at least one of a Divalent Metal Transport (DMT) protein Family and a Solute Carrier Family protein (Solute Carrier Family 39(Metal Ion Transporter));
the cells expressing the ion channel protein or the metal ion transporter include normal or diseased somatic cells or tumor cells, and the normal cells include liver cells, bile duct cells, pancreatic cells, colorectal cells, breast cells, kidney cells, stomach cells, thyroid cells, osteoblasts and the like; the tumor cells comprise liver cancer cells, bile duct cancer cells, pancreatic cancer cells, colorectal cancer cells, breast cancer cells, kidney cancer cells, stomach cancer cells, thyroid cancer cells, bone tumor cells and the like.
In some embodiments, the nanomaterial may be an imaging-capable nanomaterial that may allow the contrast agent or imaging agent to be enriched on normal or focal tissue to enable targeted imaging of the normal or focal tissue. In some embodiments, the nanomaterial 1 may be a drug-carrying nanoprobe that can enrich the drug on tumor tissue to achieve targeted therapy to the tumor tissue.
In some embodiments, the degree of targeted enrichment can be modulated by varying the content of inorganic metal ions at the surface of the nanomaterial.
Fig. 2 is a flowchart of the preparation of the nanomaterial, and the preparation of the nanomaterial includes a step S1 of preparing nanoparticles containing inorganic metal ions from the precursor and performing surface modification so that the nanoparticles can be dispersed in an aqueous phase. In some embodiments, in the first step, the nanomaterial with inorganic metal ions on the surface is prepared by a thermal decomposition method, and the hydrophilic ligand is modified on the surface so that the nanomaterial can be dispersed in the water phase; in other embodiments, the step is to synthesize the nanomaterial with inorganic metal ions on the surface directly in the aqueous phase.
Example 1: the preparation of manganese ferrite nanoparticles smaller than 5nm and the research on the specificity of hepatocytes thereof, the preparation of ultra-small ferrite nanoparticles can be performed by a thermal decomposition method, a coprecipitation method, a microwave-assisted method, etc., and the thermal decomposition is mainly taken as an example in this embodiment.
(1) Weighing 1.07g of ferric erucate, 0.62g of manganese oleate, 1.61g of oleyl alcohol and 0.56g of oleic acid, adding into 10g of benzyl ether, placing into a 50ml three-neck flask, carrying out thermal decomposition reaction, and reacting at 265 ℃ for 30 min;
(2) cooling to below 50 ℃, and cleaning the product for three times by adopting a chloroform dispersion-centrifugation mode. The final product was dispersed in 10mL chloroform;
(3) taking 1ml of the product obtained in the step (2), 50mg of phosphorylated polyethylene glycol (mPEG), adding 15ml of chloroform, heating to 50 ℃ under the protection of argon, and carrying out ligand exchange reaction;
(4) dispersing the product obtained in (3) in an aqueous phase, and studying the specific action of the SLC39A14 protein on the surface of the liver cells mediated by the surface manganese ions.
A series of characterizations are carried out on the specificity of the hepatocyte mediated by manganese ions on the surface of the prepared manganese ferrite nanoparticle, specifically, the prepared ultra-small iron oxide nanoparticle is dispersed in water, the water solution dispersed with the nanoparticle is dropped on a Cu net plated with a carbon film, and characterization is carried out after natural drying.
FIG. 3 is a transmission electron microscope image of manganese ferrite nanoparticles modified by phosphorylated polyethylene glycol, and it can be seen from the image that the manganese ferrite nanoparticles are uniform in size and morphology, and the size is about 3 nm;
FIG. 4 is an elemental analysis of a manganese ferrite nanoparticle modified with phosphorylated polyethylene glycol, showing that the nanoparticle contains two inorganic metal elements, manganese and iron;
FIG. 5 is a graph showing the distribution of the sizes of the manganese ferrite nanoparticles modified by phosphorylated polyethylene glycol, the abscissa shows the size of the particles, and the ordinate shows the number of the corresponding particles, from which it can be seen that the main distribution range of the sizes of the nanoparticles is 1.5-5.5 nm, and the preferable distribution range is 2.5-3.5 nm;
FIG. 6 is an image of interaction of manganese ferrite nanoparticles labeled with FITC, a green fluorescent molecule, and hepatocytes (SLC39A14 protein labeled blue fluorescence) using a structured light super-resolution microscope, wherein the green fluorescence is manganese ferrite nanoparticles and the blue fluorescence is SLC39A14 protein, and FIGS. 6-2 to 6-5 are enlarged views of a portion of FIG. 6-1; the results show that blue and green fluorescence overlap, indicating that the manganese ferrite nanoparticles can specifically bind to SLC39a14 protein on the hepatocyte membrane.
Example 2: rule of manganese ferrite nanoparticle hepatocyte specificity changing along with manganese content
Under the same condition, co-culturing the prepared manganese ferrite nanoparticles with different manganese contents and liver cells for the same time, cleaning the cells, digesting, performing ICP (inductively coupled plasma) to test the content of ferromanganese in the cells, quantitatively representing the rule of specific endocytosis of the manganese ferrite particles by the liver cells, and representing the specificity of the liver cells on which manganese ions depend on the surfaces of the nanoparticles;
FIG. 7 is a graph quantitatively showing that different manganese content manganese ferrite nanoparticles are endocytosed in hepatocytes, wherein the ordinate is the average endocytosed amount per cell, and the abscissa is "1", "2", "3", "4", "5", "6" respectively representing manganese content in the nanoparticles of 5%, 12%, 24%, 31%, 60% and 70% by mass, and the results show that the endocytosed amount of hepatocytes increases first and then decreases as the manganese content increases, the average endocytosed amount of 5% manganese content particles per cell is only 1.72pg, the average endocytosed amount of 12% manganese content particles per cell is 3.96 times the endocytosed amount of 5% manganese content particles, showing better specificity, and then the endocytosed amount increases slowly as the content increases, and when the manganese content is 70% the endocytosed amount of cells decreases sharply, probably because the higher manganese content causes lower endocytosed amount, therefore, the manganese content range is between 12 and 60 percent, and the specificity is better.
Example 3:
1) manganese ferrite nanoparticle hepatocyte specific magnetic resonance imaging
Using the manganese ferrite nanoparticles synthesized in example 1, after the manganese ferrite nanoparticles were intravenously injected into animals for magnetic resonance imaging, a hepatocyte-specific magnetic resonance imaging probe enhanced liver signal (arrow a), and when the probe was cleared by hepatocytes to the gallbladder, gallbladder signal was also enhanced (arrow b).
Fig. 8 shows that the manganese ferrite nanoparticles perform hepatocyte specific imaging, and it can be seen that liver signals become bright and gallbladder signals become variable, and that the bright gallbladder signals indicate that the manganese ferrite nanoparticles are metabolized to the biliary tract system via hepatocytes, which indicates that the manganese ferrite nanoparticles can specifically target hepatocytes and can perform magnetic resonance hepatobiliary imaging application.
2) Copper ion mediated targeted bone tissue magnetic resonance imaging on surface of copper ferrite nanoparticles
Osteoblast cells contain a divalent metal transport protein (DMT 1) on their surface, which specifically binds to iron, copper, zinc, etc., and is transported into the cell. Fig. 9 is a magnetic resonance imaging diagram of the ultra-small copper ferrite nanoparticles prepared by the thermal decomposition method in example 1, and the surface of the ultra-small copper ferrite nanoparticles is modified with polyethylene glycol, and the specific synthesis method is as follows: weighing 1.07g of ferric erucate, 0.62g of copper oleate, 1.61g of oleyl alcohol and 0.56g of oleic acid, adding into 10g of benzyl ether, placing into a 50ml three-neck flask, carrying out thermal decomposition reaction, and reacting at 265 ℃ for 30min to finish the reaction; when the reaction system is cooled to below 50 ℃, the product is washed for three times by adopting a chloroform dispersion-centrifugation mode, and the final product is dispersed in 10mL of chloroform; taking 1ml of chloroform-dispersed nano particles and 50mg of phosphorylated polyethylene glycol (mPEG), adding 15ml of chloroform, heating to 50 ℃ under the protection of argon, and carrying out ligand exchange reaction; the copper ferrite nanoparticles with the surface modified by polyethylene glycol can be obtained, and the content of copper ions in the nanoparticles can be regulated and controlled by regulating and controlling the proportion of ferric erucate and copper oleate. In the present example, the ratio of copper ions to iron ions after ICP testing of the copper ferrite nanoparticles was 1: 2. After intravenous injection of the copper ferrite nanoparticles into the animal body, magnetic resonance imaging was performed as shown in fig. 9, the arrows are bones, the bone signal was seen to be enhanced, and the signal appeared low in the middle and high around, indicating bone enhancement rather than bone marrow.
The present invention and the embodiments thereof have been described above, but the description is not limited thereto, and the embodiments shown in the examples are only one of the embodiments of the present invention, and the actual embodiments are not limited thereto. In summary, those skilled in the art should appreciate that the invention is not limited to the specific embodiments and examples, but rather, may be practiced without departing from the spirit and scope of the invention.
Claims (9)
1. The nano material with the surface inorganic metal ion mediated targeting effect is characterized in that the surface of the nano material is provided with inorganic metal ions, and the inorganic metal ions can be specifically combined with specific receptor proteins on cell membranes.
2. The nanomaterial of surface inorganic metal ion-mediated targeting effect according to claim 1, characterized in that the inorganic metal ion on the surface of the nanomaterial is at least one of transition metal elements in trace elements contained in human body.
3. The nanomaterial of claim 1, wherein the inorganic metal ion on the surface mediates the targeting effect, and the mass percentage of the inorganic metal ion in the nanomaterial is 12% to 60%.
4. The nanomaterial for surface inorganic metal ion-mediated targeting according to claim 1, wherein the nanomaterial is in a size range of 1.5nm to 5.5 nm.
5. The nanomaterial of surface inorganic metal ion-mediated targeting according to claim 1, wherein the nanomaterial morphology is at least one of spherical, cubic, granular, linear, and sheet.
6. A surface inorganic metal ion mediated targeting nanomaterial according to any of claims 1 to 5, wherein the nanomaterial is prepared by at least one of a high temperature thermal decomposition method, a coprecipitation method, a hydrothermal method or a sol-gel method, and the surface is modified by ligand exchange or ligand addition to enable the nanomaterial to be dispersed in an aqueous phase.
7. The use of the nanomaterial with surface inorganic metal ion-mediated targeting effect according to claim 6, wherein the nanomaterial is specifically bound to cell-expressed ion channel protein or metal ion transporter protein, so that the targeted enrichment of the nanomaterial on a specific tissue is realized, and the degree of the targeted enrichment on the specific tissue is regulated by regulating the content of the inorganic metal ions in the nanomaterial and the exposure of the surface inorganic metal ions on the surface of the nanomaterial; wherein the cell expresses an ion channel protein comprising: at least one of a sodium ion channel protein, a potassium ion channel protein, a calcium ion channel protein, and a magnesium ion channel protein; the metal ion transporter includes at least one of a divalent metal ion transporter family and a solute carrier family protein.
8. The use of the nanomaterial of surface inorganic metal ion-mediated targeting according to claim 7, wherein the cells expressing ion channel proteins or metal ion transporters comprise normal or diseased somatic or tumor cells, and the normal cells comprise at least one of hepatocytes, cholangiocytes, pancreatic cells, colorectal cells, breast cells, kidney cells, stomach cells, thyroid cells, and osteoblasts; the tumor cells comprise at least one of liver cancer cells, bile duct cancer cells, pancreatic cancer cells, colorectal cancer cells, breast cancer cells, kidney cancer cells, stomach cancer cells, thyroid cancer cells and bone tumor cells.
9. The use of the nanomaterial of surface inorganic metal ion-mediated targeting according to claim 7, wherein the specific tissue is a focal tissue or a normal tissue.
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Citations (2)
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| CN111821473A (en) * | 2020-07-14 | 2020-10-27 | 西安超磁纳米生物科技有限公司 | Composite ferrite nano-particles for synergistically enhancing liver specificity and preparation method and application thereof |
| CN113797361A (en) * | 2021-06-18 | 2021-12-17 | 中山大学附属第三医院（中山大学肝脏病医院） | Active targeting PET/MR bimodal imaging nanoprobe and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111821473A (en) * | 2020-07-14 | 2020-10-27 | 西安超磁纳米生物科技有限公司 | Composite ferrite nano-particles for synergistically enhancing liver specificity and preparation method and application thereof |
| CN113797361A (en) * | 2021-06-18 | 2021-12-17 | 中山大学附属第三医院（中山大学肝脏病医院） | Active targeting PET/MR bimodal imaging nanoprobe and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| DENG KERONG: "808 nm light responsive nanotheranostic agents based on near-infrared dye functionalized manganese ferrite for magnetic-targeted and imaging-guided photodynamic/photothermal therapy", 《JOURNAL OF MATERIALS CHEMISTRY B》 * |
| 周梦瑶: "金属转运蛋白 SLC39A14 的生理功能及作用机制研究进展", 《生命科学》 * |
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