A nano drug carrier for targeted regulation of macrophage polarization and its preparation method and application

Abstract

This application relates to the technical field of nanomedicine carriers, specifically disclosing a nanomedicine carrier for targeting and regulating macrophage polarization, its preparation method, and its application. The nanomedicine carrier comprises a nanocarrier shell and a hydrophobic core, with the nanomedicine encapsulated within the hydrophobic core. The nanocarrier shell includes a biodegradable shielding layer and a macrophage-specific targeting recognition layer shielded and protected by the biodegradable shielding layer. The nanomedicine carrier comprises the following raw materials: a biodegradable shielding amphiphilic polymer and a target-recognizing amphiphilic polymer, with a mass ratio of (0.5-3):1. The difference between the number-average molecular weight of the biodegradable shielding amphiphilic polymer and the number-average molecular weight of the target-recognizing amphiphilic polymer is at least 300. The nanomedicine carrier of this application can be used for hydrophobic drug delivery, possessing the advantages of strong targeting and minimal impact on other tissues or cells.

Description

Technical Field

[0001] The present application relates to the technical field of nano drug carriers, and more specifically, to a nano drug carrier for targeted regulation of macrophage polarization, and a preparation method and application thereof. Background Art

[0002] As an important component of the body's nonspecific and specific immunity, macrophages have multiple functions and can participate in a variety of pathological and physiological processes, including tissue development and homeostasis, clearing cell debris, eliminating pathogens, regulating inflammation and immune responses, tumors, and fibrosis. Macrophages originate from bone marrow hematopoietic stem cells. After being released into the blood circulation in the form of monocytes, they differentiate under the influence of specific factors and reach various tissues and organs; for example, Kupffer cells in the liver, microglia in the brain, and mesangial cells in the kidneys are all macrophages. Macrophages are highly plastic and can be transformed into different functional phenotypes in response to various tissue microenvironmental factors or under different pathological and physiological conditions, that is, the polarization phenomenon of macrophages: including M1 classically activated macrophages and M2 alternatively activated macrophages. M1 macrophages are closely related to the initiation and maintenance of inflammatory responses, cytotoxicity, etc., while M2 macrophages are mainly involved in the processes of inflammation resolution, tissue regeneration, wound healing, and angiogenesis. Macrophage M1 / M2 polarization is a strictly controlled process, and its disorder is closely related to the progression of many diseases. Therefore, macrophage polarization plays an important role in the occurrence and development of many diseases such as infection, tumor, metabolism and immunity, and is one of the hot spots in inflammation and immunity-related research.

[0003] Studies have found that the transition of lung tissue from acute inflammatory injury to chronic pulmonary fibrosis is accompanied by the transformation of macrophage M1 phenotype to M2 phenotype, and finally M2 macrophages are dominant. This result shows that M2 macrophages can promote the development of pulmonary fibrosis, that is, promoting the apoptosis of M2 macrophages or inhibiting the polarization of M2 macrophages is beneficial to the treatment of pulmonary fibrosis. Microglia / macrophage M1 / macrophage M2 polarization is also involved in the pathological process of ischemic stroke. Regulating the polarization of microglia can enhance neural plasticity, thereby promoting functional recovery after ischemic stroke and protecting brain nerves. Tumor-associated macrophages (TAMs) are immune cells in the tumor microenvironment. Only a small number of TAMs are M1, while M2 accounts for 70%; tumor-associated M2 macrophages have low cytotoxicity and immunosuppressive effects, which are conducive to tumor growth and metastasis. Therefore, inhibiting the polarization of macrophages to M2 phenotype or promoting the transformation of macrophages M2 to M1 can inhibit tumor growth and metastasis. In addition, the imbalance of M1 / M2 ratio is a pathological hallmark of many inflammatory diseases, such as obesity, atherosclerosis, autoimmune diseases, asthma and allergic diseases. Even fully polarized macrophages can be reprogrammed when transferred to a new microenvironment. Therefore, targeted regulation of macrophage polarization is a potential target for the treatment of the above-mentioned diseases.

[0004] In recent years, traditional Chinese medicine and its active ingredients have been regarded as an important source of macrophage polarization regulating compounds; traditional Chinese medicine and its active ingredients have the characteristics of less adverse reactions and rich pharmacological activities, such as flavonoids and terpenes, etc., which have attracted great attention and gradually become a research hotspot in recent years. However, these drugs generally have problems such as poor water solubility, poor targeting, short average half-life and low bioavailability, which affect the absorption and utilization of drugs.

[0005] Taking this type of drug as a lead compound, the bioavailability, targeting, controlled release and safety of the drug can be improved by developing its derivatives, analogs or fully synthetic products and constructing nano drug delivery systems, which will provide a clinical scientific basis for the application of a series of traditional Chinese medicines and their extracts. Among them, the advantages of lipid- and polymer-based nanocarriers for drug delivery include adjustable physicochemical properties, diverse surface modifications, and the ability to improve the accumulation and homing of drugs in specific tissues, making this drug delivery technology a potential carrier for effectively delivering drugs to target organs in a safe and reproducible manner.

[0006] However, current lipid- and polymer-based nanocarriers often have the problem of insufficient targeting when delivering drugs. For example, the nanocarrier releases the delivered drug prematurely, making it difficult for the drug to target the target, ultimately leading to poor treatment effects. Summary of the invention

[0007] In order to improve the targeting of drug delivery, the present application provides a nano drug carrier for targeted regulation of macrophage polarization and a preparation method and application thereof.

[0008] In the first aspect, the present application provides a nano drug carrier for targeted regulation of macrophage polarization, using the following technical solution:

[0009] A nano drug carrier for targeted regulation of macrophage polarization, the nano drug carrier comprising a nano carrier shell and a hydrophobic core, wherein the drug is encapsulated in the hydrophobic core; wherein the nano carrier shell comprises a decomposable shielding layer and a macrophage-specific targeting recognition layer shielded and protected by the decomposable shielding layer;

[0010] The nano drug carrier comprises the following raw materials: a decomposable shielding amphiphilic polymer and a targetable identifiable amphiphilic polymer, the mass ratio of the two being (0.5-3):1; the difference between the number average molecular weight of the decomposable shielding amphiphilic polymer and the number average molecular weight of the targetable identifiable amphiphilic polymer is at least 300;

[0011] The components of the decomposable shielding amphiphilic polymer include a first amphiphilic polymer and a chemical bond modified at the hydrophilic end of the first amphiphilic polymer, wherein the chemical bond can be decomposed under the environmental factors of the target tissue; the hydrophilic end of the first amphiphilic polymer and the chemical bond form a decomposable shielding layer;

[0012] The targetable amphiphilic polymer component includes a second amphiphilic polymer and a macrophage-specific targeting recognition molecule that blocks the hydrophilic end of the second amphiphilic polymer; the hydrophilic end of the second amphiphilic polymer and the macrophage-specific targeting recognition molecule form a macrophage-specific targeting recognition layer;

[0013] The hydrophobic end of the first amphiphilic polymer and the hydrophobic end of the second amphiphilic polymer form a hydrophobic core.

[0014] The imbalance of macrophage polarization ratio destroys the homeostasis of the immune microenvironment, and the imbalance of immune microenvironment homeostasis is usually accompanied by an increase in the concentration of reactive oxygen species (ROS). For example, high levels of ROS and proinflammatory cytokines are typical characteristics of M1 macrophages, and excessive release of ROS can further lead to tissue damage and decreased wound healing ability; at this time, M2 macrophages are recruited to prevent tissue damage. Studies have confirmed that there is a significant increase in ROS concentration in disease areas such as pulmonary fibrosis, ischemic stroke, tumors, and atherosclerosis.

[0015] According to this pathophysiological characteristic, by adjusting the chemical structure and surface properties of the nanocarrier, the design of ROS-responsive nanodrug carriers can achieve targeted selection of specific disease areas, achieve regional targeting, and reduce drug toxicity. More perfectly, a set of precise targeting strategies should be able to effectively bind to specific receptors of target cells, but not bind (or weakly bind) to other cells. Therefore, this application proposes to design a cascade-targeted nanodrug carrier that first achieves regional targeting and then cell targeting, thereby maximizing the ability of poorly soluble drugs to regulate macrophage polarization.

[0016] In the above scheme, when preparing the nano drug carrier, the nano carrier shell is composed of a degradable shielding layer and a macrophage-specific targeting recognition layer, and the degradable shielding layer shields and protects the macrophage-specific targeting recognition layer; it contains a hydrophobic core inside, and the hydrophobic drug is coated inside the hydrophobic core.

[0017] When the nano drug carrier is administered to a patient, the nano drug carrier carries the drug and is transported between body fluids and / or blood; when the outermost degradable shielding layer is transported to the target tissue, compared with normal tissue, the target tissue often undergoes changes in the physiological environment, such as increased oxygen concentration, pH changes, and increased concentrations of reducing substances, or special stimuli from the outside, such as ultrasound, magnetic fields, electric fields, light, etc. At this time, the hydrophilic end of the degradable shielding layer contains chemical bonds that are sensitive to the environment. Under the special environment of the target tissue, the chemical bonds break, exposing the macrophage-specific targeting recognition layer shielded and protected by the degradable shielding layer; the nano drug carrier continues to carry the drug to the macrophages, and the macrophage-specific targeting recognition molecules at the hydrophilic end of the macrophage-specific targeting recognition layer specifically recognize the macrophages. Specifically, the macrophage-specific targeting recognition molecules can target and bind to any one or both of M1 macrophages and M2 macrophages, and then release the drug encapsulated therein, so that it targets and specifically acts on the macrophages. Therefore, the nano drug carrier is a dual-targeted drug carrier, which targets a specific environment and macrophages at the same time, and has a strong targeting effect; in addition, the drug encapsulated in the nano drug carrier is more fully protected in the hydrophobic core before reaching the target, avoiding premature release of the drug and reducing the efficacy; it also avoids the premature release of the drug and acts on non-target cells, thereby improving the safety of medication.

[0018] In the above scheme, the degradable shielding amphiphilic polymer refers to a molecule that can break chemical bonds under the environmental factors of the target tissue; the degradable shielding amphiphilic polymer has a hydrophilic end, and the hydrophilic end is located on the outside of the nano drug carrier; at the same time, the degradable shielding amphiphilic polymer has a hydrophobic end, and the hydrophobic end is located on the inside of the nano drug carrier. The targetable amphiphilic polymer refers to a molecule that can specifically target and bind to macrophages; the targetable amphiphilic polymer has a hydrophilic end, and the hydrophilic end is located on the outside of the nano drug carrier; at the same time, the targetable amphiphilic polymer has a hydrophobic end, and the hydrophobic end is located on the inside of the nano drug carrier.

[0019] Optionally, the chemical bond on the decomposable shielding layer is selected from any one or more of aconitic anhydride bond, hydrazone bond, 2,3-dimethylmaleic anhydride, benzyl imine bond, thiopropionate bond, imine bond, orthoester bond, ketal, citraconic anhydride, acetal, cycloacetal, dimethyl maleate bond, hydrazide bond, oxime bond, disulfide bond, monoselenide bond, diselenide bond, telluride, thioether bond, thioester bond, aromatic borate ester bond, thioselenotelluride bond, peroxyoxalate bond, ferrocene, ketalthiols, nitroaromatic functional groups, azo derivatives, stilbene, triphenylmethane, unsaturated lipids, iron oxide, ferroferric oxide, other ferrites and amino acid sequences;

[0020] The environmental factors are endogenous environmental factors or exogenous environmental factors;

[0021] The endogenous environmental factors are selected from any one or more combinations of the pH value, reducing substance concentration, oxidizing substance concentration, enzyme concentration, oxygen concentration, ATP concentration and extracellular matrix of the target tissue;

[0022] The exogenous environmental factors are selected from any one or more combinations of light, magnetism, ultrasound, temperature, electricity, force and polarity.

[0023] In the above scheme, the chemical bonds on the degradable shielding layer correspond to the environmental factors of the target tissue, and the selected chemical bonds need to be responsive to the environmental factors. Under the environmental factors, the chemical bonds can be broken to expose the macrophage-specific targeting recognition layer shielded and protected by the degradable shielding layer, or at least expose the macrophage-specific targeting recognition molecules shielded and protected by the degradable shielding layer for specific targeted binding with macrophages.

[0024] The unsaturated lipid may be, for example, egg yolk phosphatidylcholine, for example, dioleoylphosphatidylcholine, for example, dilinoleoylphosphatidylcholine. The amino acid sequence may be, for example, a glycine-phenylalanine-leucine-glycine sequence.

[0025] The reducing substance is selected from any one or both of glutathione (GSH) and glutathione disulfide (GSSG).

[0026] The oxidative substance may be, for example, reactive oxygen species (ROS); further, it may be a combination of any one or more selected from hydrogen peroxide, superoxide radicals, singlet oxygen, hydroxyl radicals, and various forms of organic and inorganic peroxides.

[0027] The enzyme is selected from any one or more combinations of matrix metalloproteinases, cathepsin B, hyaluronidase, secretory phospholipase A2, alkaline phosphatase, prostate antigen, oxidoreductase, α-amylase, γ-glutamyl transferase and carboxylesterase.

[0028] The light is selected from any one or more combinations of ultraviolet light, visible light and near infrared light.

[0029] Optionally, the macrophage-specific targeting recognition molecule is selected from any one or more of a targeting ligand, an antibody, a targeting peptide and a small molecule compound;

[0030] Preferably, the macrophage-specific targeting recognition molecule is selected from any one or more of Toll-like receptors, signal regulatory protein-α, Fc receptors, programmed cell death receptor 1, folate receptors, mitogen-like receptors, CD64, CD68, CD14, CD163, CD206 monoclonal antibodies or antibody fragments, MG1 peptides, macrophage binding peptides, M2 macrophage targeting peptides, mannose, galactose, hyaluronic acid and konjac glucomannan.

[0031] In the above scheme, Toll-like receptor is abbreviated as TLR, signal regulatory protein-α is abbreviated as SIRP-α, programmed cell death receptor 1 is abbreviated as PD-1, folate receptor is abbreviated as FA, mitogen-like receptor is abbreviated as Dectin-1, macrophage binding peptide is abbreviated as CRV, M2 macrophage targeting peptide is abbreviated as M2pep, hyaluronic acid is abbreviated as HA, and konjac glucomannan is abbreviated as KGM.

[0032] Optionally, the first amphiphilic polymer includes a first hydrophilic macromolecular segment and a first hydrophobic macromolecular segment; the second amphiphilic polymer includes a second hydrophilic macromolecular segment and a second hydrophobic macromolecular segment;

[0033] The first hydrophilic macromolecular segment is selected from any one or more combinations of polyhydroxyethyl methacrylate, polyethylene glycol methacrylate, polyethylene glycol, polyacrylate, polyvinyl alcohol, polyhydroxypropyl methacrylamide, polyethylene imine, polyvinyl pyrrolidone, polylactic acid, and poly-N-isopropyl acrylamide; the second hydrophilic macromolecular segment is selected from any one or more combinations of polyhydroxyethyl methacrylate, polyethylene glycol methacrylate, polyethylene glycol, polyacrylate, polyvinyl alcohol, polyhydroxypropyl methacrylamide, polyethylene imine, polyvinyl pyrrolidone, polylactic acid, and poly-N-isopropyl acrylamide;

[0034] The first hydrophobic macromolecular segment is selected from any one or more combinations of polystyrene, polymethyl methacrylate, polycaprolactone, polyglycolide, polylactide, polyacrylate, polylactic acid-polyglycolic acid copolymer, spermine, short-chain phospholipids, cellulose derivatives, chitosan derivatives, starch derivatives, casein and liposomes, etc.; the second hydrophobic macromolecular segment is selected from any one or more combinations of polystyrene, polymethyl methacrylate, polycaprolactone, polyglycolide, polylactide, polyacrylate, polylactic acid-polyglycolic acid copolymer, spermine, short-chain phospholipids, cellulose derivatives, chitosan derivatives, starch derivatives, casein and liposomes, etc.

[0035] Optionally, the first amphiphilic polymer is selected from any one or more combinations of distearoylphosphatidyl acetamide-polyethylene glycol, polyethylene glycol-polyacrylate, polyethylene glycol-polylactic acid-polycaprolactone, polyethylene imine-polyethylene glycol, polycaprolactone-polyacrylate, polyethylene glycol-polypropylene ether-polyethylene imine, polyethylene glycol-polycaprolactone-polylactic acid, polyethylene imine-polylactic acid-polyethylene glycol, polyethylene imine-polyethylene glycol-polycaprolactone, polyethylene glycol-polylactic acid-polyacrylate, etc.

[0036] Optionally, the decomposable shielding amphiphilic polymer is selected from any one or two of distearoylphosphatidyl acetamide-polyethylene glycol-mercapto-1,4-butanediol diacrylate and distearoylphosphatidyl acetamide-thioketal-polyethylene glycol.

[0037] Further optionally, when the decomposable shielding amphiphilic polymer is distearoylphosphatidylacetamide-polyethylene glycol-mercapto-1,4-butanediol diacrylate, the distearoylphosphatidylacetamide-polyethylene glycol-mercapto-1,4-butanediol diacrylate is prepared by a method comprising the following steps:

[0038] Distearoylphosphatidylacetamide-polyethylene glycol-thiol, 1,4-butanediol diacrylate and dithiothreitol are dissolved in a first organic solvent, wherein the molar ratio of distearoylphosphatidylacetamide-polyethylene glycol-thiol to 1,4-butanediol diacrylate is greater than or equal to 1:2, and the molar ratio of distearoylphosphatidylacetamide-polyethylene glycol-thiol to dithiothreitol is greater than or equal to 1:1; the reaction is carried out at room temperature in the presence of a catalyst, and then the reaction product is dialyzed and dried to obtain a product.

[0039] Optionally, the targetable amphiphilic polymer is selected from any one or two of distearoylphosphatidylacetamide-polyethylene glycol-mannose and distearoylphosphatidylacetamide-polyethylene glycol-folic acid.

[0040] Optionally, the first organic solvent is selected from any one or more combinations of N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methanol, ethanol, acetonitrile and acetone.

[0041] In a second aspect, the present application provides a method for preparing the above-mentioned nano drug carrier for targeted regulation of macrophage polarization, using the following technical solution:

[0042] A method for preparing the above-mentioned nano drug carrier for targeted regulation of macrophage polarization comprises the following steps:

[0043] The decomposable shielding amphiphilic polymer, the targetable amphiphilic polymer and the drug are dissolved in a second organic solvent, the obtained solution is mixed with water, PBS or an acidic solution, and the mixture is dialyzed after continuous stirring at room temperature, and the supernatant is collected after centrifugation, and the mixture is centrifuged at a high speed of 10000-15000 rpm for 10-20 min to obtain the precipitate which is the nano drug carrier;

[0044] Preferably, when the decomposable shielding amphiphilic polymer, the targetable amphiphilic polymer and the drug are dissolved in the second organic solvent, the concentration of the decomposable shielding amphiphilic polymer is about 0.5-15 mg / mL, and the concentration of the targetable amphiphilic polymer is about 0.5-15 mg / mL.

[0045] In the above scheme, when the obtained solution is mixed with water, PBS or acid solution, the obtained solution can be added to water, PBS or acid solution in a dropwise manner to achieve the purpose of mixing; the mixing process can be assisted by ultrasound. Water can be any one or more of deionized water and ultrapure water. The acid solution can be a hydrochloric acid solution containing 0.01-0.015wt% of an amphiphilic polymer. After continuous stirring at room temperature, dialyzation can be performed, and when centrifugation is performed, it can be low-speed centrifugation, and the recommended speed can be 400-600rpm.

[0046] By adopting the above technical scheme, the decomposable shielding amphiphilic polymer and the targetable amphiphilic polymer are first dissolved in a second organic solvent, and then under certain conditions, the decomposable shielding amphiphilic polymer, the targetable amphiphilic polymer and the drug in the solution are self-assembled under the hydrophobic force, and the hydrophilic ends of the decomposable shielding amphiphilic polymer and the targetable amphiphilic polymer are located on the outside, and the hydrophobic ends are located on the inside, and the drug is coated inside due to its hydrophobicity.

[0047] Optionally, when the drug, the degradable shielding amphiphilic polymer, and the targetable amphiphilic polymer are dissolved together in the second organic solvent, the drug concentration is 0.1-1 mg / mL.

[0048] Optionally, the second organic solvent is selected from any one or more combinations of N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methanol, ethanol, acetonitrile and acetone.

[0049] Among them, the abbreviation of N,N-dimethylformamide is DMF, and the abbreviation of dimethyl sulfoxide is DMSO.

[0050] Optionally, the stirring time at room temperature is 7-15 min.

[0051] In a third aspect, the present application provides an application of the above-mentioned nano-drug carrier for targeted regulation of macrophage polarization, using the following technical solution:

[0052] An application of the above-mentioned nano drug carrier for targeted regulation of macrophage polarization, wherein the nano drug carrier is used to prepare a drug delivery product for treating macrophage polarization-related diseases, wherein the macrophage polarization-related diseases are selected from any one or more of autoimmune diseases, fibrotic diseases, central nervous system diseases, infectious diseases, asthma and allergic diseases, tumors, obesity, and cardiovascular diseases;

[0053] Preferably, the autoimmune disease is selected from any one or more of rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, multiple sclerosis and autoimmune hepatitis;

[0054] The fibrotic disease is selected from any one or more of pulmonary fibrosis, liver fibrosis, renal fibrosis, etc. caused by various reasons;

[0055] The central nervous system disease is selected from any one or more of ischemic stroke, chronic demyelinating disease, etc.;

[0056] The infectious disease is selected from any one or more of bacteria, viruses, parasites, fungi, etc.;

[0057] The allergic disease is selected from any one or more of allergic rhinitis, atopic eczema, etc.;

[0058] The cardiovascular disease is selected from any one or more of atherosclerosis, hypertension, arrhythmia and coronary heart disease.

[0059] Among them, when the nanodrug carrier is used for the treatment of inhibiting the polarization of M2 macrophages in pulmonary fibrosis, the nanodrug carrier is delivered by nebulization inhalation or intratracheal instillation. Due to the increased ROS concentration in the pulmonary fibrosis area, the ROS response group of the nanodrug carrier in this area is cleaved, exposing specific targeting molecules that can recognize M2 macrophages, so that it can accurately act on the M2 macrophages in the pulmonary fibrosis area and release hydrophobic drugs. This drug can effectively delay the progression of pulmonary fibrosis by inhibiting the polarization of M2 macrophages.

[0060] Optionally, the administration method of the nano drug carrier is selected from one or more of intravenous injection, intramuscular injection, oral administration, intratracheal injection, rectal administration, skin administration, atomization inhalation, stereotactic brain injection and intranasal administration.

[0061] Optionally, the drug is poorly soluble or insoluble in water, the drug can regulate macrophage polarization, and the drug is selected from any one or more of astragaloside IV, octyl gallate, paclitaxel, zoledronic acid, soy isoflavones, chlorogenic acid, gefitinib, imatinib, celastrol, puerarin, mebendazole, triptolide, diosgenin, chloroquine, baicalein, resveratrol, minocycline, butylphthalide, curcumin, dihydroartemisinin and quercetin.

[0062] In summary, this application has the following beneficial effects:

[0063] The nano drug carrier of the present application includes a nano carrier shell and a hydrophobic core. In particular, the nano carrier shell includes a decomposable shielding layer and a macrophage-specific targeting recognition layer shielded and protected by the decomposable shielding layer. Under the shielding and protection of the decomposable shielding layer, before the nano drug carrier reaches the target (M1 macrophage and / or M2 macrophage), the macrophage-specific targeting recognition layer will not non-specifically bind to other components, so as to ensure that the drug is only released at the target, thereby exerting its efficacy. During drug delivery, the nano drug carrier of the present application can achieve dual-targeted delivery, specifically: 1. The decomposable shielding layer first identifies the environmental factors of the target tissue, so that the chemical bonds sensitive to the target tissue environmental factors at the hydrophilic end of the decomposable shielding amphiphilic polymer on the decomposable shielding layer are broken, thereby exposing the macrophage-specific targeting recognition layer; 2. The macrophage-specific targeting recognition molecules located at the hydrophilic end of the targetable amphiphilic polymer on the exposed macrophage-specific targeting recognition layer specifically recognize macrophages (M1 type and / or M2 type), and release the drug after being engulfed by the cells. The nano drug carrier simultaneously achieves dual-targeted recognition of target tissue environmental factors and macrophages, so that the drug is delivered to the target more accurately, so as to significantly improve the efficacy. In addition, this dual-target delivery method also effectively reduces the damage and impact of the drug on other non-target tissues, cells, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Figure 1 It is the DSPE-peg-s-BD prepared in Preparation Example 1 and the raw material DSPE-PEG2000-SH. 1 H NMR images;

[0065] Figure 2 is the infrared spectra of DSPE-peg-s-BD prepared in Preparation Example 1 and the raw material DSPE-PEG2000-SH;

[0066] Figure 3 The nano drug carriers prepared in Examples 1-4 were subjected to transmission electron microscopy; Figure 3 a is the nano drug carrier prepared in Example 1 with a mass ratio of DSPE-peg-s-BD:DSPE-PEG2000-Mannose=1:1, Figure 3 b (negative staining) is the nano drug carrier prepared in Example 2 with a mass ratio of DSPE-peg-s-BD:DSPE-PEG2000-Mannose=2:1, Figure 3 c (negative staining) is the nano drug carrier prepared in Example 3 with a mass ratio of DSPE-peg-s-BD:DSPE-PEG2000-Mannose=3:1, Figure 3d (negative staining) is the nano drug carrier prepared in Example 4 with a mass ratio of DSPE-peg-s-BD:DSPE-PEG2000-Mannose=1:2;

[0067] Figure 4 (Negative staining) is a transmission electron micrograph of the material obtained after the nano drug carrier of Example 4 is loaded with dihydroartemisinin; wherein, Figure 4 a is a transmission electron microscope image at a scale of 100 nm. Figure 4 b is a transmission electron microscopy image at a scale of 50 nm;

[0068] Figure 5 is a particle size distribution diagram of different nano drug carriers; wherein 2:1 refers to the nano drug carrier of Example 2, 3:1 refers to the nano drug carrier of Example 3, 1:2 refers to the nano drug carrier of Example 4, and DHA@DP NPs refers to the nano drug carrier prepared in Application Example;

[0069] Figure 6 Fluorescence Merge images of M2 macrophages and different nano-drug carriers after incubation for different time periods under a laser confocal microscope. The cell nuclei are labeled with DAPI. Scale bar = 10 μm.

[0070] Figure 7 This is the quantitative analysis result of intracellular MAP10-FE fluorescence intensity after incubation of M2 macrophages with different nano-drug carriers for different time periods (n=3). The data are expressed as mean±SD. * means p<0.05, ** means p<0.01, *** means p<0.001, **** means p<0.0001, and ns means no statistical difference.

[0071] Figure 8 Fluorescence Merge images of M0 macrophages, M1 macrophages, M2 macrophages, and lung epithelial cells after incubation with MAP10-FE@DPM NPs for 1 h under a laser confocal microscope. The cell nuclei were labeled with DAPI. Scale bar = 10 μm.

[0072] Fig. 9 is the quantitative analysis result of intracellular MAP10-FE fluorescence intensity after incubation of M0 macrophages, M1 macrophages, M2 macrophages and lung epithelial cells with MAP10-FE@DPM NPs for 1 h (n=3), the data are expressed as mean±SD, * means p<0.05, ** means p<0.01, *** means p<0.001, **** means p<0.0001, ns means no statistical difference;

[0073] Fig.10Fluorescence Merge images of M2 macrophages and MAP10-FE@DPM NPs after incubation for different time periods and MAP10-FE@DPM-DPSB NPs treated with H2O2 under laser confocal microscopy, the cell nuclei were labeled with DAPI, scale bar = 10 μm;

[0074] Fig.11 This is the quantitative analysis result of the intracellular MAP10-FE fluorescence intensity of M2 macrophages and MAP10-FE@DPM NPs after incubation for different time periods and MAP10-FE@DPM-DPSB NPs treated with H2O2 (n=3). The data are expressed as mean ± SD. * means p<0.05, ** means p<0.01, *** means p<0.001, **** means p<0.0001, and ns means no statistical difference. DETAILED DESCRIPTION

[0075] The present application is further described in detail below in conjunction with the accompanying drawings and examples. It is particularly noted that if no specific conditions are specified in the following examples, the experiments are carried out under conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, the raw materials used in the following examples can all be sourced from common commercial sources.

[0076] DSPE-PEG2000-SH refers to distearoylphosphatidylacetamide-polyethylene glycol 2000-thiol, BDDA refers to 1,4-butanediol diacrylate, DTT refers to dithiothreitol, DMF refers to N,N-dimethylformamide, DSPE-PEG2000-Mannose refers to distearoylphosphatidylacetamide-polyethylene glycol 2000-mannose, DSPE-PEG2000 refers to distearoylphosphatidylacetamide-polyethylene glycol 2000, DSPE-PEG2000-FA refers to distearoylphosphatidylacetamide-polyethylene glycol 2000-folic acid, DSPE-PEG1000-FA refers to distearoylphosphatidylacetamide-polyethylene glycol 1000-folic acid, and DSPE-TK-PEG2000 refers to distearoylphosphatidylacetamide-thioketal-polyethylene glycol 2000.

[0077] Preparation example of decomposable shielding amphiphilic polymer

[0078] Preparation Example 1

[0079] 50 mg of distearoylphosphatidyl acetamide-polyethylene glycol 2000-thiol (DSPE-PEG2000-SH, purchased from Nanosoft Polymers, number average molecular weight of about 2890) was used as a macromonomer, dissolved in 3 mL of N,N-dimethylformamide (DMF) with 10 mg of 1,4-butanediol diacrylate (BDDA) and 5 mg of dithiothreitol (DTT), and a trace amount of hexylamine was added as a catalyst. Click reaction occurred at room temperature for 4 hours, and then the solution was transferred to a dialysis bag (MWCO 2000), dialyzed twice in a water / DMF mixture (v:v=50:50) and three times in water. After freeze-drying, the dialyzed product was collected to obtain a decomposable shielded amphiphilic polymer, referred to as DSPE-peg-s-BD, which is a long chain of ROS-responsive polymer. Among them, the molar ratio of DSPE-PEG2000-SH, BDDA and DTT is about 1:3:2.

[0080] The raw material DSPE-PEG2000-SH and the prepared product DSPE-peg-s-BD were tested by nuclear magnetic resonance and infrared spectroscopy, respectively. The specific results are shown in Figure 1 and Figure 2 . Figure 1 of 1 The results of H NMR spectrum show that the product DSPE-peg-s-BD has absorption peaks of the last three hydrogens after BDDA capping (—CH═CH2, δ=6.05, 5.77, 6.34). Figure 1 The NMR results showed that the molecular weight of the product DSPE-peg-s-BD increased by at least 400 compared with that of DSPE-PEG2000-SH.

[0081] Figure 2 The infrared spectrum shows that the thiol absorption peak (2494 cm -1 ) disappears in the product DSPE-peg-s-BD, and the thiol groups react to generate long chains of ROS-responsive polymers.

[0082] Preparation Example 2-5

[0083] The difference between the following preparation example and preparation example 1 is that the molar ratios of DSPE-PEG2000-SH, BDDA and DTT are different, as follows:

[0084] In Preparation Example 2, the molar ratio of DSPE-PEG2000-SH, BDDA and DTT is 1:2:2;

[0085] In Preparation Example 3, the molar ratio of DSPE-PEG2000-SH, BDDA and DTT is 1:3:2;

[0086] In Preparation Example 4, the molar ratio of DSPE-PEG2000-SH, BDDA and DTT is 1:3:3;

[0087] In Preparation Example 5, the molar ratio of DSPE-PEG2000-SH, BDDA and DTT is 1:2:1. Example

[0088] Example 1

[0089] The preparation method of the nano drug carrier for targeted regulation of macrophage polarization is as follows:

[0090] 1.5 mg DSPE-peg-s-BD and 1.5 mg DSPE-PEG2000-Mannose (distearoylphosphatidylacetamide-polyethylene glycol 2000-mannose, purchased from Yuci Pharmaceutical, with a molecular weight of about 2963) (i.e., the mass ratio of DSPE-peg-s-BD to DSPE-PEG2000-Mannose is 1:1) prepared by the method of Preparation Example 1 were dissolved in 3 mL of deionized water (total concentration of 1 mg / mL), fully dissolved to allow self-assembly, and freeze-dried to obtain a nano drug carrier.

[0091] Embodiment 2-4

[0092] The difference between the following examples and Example 1 is that when preparing the nano drug carrier for targeted regulation of macrophage polarization, the mass ratio of DSPE-peg-s-BD and DSPE-PEG2000-Mannose is different while keeping the total concentration of DSPE-peg-s-BD and DSPE-PEG2000-Mannose unchanged, as follows:

[0093] In Example 2, the mass ratio of DSPE-peg-s-BD and DSPE-PEG2000-Mannose is 2:1;

[0094] In Example 3, the mass ratio of DSPE-peg-s-BD and DSPE-PEG2000-Mannose is 3:1;

[0095] In Example 4, the mass ratio of DSPE-peg-s-BD to DSPE-PEG2000-Mannose is 0.5:1.

[0096] The nano drug carriers prepared in Examples 1-4 were examined by transmission electron microscopy. Figure 3 .

[0097] from Figure 3 It can be seen from the results that when the mass ratio of DSPE-peg-s-BD and DSPE-PEG2000-Mannose is 0.5:1, the obtained nano drug carrier has better morphology and more uniform particle size distribution, so this ratio is used for subsequent drug loading.

[0098] Application Example 1

[0099] The drug carrier of Example 4 is used to load the drug, and the specific method is as follows:

[0100] The preparation method of the nano drug carrier for targeted regulation of macrophage polarization is as follows:

[0101] 4 mg DSPE-peg-s-BD and 3 mg DHA (dihydroartemisinin, C 15 H 24 O5, purchased from MCE, CAS No.: 71939-50-9), 8 mg DSPE-PEG2000-Mannose (distearylphosphatidyl acetamide-polyethylene glycol 2000-mannose, purchased from Yuci Pharmaceutical) were dissolved in 400 μL DMF (wherein, the mass ratio of drug: carrier was 1:4, and the mass ratio of DSPE-peg-s-BD:DSPE-PEG2000-Mannose was 0.5:1) and the resulting solution was added dropwise to a HCl solution (pH = 4.0) containing 0.03% (w / v, mass volume concentration) DSPE-PEG2000 (distearylphosphatidyl acetamide-polyethylene glycol 2000, purchased from Carbon Water Technology, CAS No. 147867-65-0) (or slowly added dropwise to 4.6 mL deionized water / phosphate buffered saline (PBS) under ultrasonic conditions). The mixture was then stirred at room temperature for 10 minutes, and dialyzed (MWCO 1000) in 500 mL of deionized water for 3 times, 20 minutes each time; the mixture was then centrifuged at 500 rpm for 3 minutes to remove aggregates; the supernatant was collected and centrifuged at 12000 rpm for 15 minutes (generally 10-20 minutes is sufficient); the obtained precipitate was dispersed in PBS; the steps of "centrifugation at 12000 rpm for 15 minutes; dispersing the obtained precipitate in PBS" were repeated 3 times to remove free DHA, and the nano-drug carrier loaded with DHA was obtained after freeze-drying.

[0102] The nano drug carrier prepared in Application Example 1 was tested by transmission electron microscopy. Figure 4 . Figure 4 The results showed that the nanoparticles were successfully synthesized and had a uniform spherical morphology.

[0103] 1. Particle size determination

[0104] The particle sizes of the four nanoparticles obtained in Examples 2-4 and Application Example 1 were measured by dynamic light scattering. Figure 5 ,from Figure 5 The results show that the average particle size of the nano drug carrier increases after loading the drug.

[0105] 2. Verification of shielding effect

[0106] The preparation method of near-infrared fluorescent dye (MAP10-FE) is as follows:

[0107] (1) 4-(2,5-dibromo-1h-pyrrole-1-yl)benzoate (0.7458 g, 2.00 mmol), 4-butylphenylboronic acid (0.6118 g, 4.50 mmol) and Pd(PPh3)4 (0.0924 g, 0.08 mmol) were dissolved in acetonitrile (15 mL), and then a saturated aqueous solution of K2CO3 (5 mL) was added. The mixture was stirred at 80 °C for 24 h under nitrogen. Afterwards, the solution was cooled to room temperature, extracted with dichloromethane, and washed with water. The organic layer was then dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure and the mixture was heated to 40 °C with a mixture of dichloromethane / petroleum ether (1 / 8, V d / V p ) as the eluent, and purify the residue by silica gel column chromatography to obtain MAP10. (2) At 0°C, POCl3 (150 μL, 1.64 mmol) was added dropwise to DMF (15 mL), stirred at room temperature for 30 min, and then MAP10 (1.00 mmol) was added. After the mixture was stirred for 12 h, the residue was poured into a diluted Na2CO3 aqueous solution (250 mL) and extracted with dichloromethane. The organic layer was then dried over anhydrous MgSO4 and filtered by suction. The solvent was evaporated under reduced pressure and the mixture was quenched with a dichloromethane / petroleum ether mixture (1 / 3, V d / V p ) as the eluent, and the residue was purified by silica gel column chromatography to obtain compound MAP10-CHOs. (3) MAP10-CHOs and 2-(3-cyano-4,5,5-trimethylfuran-2(5H)-ethyl)malononitrile were dissolved in ammonium acetate, and then THF / ethanol was added to obtain compound MAP10-FE.

[0108] MAP10-FE@DP NPs (MAP10-FE+DSPE-PEG), MAP10-FE@DPM NPs (MAP10-FE+DSPE-PEG-Mannose), and MAP10-FE@DPM-DPSB NPs (MAP10-FE+DSPE-peg-s-BD+DSPE-PEG-Mannose) labeled with near-infrared fluorescent dye (MAP10-FE) were prepared respectively. After incubation with M2 macrophages for 0.5, 1, and 4 h (the concentration of each nanoparticle solution was 10 μmol / L), the fluorescence intensity was observed by laser confocal microscopy to demonstrate the targeting of MAP10-FE@DPMNPs to M2 macrophages and the long-chain shielding effect of MAP10-FE@DPM-DPSB NPs.

[0109] Specifically, the preparation method of MAP10-FE@DP NPs is as follows: dissolve 1 mg MAP10-FE and 3 mg DSPE-PEG2000 in 1 mL DMSO, shake well to dissolve, add to 9 mL PBS solution under ultrasonic water bath conditions, ultrasonicate for 10 minutes, and then dialyze for 24 hours to obtain MAP10-FE@DP NPs nanoparticle solution, and filter the solution through a 0.22 μm filter membrane for sterilization.

[0110] The preparation method of MAP10-FE@DPM NPs is as follows: dissolve 1 mg MAP10-FE and 3 mg DSPE-PEG2000-Mannose in 1 mL DMSO, shake well to dissolve, add to 9 mL PBS solution under ultrasonic water bath conditions, ultrasonicate for 10 minutes, and then dialyze for 24 hours to obtain MAP10-FE@DPM NPs nanoparticle solution, and filter the solution through a 0.22 μm filter membrane for sterilization.

[0111] The preparation method of MAP10-FE@DPM-DPSB NPs is as follows: dissolve 1 mg MAP10-FE, 1 mg DSPE-peg-s-BD and 2 mg DSPE-PEG2000-Mannose in 1 mL DMSO, shake well to dissolve, add to 9 mL PBS solution under ultrasonic water bath conditions, ultrasonicate for 10 minutes, and then dialyze for 24 hours to obtain MAP10-FE@DPM-DPSB NPs nanoparticle solution, and filter the solution through a 0.22 μm filter membrane for sterilization.

[0112] The images obtained under the laser confocal microscope are shown in Figure 6 , fluorescence intensity see Figure 7 .

[0113] Combination Figure 6 and Figure 7 The results showed that: ① Within 1 hour, the uptake of MAP10-FE@DPM NPs by M2 macrophages increased in a cell-dependent manner.

[0114] ② The fluorescence intensity of the MAP10-FE@DPM group was significantly higher than that of the MAP10-FE@DP group and the MAP10-FE@DPM-DPSB group, indicating that M2 macrophages took up the most MAP10-FE@DPM NPs, and the mannose receptor in DSPE-PEG2000-Mannose had targeting specificity for M2 macrophages.

[0115] ③ The fluorescence intensity of the MAP10-FE@DPM-DPSB group was significantly lower than that of the MAP10-FE@DPM group, and had no significant difference from the MAP10-FE@DP group, indicating that the ROS-responsive polymer long chain DSPE-peg-s-BD can shield the short chain of the mannose receptor.

[0116] 3. Target specificity verification

[0117] M0 macrophages, M1 macrophages, M2 macrophages, and lung epithelial cells (MLE-12) were incubated with MAP10-FE@DPM NPs (concentration 10 μmol / L) for 1 h, and the fluorescence intensity was observed by laser confocal microscopy to demonstrate the targeting specificity of MAP10-FE@DPM NPs to M2 macrophages.

[0118] The preparation method of MAP10-FE@DPM NPs was as described in “2. Validation of shielding effect”. Macrophages were purchased from Wuhan Punosai Life Science Co., Ltd., and lung epithelial cells were purchased from Shanghai Zhongqiao Xinzhou Biotechnology Co., Ltd.

[0119] The images obtained under the laser confocal microscope are shown in Figure 8 , fluorescence intensity see Fig. 9 . Combined Figure 8 and Fig. 9 It can be seen that the uptake of MAP10-FE@DPM NPs by M2 macrophages is significantly higher than that of cells in other groups, indicating the targeting specificity of mannose receptor on M2 macrophages.

[0120] 4. Verification of dual targeting effect

[0121] MAP10-FE@DPM-DPSB NPs were treated with H2O2 (1mM) for 8h, 16h, and 24h to hydrolyze the ROS-responsive polymer long chain DSPE-peg-s-BD. Then, M2 macrophages were incubated with MAP10-FE@DPM NPs (concentration 10 μmol / L) and MAP10-FE@DPM-DPSB NPs (concentration 10 μmol / L) treated with H2O2 for different times for 0.5, 1, and 4h, respectively. The fluorescence intensity was observed by laser confocal microscopy to prove that the ROS-responsive polymer long chain DSPE-peg-s-BD treated with H2O2 could expose mannose receptors after hydrolysis, thereby significantly increasing the targeting ability of the nanoparticles to M2 macrophages.

[0122] The preparation methods of MAP10-FE@DPM-DPSB NPs and MAP10-FE@DPM NPs refer to those described in “2. Verification of shielding effect”, and the source of M2 macrophages is the same as that described in “2. Verification of shielding effect”.

[0123] The images obtained under the laser confocal microscope are shown in Fig.10 , fluorescence intensity see Fig.11 . Combined Fig.10 and Fig.11 It can be seen that after MAP10-FE@DPM-DPSB NPs were treated with H2O2 for 8, 16, and 24 hours, there was no significant difference in the uptake of MAP10-FE@DPM-DPSB NPs by M2 macrophages and MAP10-FE@DPM NPs, indicating that the long chains of DPM-DPSB NPs treated with H2O2 were hydrolyzed to expose mannose receptors, making the targeting ability of the nanoparticles to M2 macrophages comparable to that of MAP10-FE@DPM NPs.

[0124] This result indicates that the long ROS-responsive polymer chain on the decomposable shielding amphiphilic polymer DSPE-peg-s-BD mainly plays the role of protecting and shielding the macrophage-specific targeting recognition layer. After ROS-responsive hydrolysis, the mannose receptor on the macrophage-specific targeting recognition layer can be exposed without affecting its targeting recognition ability for M2 macrophages.

[0125] Application Example 2

[0126] A method for preparing a nano drug carrier for targeted regulation of macrophage polarization comprises the following steps:

[0127] 4 mg DSPE-peg-s-BD and 8 mg DSPE-PEG2000-FA (distearoylphosphatidyl acetamide-polyethylene glycol 2000-folic acid, purchased from Shanghai Avituo Pharmaceutical Technology Co., Ltd.) prepared by the method of Preparation Example 4 were dissolved in 400 μL DMF at a mass ratio of 0.5:1, and 3 mg curcumin (C 21 H 20 O6, purchased from MCE, CAS No. 458-37-7), and the obtained solution was added dropwise to a HCl solution (pH = 4.0) containing 0.01% (w / v, mass volume concentration) DSPE-PEG2000. Then, the suspension was stirred at room temperature for 7 minutes, and then dialyzed (MWCO 1000) in 500 mL of deionized water for 3 times; then, the aggregates were removed by centrifugation at 400 rpm for 5 minutes; the supernatant was collected and centrifuged at 10,000 rpm for 15 minutes; the obtained precipitate was dispersed in phosphate buffered saline (PBS); the steps of "centrifugation at 10,000 rpm for 15 minutes; the obtained precipitate was dispersed in phosphate buffered saline (PBS)" were repeated 3 times to remove free curcumin and obtain a nano drug carrier.

[0128] Application Example 3

[0129] A method for preparing a nano drug carrier for targeted regulation of macrophage polarization comprises the following steps:

[0130] 9 mg of distearoylphosphatidyl acetamide-thioketal-polyethylene glycol 2000 (DSPE-TK-PEG2000, purchased from Yuci Pharmaceutical) and 3 mg of DSPE-PEG2000-Mannose were dissolved in 400 μL DMF at a mass ratio of 3:1, and 3 mg of baicalin (C 21 H 18 O 11 , purchased from MCE, CAS number: 21967-41-9), and the obtained solution was added dropwise to a HCl solution (pH = 4.0) containing 0.05% (w / v, mass volume concentration) DSPE-PEG2000 (distearoylphosphatidyl acetamide-polyethylene glycol 2000). Then, the suspension was stirred at room temperature for 15 minutes, and then dialyzed (MWCO 1000) in 500 mL of deionized water for 3 times; then, the mixture was centrifuged at 600 rpm for 2 minutes to remove aggregates; the supernatant was collected and centrifuged at 15000 rpm for 5 minutes; the obtained precipitate was dispersed in phosphate buffered saline (PBS); the steps of "centrifuging at 15000 rpm for 5 minutes; dispersing the obtained precipitate in phosphate buffered saline (PBS)" were repeated 3 times to remove free baicalin and obtain a nano drug carrier.

[0131] Application Example 4

[0132] A method for preparing a nano drug carrier for targeted regulation of macrophage polarization comprises the following steps:

[0133] 8 mg of distearoylphosphatidyl acetamide-thioketal-polyethylene glycol 2000 (DSPE-TK-PEG2000) and 4 mg of DSPE-PEG1000-FA (distearoylphosphatidyl acetamide-polyethylene glycol 1000-folate) were dissolved in 400 μL DMF at a mass ratio of 2:1, and 3 mg of quercetin (C 15 H 10 O7, purchased from MCE, CAS number: 117-39-5), and the obtained solution was added dropwise to a HCl solution (pH = 4.0) containing 0.03% (w / v, mass volume concentration) DSPE-PEG2000 (distearoylphosphatidyl acetamide-polyethylene glycol 2000). Then, the suspension was stirred at room temperature for 10 minutes, and then dialyzed (MWCO1000) in 500 mL of deionized water for 3 times; then, the aggregates were removed by centrifugation at 500 rpm for 3 minutes; the supernatant was collected and centrifuged at 12000 rpm for 10 minutes; the obtained precipitate was dispersed in phosphate buffered saline (PBS); the steps of "centrifugation at 12000 rpm for 10 minutes; the obtained precipitate was dispersed in phosphate buffered saline (PBS)" were repeated 3 times to remove free quercetin and obtain a nano drug carrier.

[0134] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed. However, as long as it is within the scope of the claims of the present application, it shall be protected by the patent law.

Claims

1. A nano drug carrier targeting polarized macrophages, characterized in that: The nano drug carrier comprises a nano carrier shell and a hydrophobic core, and the drug is coated in the hydrophobic core; wherein the nano carrier shell comprises a degradable shielding layer and a macrophage-specific targeting recognition layer shielded and protected by the degradable shielding layer; The nano drug carrier comprises the following raw materials: a decomposable shielding amphiphilic polymer and a targetable identifiable amphiphilic polymer, the mass ratio of the two being (0.5-3):1; the difference between the number average molecular weight of the decomposable shielding amphiphilic polymer and the number average molecular weight of the targetable identifiable amphiphilic polymer is at least 300; The components of the decomposable shielding amphiphilic polymer include a first amphiphilic polymer and a chemical bond modified at the hydrophilic end of the first amphiphilic polymer, wherein the chemical bond can be decomposed under the environmental factors of the target tissue to expose the macrophage-specific targeting recognition layer shielded and protected by the decomposable shielding layer; the hydrophilic end of the first amphiphilic polymer and the chemical bond form a decomposable shielding layer; The targetable amphiphilic polymer component includes a second amphiphilic polymer and a macrophage-specific targeting recognition molecule that blocks the hydrophilic end of the second amphiphilic polymer; the hydrophilic end of the second amphiphilic polymer and the macrophage-specific targeting recognition molecule form a macrophage-specific targeting recognition layer; The hydrophobic end of the first amphiphilic polymer and the hydrophobic end of the second amphiphilic polymer form a hydrophobic core; The first amphiphilic polymer is distearoylphosphatidyl acetamide-polyethylene glycol; The second amphiphilic polymer is distearoylphosphatidyl acetamide-polyethylene glycol; The decomposable shielding amphiphilic polymer is DSPE-peg-s-BD; the targetable amphiphilic polymer is distearoylphosphatidyl acetamide-polyethylene glycol 2000-mannose; The macrophage-specific targeting recognition molecule is mannose; The drug can regulate macrophage polarization, and the drug is dihydroartemisinin.

2. A method for preparing a nano drug carrier targeting polarized macrophages according to claim 1, characterized in that: The following steps are involved: The decomposable shielding amphiphilic polymer, the targetable amphiphilic polymer and the drug are dissolved together in a second organic solvent, and the obtained solution is added to water, PBS or an acidic solution, and the solution is dialyzed after continuous stirring at room temperature, and the supernatant is collected after centrifugation, and the solution is centrifuged at a high speed of 10000-15000 rpm for 10-20 min to obtain the precipitate which is the nano drug carrier; When the decomposable shielding amphiphilic polymer, the targetable identifiable amphiphilic polymer and the drug are dissolved in a solvent, the concentration of the decomposable shielding amphiphilic polymer is 0.5-15 mg / mL, and the concentration of the targetable identifiable amphiphilic polymer is 0.5-15 mg / mL.

3. The nano drug carrier targeting polarized macrophages according to claim 1, characterized in that: The administration method of the nano drug carrier is selected from one or more of intravenous injection, intramuscular injection, oral administration, intratracheal injection, rectal administration, skin administration, atomization inhalation, stereotactic brain injection and intranasal administration.

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