CN111358955A - Inflammation-targeted bindarit nanoparticle for treating lipid metabolism diseases, and preparation method and application thereof - Google Patents

Inflammation-targeted bindarit nanoparticle for treating lipid metabolism diseases, and preparation method and application thereof Download PDF

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CN111358955A
CN111358955A CN202010251463.0A CN202010251463A CN111358955A CN 111358955 A CN111358955 A CN 111358955A CN 202010251463 A CN202010251463 A CN 202010251463A CN 111358955 A CN111358955 A CN 111358955A
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bindarit
inflammation
targeted
drug
soluble
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CN111358955B (en
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周兴
徐春媚
娄杰
张成元
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Chongqing Quansheng Pharmaceutical Technology Co ltd
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Chongqing University of Technology
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Abstract

The invention provides an inflammation targeted bindarit nanoparticle for treating lipid metabolism diseases, which relates to a biomedical polymer material and is prepared by forming an inflammation targeted drug delivery system by using water-soluble β -1, 3-D-glucan and a bindarit positive charge nano-drug through electrostatic adsorption, wherein the water-soluble β -1, 3-D-glucan and the bindarit positive charge nano-drug are subjected to electrostatic adsorption, the bindarit positive charge nano-drug is absorbed into blood by gastrointestinal tracts after oral administration and can be specifically distributed in peripheral blood mononuclear cells, the water-soluble β -1, 3-D-glucan can carry out targeted transport of the modified nanoparticle to the mononuclear cells, depending on the monocyte recruitment effect in chronic inflammation existing in each focus caused by lipid metabolism disorder, the nanoparticle is targeted transported to each inflammation focus, and after reaching each focus position, the expression of MCP-1 in the focus position is inhibited through the anti-inflammatory activity of the bindarit, so that the aggregation of the inflammation cells at the focus position is further reduced.

Description

Inflammation-targeted bindarit nanoparticle for treating lipid metabolism diseases, and preparation method and application thereof
Technical Field
The invention relates to the technical field of biomedical polymer materials, in particular to an inflammation-targeted bindarit nanoparticle for treating lipid metabolism diseases, a preparation method and application thereof.
Background
Lipid metabolism disorder refers to the abnormality of the quality and quantity of lipids (lipids) and their metabolites in blood and other tissues and organs caused by congenital or acquired factors, and the lipid metabolism includes digestion and absorption of lipids in the small intestine, entry into the blood circulation from the lymphatic system (through lipoprotein transport), conversion by the liver, storage in adipose tissue, utilization by tissues when necessary, regulation by the biological enzyme HICBI, and perfection of lipid metabolism disorder.
Lipid metabolism disorder can cause obesity, fatty liver, diabetes and other metabolic diseases, and in recent years, a plurality of studies have proved that the pathogenesis of various lipid metabolism disorder diseases such as obesity, fatty liver, diabetes and atherosclerosis is related to inflammation. The accumulation of fat in the body, particularly visceral fat, can cause the occurrence of chronic inflammation, and the secretion of a large amount of proinflammatory cytokines can further promote the occurrence and development of related diseases.
The traditional targeted delivery system is usually constructed and formed based on surface antigens or receptors of focus microenvironment or pathological cells, and has shown active targeted delivery capability in diseases with single focus characteristics, such as tumors, local inflammations, and the like.
However, for systemic metabolic diseases with multifocal diseases caused by lipid metabolism disorder, the traditional targeted delivery strategy is difficult to realize the targeted delivery of the multifocal diseases, and the treatment of the multifocal diseases cannot be realized, so that a targeted drug capable of treating the multifocal diseases needs to be designed.
Disclosure of Invention
One of the purposes of the invention is to provide an inflammation targeted bindarit nanoparticle for treating lipid metabolism diseases, which is used for realizing the technical effect of targeted treatment of lipid metabolism related diseases with multiple focuses.
The invention is realized by the technical scheme that the nano-drug comprises water-soluble β -1, 3-D-glucan and a bindarit positive charge nano-drug, and forms inflammation targeted bindarit nano-particles through electrostatic adsorption.
The action mechanism is as follows:
the positive charge nano-drug is formed by self-assembly of the bindarit and an amino-containing cationic polymer, the bindarit exists as a hydrophobic core in the system, the surface of the bindarit consists of the amino-containing cationic polymer, and then the water-soluble β -1, 3-D-glucan modified bindarit nano-particle is formed by utilizing the electrostatic adsorption effect between the water-soluble β -1, 3-D-glucan and the bindarit positive charge nano-drug.
Compared with the insoluble β -1, 3-D-glucan, the water-soluble β -1, 3-D-glucan provided by the invention is used for preparing the targeted bindarit nanoparticles, the material source is simple, the targeted bindarit nanoparticles can be directly purchased, and meanwhile, the targeted bindarit nanoparticles provided by the invention have smaller particle size and cannot generate deposition.
The water-soluble β -1, 3-D-glucan provided by the present invention is preferably laminarin, which is recognized by the dectin-1 receptor of mononuclear macrophages and phagocytosed, thus conferring targeting capabilities to the system.
The inflammation targeted bindarit nanoparticle provided by the invention can target inflammation parts of multiple focuses and target a therapeutic drug to corresponding focus parts, thereby achieving the effect of targeted therapy.
To better practice the invention, further the water soluble β -1, 3-D-glucan is selected from laminarin, laminarin sulfate, or laminarin derivatives.
Laminarin sulfate is preferred in the present invention mainly because laminarin sulfate has a higher negative charge and a higher adsorption efficiency.
In order to better realize the invention, further, the bindarit positive charge nano-drug comprises bindarit and an amino-containing polymer, and is prepared by dialysis self-assembly.
In order to better realize the invention, the mass fraction of the bindarit is 1-80 wt%, the mass fraction of the amino-containing polymer is 1-80 wt%, and the mass fraction of the water-soluble β -1, 3-D-glucan is 0.1-30 wt%.
The mass fraction of the bindarit is preferably 80%, when the mass fraction of the bindarit is 80%, the drug loading rate is higher, in the preparation process, the smaller the mass fraction of the amino-containing polymer is, the better the amino-containing polymer is, and when the mass fraction of the water-soluble β -1, 3-D-glucan is 0.1-30 wt%, the nanoparticle surface can be effectively covered, and the nanoparticle with the monocyte targeting characteristic is effectively formed.
In order to better implement the present invention, further, the amino group-containing polymer is selected from one or more of polyethyleneimine, polylysine, polypropyleneimine, and polyvinylamide.
In addition to the above-listed polymers, other amino group-containing cationic polymers such as polylysine and the like are also included.
The preparation mainly comprises the components of Birdril and water-soluble β -1, 3-D-glucan, is prepared by self-assembling water-soluble β -1, 3-D-glucan and Birdril positive charge nano-drugs, can be specifically distributed in peripheral blood mononuclear cells after being taken orally and absorbed into blood by gastrointestinal tracts, can transport the modified targeted nanoparticles into the mononuclear cells by the water-soluble β -1, 3-D-glucan, depends on the monocyte recruitment effect in chronic inflammation in each focus caused by lipid metabolism disorder, carries the nanoparticles to each inflammation focus in a targeted manner, and inhibits the expression of MCP-1 in the focus position by the anti-inflammatory activity of the Birdril after reaching each focus position, thereby reducing the aggregation of the inflammatory cells in the focus position and realizing the targeted treatment of lipid metabolism related diseases including obesity, fatty liver, insulin, atherosclerosis and the like.
According to long-term experiments, the prepared inflammation-targeted Bidali nanoparticles are more concentrated in distribution of fat tissues, fatty liver tissues and atherosclerotic plaque parts of obese mice, and the treatment effect is better.
The second purpose of the invention is to provide a method for preparing inflammation-targeted bindarit nanoparticles for treating lipid metabolism diseases, the method can successfully prepare the inflammation-targeted bindarit nanoparticles, and the preparation process is simple and easy to operate.
The second purpose of the invention is realized by the following technical scheme: the method comprises the following steps:
preparing the Bidary positive charge nano-drug:
fully dissolving the bindarit and the amino-containing polymer in an organic solvent, placing the mixture into a dialysis bag with the molecular weight cutoff of 1000-5000 da after the dissolution, and dialyzing for 8-48 hours to obtain the bindarit positive charge nano-drug;
preparation of water-soluble β -1, 3-D-glucan solution:
dissolving laminarin or laminarin sulfate in pure water to obtain β -1, 3-D-dextran solution;
preparing inflammation targeted bindarit nanoparticles:
and (3) dropwise adding the prepared water-soluble β -1, 3-D-glucan solution into the bindarit positive charge nano-drug, continuously stirring for 1-48 hours, fully mixing and adsorbing, centrifuging, taking the precipitate, and freeze-drying to obtain the targeted bindarit nano-particle.
In order to better implement the invention, the organic solution can be selected from one or more of dimethyl sulfoxide, dimethylformamide, ethanol, tetrahydrofuran, methanol, ethanol, acetone, acetonitrile, 1, 4-dioxane and dimethylacetamide.
The preparation method is characterized in that the water-soluble β -1, 3-D-glucan and the Birdril positive charge nano-drug are subjected to electrostatic adsorption, the preparation process is simple, the operation is easy, and the diameter of the inflammation targeted Birdril nano-particle is 10-100 nm, so that the dispersion and the stability are better.
The invention also aims to provide application of the inflammation targeted bindarit nanoparticle in preparing a medicament for improving lipid metabolism diseases.
To better practice the invention, the lipid metabolism disorder includes obesity, fatty liver, diabetes caused by insulin resistance, atherosclerosis or other lipid storage disorders.
The fourth purpose of the invention is to provide a targeted drug delivery system for treating lipid metabolism diseases, which comprises an amino-containing polymer forming nanoparticles, an anti-inflammatory drug molecule and a modification material, wherein the modification material is selected from water-soluble β -1, 3-D-glucan.
In order to better realize the invention, the drug molecules comprise bindarit, a non-steroidal anti-inflammatory drug indometacin, a dipeptidyl peptidase 4 inhibitor cetosterin, an anti-inflammatory drug taking TNF- α/IL-1/IL-6 as a target and an anti-inflammatory drug.
The invention has the beneficial effects that:
the inflammation targeted bindarit nanoparticle for treating lipid metabolism diseases is prepared by electrostatically adsorbing water-soluble β -1, 3-D-glucan and a bindarit positive charge nano-drug, can be specifically distributed in peripheral blood mononuclear cells after being absorbed into blood through gastrointestinal tracts by oral administration, can target and transport the modified nanoparticle to the mononuclear cells by the water-soluble β -1, 3-D-glucan, depends on the monocyte recruitment effect in chronic inflammation existing in each focus caused by lipid metabolism disorder, targets and transports the nanoparticle to each inflammation focus, and inhibits the expression of MCP-1 at the focus position by the anti-inflammatory activity of the bindarit after reaching each focus position, thereby reducing the aggregation of the inflammation cells at the focus position and realizing the targeted treatment of lipid metabolism related diseases including obesity, fatty liver, insulin resistance, atherosclerosis and the like.
According to the invention, water-soluble β -1, 3-D-glucan is electrostatically adsorbed on the bindarit positive charge nanoparticles, and the self-assembly mode is simple to operate, easy to prepare and controllable in reaction conditions.
Drawings
In order to more clearly illustrate the technical solution of the present invention, the drawings that are required to be used in the present invention will be briefly described below to understand that the following drawings only show some embodiments of the present invention and therefore should not be considered as limiting the scope, and it is obvious to those skilled in the art that other related drawings can be obtained from the drawings without inventive efforts.
FIG. 1 is a TEM transmission view of an inflammation-targeted bindarit nanoparticle for treating a lipid metabolism disease provided by the invention;
FIG. 2 is a first in vitro imaging chart of the finished product prepared by the experimental example and the comparative example provided by the invention;
FIG. 3 is a graph II of an in-vitro imaging of a finished product prepared by an experimental example and a comparative example provided by the invention;
FIG. 4 is a graph of body weight gain in obese mice as provided by the present invention;
FIG. 5 is a HE slice of adipose tissue from an obese mouse as provided by the present invention;
FIG. 6 is a graph showing blood glucose levels in serum of obese mice, provided by the invention;
FIG. 7 is a graph showing the serum insulin levels in obese mice according to the present invention;
FIG. 8 is a graph showing the levels of free fatty acids in serum of obese mice, provided by the invention;
FIG. 9 is a schematic mass diagram of the liver of an obese mouse provided herein;
FIG. 10 is a section of fat red stained liver of an obese mouse as provided by the present invention;
FIG. 11 is a graph showing the atherosclerotic plaque targeting effect of obese mice provided by the present invention;
FIG. 12 is a graph showing the therapeutic effect of atherosclerotic plaques in obese mice provided by the present invention.
Detailed Description
The technical solution of the present invention will be described below with reference to the accompanying drawings.
Examples
Inflammation-targeted bindarit nanoparticle for treating lipid metabolism diseases
Preparing the Bidary positive charge nano-drug:
weighing 10mg of bindarit and 10mg of polyethyleneimine, dissolving in 1ml of dimethyl sulfoxide, fully dissolving, placing in a dialysis bag with a molecular cut-off of 1000da, and dialyzing for 12 hours to obtain the bindarit positive charge nano-drug.
Preparation of water-soluble β -1, 3-D-glucan solution:
weighing laminarin 5g, and dissolving in 100ul pure water to obtain laminarin water solution.
Preparing inflammation targeted bindarit nanoparticles:
dropwise adding the prepared laminarin aqueous solution into the Birdril positive charge nano-drug, stirring at a high speed for 4 hours, centrifuging at 12500 r, taking the precipitate, and drying the precipitate to obtain the inflammation targeted Birdril nano-particle, wherein the drug-loading rate of the inflammation targeted Birdril nano-particle is 37.8%.
Comparative example
Bindaril nanoparticles
Weighing 10mg of bindarit and 10mg of polyethyleneimine, dissolving in 1ml of dimethyl sulfoxide, fully dissolving, placing in a dialysis bag with the molecular weight cutoff of 1000da, dialyzing for 12 hours to obtain a bindarit positive charge nanoparticle solution, placing in 12500 r for centrifugation, taking a precipitate, and drying to obtain the bindarit nanoparticles.
Experimental data
The structure of the inflammation-targeting bindarit nanoparticle prepared in the above example is shown in fig. 1 by a transmission electron microscope.
The subject is selected from high fat diet-mediated obese mice.
The experimental method comprises the following steps: the inflammation-targeted bindarit nanoparticles prepared in the embodiment and the bindarit nanoparticles prepared in the comparative example are subjected to fluorescence labeling by adopting fluorescein anthocyanin 5.5, and the distribution condition of the drug in the fat tissue of an obese mouse and the pharmacological characteristics of the drug are observed by the fluorescence labeling.
and a, observing the distribution conditions of the inflammation-targeted bindarit nanoparticles obtained in the embodiment and the bindarit nanoparticles obtained in the comparative example in fat tissues of fat mice, as shown in fig. 2, wherein the distribution area of the inflammation-targeted bindarit nanoparticles prepared in the embodiment in fat tissues of the fat mice is larger than that of the bindarit nanoparticles prepared in the comparative example, so that the inflammation-targeted bindarit nanoparticles prepared in the embodiment have good targeting property and are more concentrated in the distribution of target parts.
b, observing the targeting conditions of the inflammation-targeted bindari nanoparticles obtained in the embodiment and the comparative example bindari nanoparticles in the adipose tissues of the obese mice, as shown in fig. 3, it can be obtained from the figure that the inflammation-targeted bindari nanoparticles prepared in the embodiment have better targeting effect, are more distributed in the adipose tissues and can act on MCP-1 in each focus more, so that the targeting of each focus is realized, the targeting conditions of the bindari nanoparticles prepared in the comparative example are obviously less, the parts acting on the focuses are relatively less, and the targeting to each focus is obviously lower.
c, observing the drug effect conditions of the inflammation-targeted bindarit nanoparticles obtained in the embodiment and the bindarit nanoparticles obtained in the comparative example on adipose tissues of the obese mouse, orally administering the inflammation-targeted bindarit nanoparticles once every 3 days at a dose of 20mg/kg, and observing the control effects of the inflammation-targeted bindarit nanoparticles on obesity, insulin resistance and fatty liver, wherein fig. 4 is a graph of the weight gain ratio of the obese mouse; as shown in fig. 5, which is a photograph of HE section of adipose tissue of an obese mouse, it can be seen from fig. 4 and 5 that the inflammation-targeted bindarit nanoparticle can significantly inhibit the excessive weight gain of the obese mouse and can reduce the size of adipocytes.
In order to further verify the drug property of the inflammation-targeted bindarit nanoparticles and further observe the blood sugar, insulin and free fatty acid levels in the serum of an obese mouse, the results are shown in fig. 6-8, wherein x and # respectively represent that p of vs NS or PBS is less than 0.05, and it can be obtained from the figure that the inflammation-targeted bindarit nanoparticles can maintain the blood sugar at a normal level without increasing the insulin level in the serum, and the fatty acid level is not increased.
Further observation of the effect of the administration of the inflammation-targeting bindarit nanoparticles on the liver of the obese mice showed that the results are shown in fig. 9 and 10, where x and # represent the p of vs NS or PBS <0.05, respectively, and it can be seen from the figure that the inflammation-targeting bindarit nanoparticles can significantly inhibit the increase of the liver weight of the obese mice and reduce the fat level in the liver.
The effect of the inflammation-targeting bindarit nanoparticles on atherosclerosis caused by abnormal lipid metabolism was further observed, and the results are shown in fig. 11 and 12. As can be seen from the figure, the inflammation-targeting nanoparticles were more distributed at the site of atherosclerotic plaques in mice and the plaque formation could be significantly reduced.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (10)

1. An inflammation-targeted bindarit nanoparticle for treating lipid metabolism diseases is characterized by comprising water-soluble β -1, 3-D-glucan and a bindarit positive charge nano-drug, and forming the inflammation-targeted bindarit nanoparticle through electrostatic adsorption.
2. The inflammation-targeting bindarit nanoparticle according to claim 1, wherein said water-soluble β -1, 3-D-glucan is selected from the group consisting of laminarin, laminarin sulfate, and laminarin derivatives.
3. The inflammation-targeting bindarit nanoparticle according to claim 2, wherein the bindarit positively-charged nanomedicine comprises a bindarit and an amino-containing polymer, and is prepared by dialysis self-assembly.
4. The inflammation-targeting bindaride nanoparticle according to claim 3, wherein the mass fraction of the bindaride is 1-80 wt%, the mass fraction of the amino-containing polymer is 1-80 wt%, and the mass fraction of the water-soluble β -1, 3-D-glucan is 0.1-30 wt%.
5. The inflammation-targeting bindarit nanoparticle according to claim 3, wherein said amino group-containing polymer is one or more selected from the group consisting of polyethyleneimine, polylysine, polypropyleneimine, and polyvinylamide.
6. A method for preparing inflammation-targeting bindarit nanoparticles according to claim 3, wherein: the method comprises the following steps:
preparing the Bidary positive charge nano-drug:
fully dissolving the bindarit and the amino-containing polymer in an organic solvent, placing the mixture into a dialysis bag with the molecular weight cutoff of 1000-5000 da after the dissolution, and dialyzing for 8-48 hours to obtain the bindarit positive charge nano-drug;
preparation of water-soluble β -1, 3-D-glucan solution:
dissolving laminarin or laminarin sulfate in pure water to obtain β -1, 3-D-dextran solution;
preparing inflammation targeted bindarit nanoparticles:
dropwise adding the prepared water-soluble β -1, 3-D-glucan solution into the bindarit positive charge nano-drug, continuously stirring for 1-48 hours, fully mixing and adsorbing, centrifuging, taking the precipitate, and freeze-drying to obtain the inflammation-targeted bindarit nano-particle.
7. An application of inflammation targeted bindarit nanoparticles for treating lipid metabolism diseases in preparing the medicines for improving the lipid metabolism diseases.
8. The application of the inflammation-targeting bindarit nanoparticles according to claim 7, wherein the lipid metabolism disease comprises obesity, fatty liver, diabetes caused by insulin resistance, atherosclerosis or lipid storage disease.
9. A targeted drug delivery system for treating lipid metabolism diseases is characterized by comprising an amino-containing polymer forming nanoparticles, an anti-inflammatory drug molecule and a modification material, wherein the modification material is selected from water-soluble β -1, 3-D-glucan.
10. The targeted drug delivery system of claim 9, wherein the drug molecule comprises bindarit, indomethacin, cilastatin, which is a dipeptidyl peptidase 4 inhibitor, anti-inflammatory agents that target TNF- α/IL-1/IL-6, anti-inflammatory agents.
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