WO2022225203A1 - Composition de modulation de l'activité des macrophages - Google Patents

Composition de modulation de l'activité des macrophages Download PDF

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WO2022225203A1
WO2022225203A1 PCT/KR2022/004011 KR2022004011W WO2022225203A1 WO 2022225203 A1 WO2022225203 A1 WO 2022225203A1 KR 2022004011 W KR2022004011 W KR 2022004011W WO 2022225203 A1 WO2022225203 A1 WO 2022225203A1
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liposome
phosphatidylserine
composition
macrophages
mol
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PCT/KR2022/004011
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English (en)
Korean (ko)
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양형철
김용준
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서울대학교산학협력단
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Publication of WO2022225203A1 publication Critical patent/WO2022225203A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a composition for regulating the activity of macrophages.
  • the composition for regulating macrophage activity of the present invention can be used for anti-inflammatory, anti-fibrosis, autoimmune disease treatment, tissue regeneration or bone formation.
  • Macrophages can be polarized from M0 type to M1 type or M2 type, M1 type is polarized by LPS or IFN- ⁇ , etc., and M2 type is polarized by IL-4, IL-6, IL-10, etc.
  • M1-type macrophages proinflammatory cytokines and enzymes that cause an inflammatory response are secreted, and specifically, secretion of TNF- ⁇ , IL-1 ⁇ , IL-6, MCP-1, O 2 - is promoted.
  • M2-type macrophages the secretion of anti-inflammatory cytokines IL-10 or TGF- ⁇ is promoted, and the secretion of pro-inflammatory cytokines TNF- ⁇ , IL-1 ⁇ , IL-6, and MCP-1 is inhibited. make it That is, by polarizing the M0 type macrophages to the M2 type, it is possible to suppress the secretion of pro-inflammatory cytokines and to promote the secretion of anti-inflammatory cytokines to suppress the inflammatory response.
  • Apoptotic cells generated due to tissue damage or the like are removed from the tissue by phagocytosis of macrophages. Unlike normal cells, apoptotic cells are exposed to phosphatidylserine on the cell surface. The phosphatidylserine reacts with the phosphatidylserine receptor of macrophages, promotes phagocytosis of macrophages, suppresses secretion of inflammatory factors by macrophages, and promotes secretion of anti-inflammatory factors.
  • Liposomes containing phosphatidylserine can mimic apoptotic cells to suppress the secretion of inflammatory factors of phagocytes, such as macrophages, dendritic cells, and microglia, and promote the secretion of anti-inflammatory factors.
  • phosphatidylserine inhibits the differentiation of monocytes into dendritic cells and osteoclasts.
  • phosphatidylserine promotes myocardial angiogenesis in an animal model of myocardial infarction, and has been shown to be effective in the treatment of myocardial infarction.
  • phosphatidylserine has been confirmed to have a therapeutic effect on type 1 diabetes and multiple sclerosis, and can be used as a therapeutic agent for autoimmune diseases.
  • liposomes containing phosphatidylserine are not effective enough to be used in actual clinical practice, liposomes containing phosphatidylserine are not actually used as therapeutic agents in clinical practice. Therefore, in order to apply the liposomes containing phosphatidylserine to clinical practice, it is necessary to further increase the drug efficacy.
  • An object of the present invention is to provide a liposome for regulating the activity of macrophages comprising phosphatidylserine and RGD motif.
  • an object of the present invention is to provide a composition for preventing or treating anti-inflammatory, anti-fibrotic, autoimmune disease, tissue regeneration, or osteogenic composition
  • a composition for preventing or treating anti-inflammatory, anti-fibrotic, autoimmune disease, tissue regeneration, or osteogenic composition comprising a liposome including the phosphatidylserine and RGD motif.
  • liposomes containing phosphatidylserine have been generally used as carriers or vehicles for drug delivery, but the present inventors found that liposomes containing phosphatidylserine themselves have an effect of regulating the activity of macrophages. , and diligent research efforts were made to further enhance its effect. As a result, the present inventors found that when a lipid molecule containing an RGD motif is combined with a liposome exposed to an external surface of phosphatidylserine, the liposome converts the polarity of macrophages to M2 type, thereby significantly increasing the secretion of proinflammatory cytokines. A surprising discovery was made that it exerts an effect sufficient for clinical application by inhibiting it and remarkably promoting the secretion of anti-inflammatory cytokines.
  • the liposome can regulate the activity of macrophages, preferably polarizing the polarity of macrophages to M2 type.
  • the liposome inhibits the secretion of TNF- ⁇ and the like and effectively promotes the secretion of TGF- ⁇ and VEGF, etc., thereby alleviating tissue inflammation, promoting regeneration of damaged tissues, and preventing inflammatory autoimmune diseases. can be effectively suppressed.
  • the RGD motif can improve the function of the liposome by binding to the integrin on the surface of the macrophage and helping the activation of the macrophage.
  • One aspect of the present disclosure provides a liposome for regulating the activity of macrophages comprising an RGD motif and phosphatidylserine.
  • the RGD motif and phosphatidylserine may be exposed to the outside of the liposome.
  • the RGD motif may include a lipophilic group to be introduced into liposomes or may be bound to a lipid molecule.
  • the liposome may not include a separate active ingredient therein.
  • liposomes have been mainly used as carriers or transporters for delivering active ingredients such as drugs therein to target cells.
  • the present inventors found that, although the liposome containing the RGD motif and phosphatidylserine does not contain a separate active ingredient, the liposome itself effectively regulates the activity of macrophages, preferably polarizing macrophages to M2 type. was discovered, and the present invention was completed based on this surprising discovery.
  • the RGD motif is a tripeptide composed of arginine-glycine-aspartate (Arg-Gly-Asp), and is derived from an amino acid sequence in fibronectin, an extracellular matrix protein that mediates cell adhesion.
  • the lipid molecule bound to the RGD motif may be any one or more selected from the group consisting of phospholipids, glycolipids, fatty acids, and the like.
  • the phospholipid may be at least one selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol and phosphatidylinositol.
  • the content of phosphatidylserine in the liposome may be 10-99 mol%, preferably 20-99 mol%, more preferably 30-99 mol%, based on the total mol% of the liposome.
  • the content of the phosphatidylserine is less than 10 mol% compared to the total mol% of the liposome, the effect of polarizing macrophages to M2 type may be weak.
  • the content of the phosphatidylserine is greater than 99 mol% relative to the total mol% of the liposome, the content of the RGD motif is relatively decreased, and the anti-inflammatory effect by the RGD motif may be reduced.
  • the content of the RGD motif bound to the lipid molecule in the liposome is 0.1 to 15 mol%, preferably 0.5 to 10 mol%, more preferably 1 to 5 mol%, most of the total mol% of the liposome. Preferably it may be 2 to 4 mol%.
  • the content of the RGD motif bound to the lipid molecule is less than 0.1 mol% compared to the total mol% of the liposome, the binding to the integrin may be poor, and the effect on macrophages may be weak.
  • the content of the RGD motif bound to the lipid molecule is more than 15 mol% relative to the total mol% of the liposome, the stability of the liposome may be inhibited.
  • the liposome may further include any one or more selected from the group consisting of phosphatidylserine and RGD motif-bound lipid molecules, as well as phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol and cholesterol. , but not limited thereto.
  • the liposome for regulating the activity of macrophages may be used for anti-inflammatory, anti-fibrosis, prevention or treatment of autoimmune diseases, tissue regeneration or bone formation, and the like, but is not limited thereto.
  • the anti-inflammatory uses include prevention or treatment of atherosclerosis, myocardial infarction, arthritis or septic shock, or the like, or retinal nerve survival;
  • the antifibrotic uses include prophylaxis or treatment for cirrhosis of the liver, pulmonary fibrosis, glomerulosclerosis, chronic pancreatitis, or coronary artery disease and the like;
  • the autoimmune disease includes atopic dermatitis, atopic dermatitis, multiple sclerosis or type 1 diabetes;
  • the tissue regeneration includes regeneration of soft tissue or hard tissue;
  • the bone formation may be used for prevention or treatment of osteoporosis, multiple myelopathy, osteoarthritis, or bone defects, but is not limited thereto.
  • compositions for regulating the activity of macrophages comprising the liposome for regulating the activity of macrophages.
  • the composition may be used for regulating the activity of macrophages in a pharmaceutical composition, a quasi-drug composition, a cosmetic composition, or a food composition.
  • One aspect of the present disclosure provides a pharmaceutical composition for regulating the activity of macrophages comprising the liposome for regulating the activity of macrophages in an effective amount.
  • the pharmaceutical composition can be effectively used for anti-inflammatory, anti-fibrosis, prevention or treatment of autoimmune diseases, tissue regeneration, or bone formation.
  • the liposome for regulating the activity of macrophages is generally administered in a therapeutically effective amount.
  • the liposome for regulating macrophage activity of the present invention may be administered by any suitable route, in the form of a pharmaceutical composition suitable for such route, and in an effective dosage for the intended treatment.
  • an effective amount may refer to an amount of liposomes sufficient to modulate the activity of macrophages, preferably to polarize macrophages to type M2 to provide therapeutic benefits in applications such as anti-inflammatory.
  • the “effective amount” also refers to an amount sufficient to modulate the activity of macrophages either in vitro or in vivo.
  • Another aspect of the present disclosure is anti-inflammatory, anti-fibrosis, prevention or treatment of autoimmune diseases comprising administering a therapeutically effective amount of the composition for regulating macrophage activity to an individual in need thereof, tissue regeneration, or a method for bone formation.
  • the subject may be a human.
  • one aspect of the present disclosure provides a pharmaceutical use, characterized in that the liposome for regulating the activity of macrophages is used as an active ingredient.
  • the pharmaceutical use may be used for polarizing macrophages to M2 type, and for preventing or treating anti-inflammatory, anti-fibrosis, autoimmune diseases, tissue regeneration, or bone formation.
  • prevention refers to any action that suppresses or delays the progression of inflammation, fibrosis or autoimmune disease by administration of the composition of the present disclosure
  • treatment refers to any action that inhibits or delays the progression of inflammation, fibrosis, or fibrosis by administration of the composition of the present disclosure. Or it means any action that improves or beneficially changes the symptoms of autoimmune disease.
  • the effective dosage of the liposome for regulating the activity of macrophages is usually from about 0.0001 to about 200 mg/(body weight) kg/day, preferably from about 0.0005 to about 100 mg/kg/day in single or divided administration. day, more preferably from about 0.001 to about 30 mg/kg/day, even more preferably from about 0.01 to about 10 mg/kg/day, and most preferably from about 0.05 to about 1.2 mg/kg/day. Dosage levels below the lower limit of this range may be suitable depending on the age, species, and disease or condition being treated. In other cases, still larger doses can be used without deleterious side effects. The larger dose may be divided into several smaller doses for administration throughout the day. Methods for determining appropriate dosages are well known in the art.
  • the liposome described in the present disclosure, or the composition comprising the liposome may be administered to a subject by oral administration, parenteral administration, or topical administration.
  • compositions for regulating macrophage activity comprising an RGD motif and phosphatidylserine.
  • the composition for regulating macrophage activity may include an RGD motif and phosphatidylserine bound to a lipid molecule.
  • the RGD motif and phosphatidylserine bound to the lipid molecule may not constitute a liposome form in the composition.
  • the content of the RGD motif bound to a lipid molecule in the composition for regulating the activity of macrophages is 0.1 to 20 mol%, preferably 1 to 18 mol%, more preferably 2 to 20 mol% relative to the total mol% of phospholipids 15 mol%, more preferably 3-12 mol%, even more preferably 4-10 mol%, most preferably 5-7 mol%.
  • the content of the RGD motif bound to the lipid molecule is less than 0.1 mol % relative to the total mol % of the phospholipids, the binding to integrin may be poor, and the effect on macrophages may be weak.
  • the content of the RGD motif bound to the lipid molecule is more than 20 mol% relative to the total mol% of the phospholipid, the stability of the liposome may be inhibited.
  • the composition for regulating macrophage activity including the RGD motif and phosphatidylserine may include a biodegradable polymer.
  • the biodegradable polymer is polycaprolactone (PCL), polylactic acid (PLA), aliphatic polyester, polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (poly(lactic-co-glycolic acid, PLGA) synthetic polymers such as, or natural polymers such as starch, chitin, or cellulose, etc.
  • the RGD motif and phosphatidylserine are exposed to the outer surface of the biodegradable polymer, or the biodegradable polymer It can react effectively with macrophages by coating.
  • the composition for regulating macrophage activity may include poly(lactic-co-glycolic acid) (PLGA) core particles as a biodegradable polymer, in which case poly(lactic-co-glycolic acid) Lipid molecules and phosphatidylserine bound to the RGD motif may be coated on the surface of the core particle and exposed to the outside.
  • PLGA poly(lactic-co-glycolic acid)
  • the composition for regulating the activity of macrophages may include poly (lactic-co-glycolic acid) as a biodegradable polymer, and the composition including the biodegradable polymer is a titanium rod, etc. It can be used to coat a biocompatible material, or a biocompatible medical device. The titanium rod coated with the composition is exposed to the RGD-motif and phosphatidylserine on the PLGA-based surface, thereby effectively polarizing macrophages to M2 type.
  • the RGD motif and phosphatidylserine in the composition for regulating the activity of macrophages are exposed to the outside of the biodegradable polymer, and as the polarity of macrophages is converted to M2 type, anti-inflammatory, anti-fibrosis, autoimmune It can be effectively used for prevention or treatment of diseases, tissue regeneration, or bone formation.
  • the liposome containing phosphatidylserine and RGD motif of the present invention, the composition containing the liposome, and the composition for regulating macrophage activity including the RGD motif and phosphatidylserine are anti-inflammatory, It is remarkably excellent in anti-fibrosis, prevention or treatment of autoimmune diseases, tissue regeneration and osteogenic effects.
  • 1 is a schematic diagram showing a liposome containing phosphatidylserine and RGD motif.
  • Figure 2 is a graph measuring the mRNA production of IL-1 ⁇ , IL-6, TNF- ⁇ , Arg-1, FIZZ1, YM-1 in order to evaluate the effect on macrophages of the liposomes prepared in Examples and Comparative Examples is shown as
  • Figure 3 is a graph showing the measurement of nitric oxide (NO) release amount, and measuring the protein production amount of TNF- ⁇ , Arg-1 in order to evaluate the effect on macrophages of the liposomes prepared in Examples and Comparative Examples.
  • NO nitric oxide
  • Example 5 is a graph showing the evaluation of the effect on bone formation using the liposomes of Example 2 and Comparative Example 1.
  • Example 6 is a photograph of the degree of bone formation by microCT after 2, 4, 6, 8, and 10 weeks after treatment with the liposomes of Example 2 and Comparative Example 1.
  • the yellow line represents the entire scaffold, and the yellow-green line represents the ingrown tip.
  • FIG. 9 is a graph (B) showing a photograph (A) of a representative tissue of each group and a graph (B) by measuring the thickness of the fibrotic tissue in an anti-fibrosis evaluation experiment.
  • FIG. 10 is a schematic diagram showing a state in which RGD motif and phosphatidylserine are exposed to the outer surface in a PLGA core coated with RGD motif and phosphatidylserine, and a titanium rod coated with PLGA with RGD motif and phosphatidylserine.
  • a liposome composed of phosphatidylethanolamine and RGD covalently bonded to 1 mol% of phosphatidylethanolamine-RGD, 50 mol% of phosphatidylserine, 24 mol% of phosphatidylcholine, and 25 mol% of cholesterol was prepared. After dissolving in a chloroform-methanol mixed solution 9:1 v/v so that the total concentration of all molecules contained in the liposome was 10 mM, it was diluted with a chloroform-methanol mixed solution and the solution was completely evaporated. Distilled water or physiological saline was added to the bottom of the evaporated container and allowed to stand for 1 hour. After standing, the container was shaken to release the lipid layer from the bottom, and liposomes of a certain size were prepared through injection filtration. The diameter of the liposome was prepared in the size of 0.1 ⁇ m.
  • Liposomes (Example 2) were prepared in the same manner as in Example 1. prepared. Liposomes were prepared in a size of 0.1 ⁇ m in diameter.
  • Phosphatidylethanolamine and RGD covalently bonded to phosphatidylethanolamine-RGD 5 mol%, phosphatidylserine 50 mol%, phosphatidylcholine 20 mol%, and cholesterol 25 mol% of liposomes were prepared in the same manner as in Example 1. prepared. Liposomes were prepared in a size of 0.1 ⁇ m in diameter.
  • a liposome composed of 50 mol% of phosphatidylserine, 25 mol% of phosphatidylcholine, and 25 mol% of cholesterol was prepared in Comparative Example 1. Liposomes were prepared in a size of 0.1 ⁇ m in diameter.
  • the effects of the liposomes prepared in Examples and Comparative Examples on macrophages were evaluated.
  • macrophages mouse bone marrow-derived macrophages were used.
  • mRNA production of IL-1 ⁇ , IL-6, TNF- ⁇ , Arg-1, FIZZ1, and YM-1 was measured and shown in FIG. 2 .
  • NO nitric oxide
  • macrophages were treated with 50 ng/ml of lipopolysaccharide (LPS), an inflammation inducer, and liposomes for 12 hours, and then the proinflammatory cytokine TNF- ⁇ gene.
  • LPS lipopolysaccharide
  • mRNA expression was measured by real-time PCR.
  • the concentration of the liposome was such that the total lipid was 12.5 ng/ml. Measurement values are relative, and the measurement result value of the untreated negative control group was set to 1.
  • the positive control group is cells treated with LPS only.
  • the evaluation results are expressed as the average value and standard deviation of the results of three independent experiments.
  • Experimental Example 1-2 mRNA expression evaluation of IL-1 ⁇ and IL-6 genes
  • IL-1 ⁇ and IL-6 genes disclosed in FIG. 2 it was confirmed that the mRNA expression of the IL-1 ⁇ and IL-6 genes was statistically significantly reduced in Examples 1 to 3 compared to the positive control group. did. That is, it was confirmed that the mRNA expression of IL-1 ⁇ and IL-6, which are pro-inflammatory cytokines, was remarkably inhibited in the liposome-treated group containing the RGD motif.
  • the amount of nitrate generated by the inflammatory reaction was evaluated when the liposome containing the RGD motif was treated.
  • the generation of nitrate was statistically significantly reduced in Examples 1 to 3 compared to the positive control group. That is, it was confirmed that the generation of nitrate was reduced in the liposome-treated group containing the RGD motif, and the inflammatory response was remarkably suppressed.
  • the production amount of Arg-1 enzyme was measured. From the measurement result of the production amount of Arg-1 enzyme disclosed in FIG. 3, it was confirmed that the production amount of Arg-1 enzyme was statistically significantly increased in Examples 1 to 3 compared to the positive control group. That is, in the liposome-treated group containing the RGD motif, when the production amount of Arg-1 enzyme was significantly increased, it was confirmed that macrophages were converted to M2 type and anti-inflammatory reaction occurred.
  • liposomes containing phosphatidylserine and RGD motif inhibit the expression of proinflammatory cytokines (TNF- ⁇ , IL-1 ⁇ , IL-6), and It suppresses the production of nitrate, a factor, and promotes the expression of Arg-1 enzyme, FIZZ1 protein and YM-1 protein. That is, the liposome can promote anti-inflammatory activity by polarizing macrophages to M2 type, suppress fibrosis and autoimmune diseases, and promote tissue regeneration.
  • Experimental Example 2 Measurement of mRNA expression level of Arg-1 enzyme when using a biomaterial coated with a composition containing phosphatidylserine and RGD motif
  • Comparative Example 2 is a titanium disk coated with PLGA alone (PLGA), Comparative Example 3 is coated with PLGA, phosphatidylserine, and phosphatidylcholine (PS/PC), Comparative Example 4 is phosphatidylcholine and phosphatidylethanolamine-RGD (6 mol%) (PC/6% RGD), and Example 4 was coated with phosphatidylserine and phosphatidylethanolamine-RGD (3 mol%) (PS/PC/3% RGD).
  • Example 5 a titanium disk was coated with phosphatidylserine and phosphatidylethanolamine-RGD (6 mol%), and Example 6 was coated with phosphatidylserine and phosphatidylethanolamine-RGD (12 mol%).
  • An uncoated titanium disk was used as a negative control (Uncoated).
  • Comparative Examples 2 to 4 and Examples 4 to 6 Arg-1 mRNA expression levels were measured and shown in the first graph of FIG. 4 .
  • the mRNA expression levels of FIZZ1 and YM-1 were measured on the titanium disk coated with the compositions of Comparative Examples 2 to 4 and Example 5, and are shown in the second and third graphs of FIG. 4 , respectively.
  • Example 2 The effect on bone formation was evaluated using the liposomes of Example 2 and Comparative Example 1.
  • 6 rats per group were used, and the skull defect of rats was treated with apatite-alginate-gelatin containing liposomes, and bone formation was performed by microCT at 2, 4, 6, 8, and 10 weeks. The degree was evaluated. The degree of bone formation was expressed for each group as bone volume (BV) in the defect with respect to the total volume (TV) of the defect ( FIGS. 5 and 6 ).
  • BV/TV of Example 2 (3% RGD-PSL) from 2 weeks to 10 weeks at the end of the experiment was statistically significantly higher than that of the negative control group, and from 4 weeks to 10 weeks, Example 2 was compared. It was statistically significantly higher than Example 1 (PSL).
  • the negative control group and Comparative Example 1 did not show a statistically significant difference during the observation. 5 and 6, it was confirmed that bone formation was remarkably promoted when liposomes containing RGD motif and phosphatidylserine were treated.
  • the effect on soft tissue growth was evaluated using the liposomes of Examples 1 to 3 and Comparative Example 1.
  • Liposomes were inserted into an alginate-gelatin-polyvinyl alcohol (PVA) scaffold containing carrageenan causing inflammation and transplanted into the subcutaneous tissue of the rat's back, and after 1 week, the soft tissue ingrowth to the inside of the PVA was measured and evaluated. . 7 and 8, soft tissue ingrowth increased statistically significantly in Example 2 (3% RGD-PSL), confirming that the liposome of Example 2 significantly promoted soft tissue growth.
  • PVA alginate-gelatin-polyvinyl alcohol
  • the effect on tissue fibrosis around the scaffold was evaluated using the liposome of Example 2 above. Liposomes were inserted into an alginate-gelatin-polyvinyl alcohol (PVA) scaffold containing carrageenan that promotes fibrosis through an inflammatory response and transplanted into the subcutaneous tissue of the dorsal fossa of a rat. After 4 weeks, the thickness of the fibrotic tissue around the PVA was measured. and evaluated.
  • PVA alginate-gelatin-polyvinyl alcohol
  • the thickness of the fibrous tissue was significantly increased in the scaffold containing carrageenan than in the negative control group, and in Example 2 (3% RGD-PSL) containing both carrageenan and liposome, the thickness of the fibrotic tissue was statistically It decreased significantly, and it appeared to a similar degree to that of the negative control group. From the results disclosed in FIG. 9 , it was confirmed that tissue fibrosis was significantly inhibited when liposomes containing the RGD motif and phosphatidylserine were treated.

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Abstract

La présente invention concerne un liposome comprenant de la phosphatidylsérine et un motif RGD, et une composition de modulation de l'activité des macrophages, comprenant de la phosphatidylsérine et un motif RGD. Un liposome, et une composition de modulation de l'activité des macrophages, selon la présente invention, permettent de convertir la polarisation des macrophages en un type M2 et possèdent ainsi d'excellents effets d'anti-inflammatoires, anti-fibrotiques, de prévention ou de traitement de maladies auto-immunes, de régénération tissulaire et d'ostéogenèse.
PCT/KR2022/004011 2021-04-23 2022-03-22 Composition de modulation de l'activité des macrophages WO2022225203A1 (fr)

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KR10-2021-0163837 2021-11-24
KR1020210163837A KR20220146308A (ko) 2021-04-23 2021-11-24 대식세포의 활성 조절용 조성물

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