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CN-121971403-A - Application of CD177 targeted membrane modified liposome in preparation of medicine for preventing and/or treating rheumatoid arthritis

CN121971403ACN 121971403 ACN121971403 ACN 121971403ACN-121971403-A

Abstract

The invention discloses an application of CD177 targeting membrane modified liposome in preparing a medicament for preventing and/or treating rheumatoid arthritis. The structure of the CD177 targeting membrane modified liposome comprises a liposome loaded with a PADI4 inhibitor, a targeting recognition layer formed by coupling CD177 targeting peptide on the surface of the liposome, and a bionic functional layer formed by coating a natural neutrophil membrane on the outermost layer. Based on the RA 'CD 177 + neutrophil-NETs' core pathological mechanism, the invention creatively integrates the inflammatory chemotaxis/cytokine neutralization function of neutrophil membrane, the precise targeting function of synovial pathogenic cells of CD177 peptide and the NETs source blocking function of PADI4 inhibitor organically, and the constructed GNLC realizes the synergistic treatment effect of joint targeting enrichment-pathological mechanism blocking-synovial microenvironment remodeling, and has excellent stability and long-term safety.

Inventors

  • ZHANG HUI
  • Hu Chaotao
  • LIU YUDONG
  • ZHAO NANA

Assignees

  • 北京医院
  • 北京化工大学

Dates

Publication Date
20260505
Application Date
20260127

Claims (10)

  1. 1. Application of membrane modified liposome of targeted CD177 positive neutrophil in preparing medicine for preventing and/or treating rheumatoid arthritis; The membrane modified liposome of the drug-targeted CD177 positive neutrophil comprises three layers, wherein the liposome loaded with a PADI4 inhibitor is used as a drug core layer, a targeted recognition layer formed by coupling CD177 targeted peptide on the surface of the liposome, and a bionic functional layer formed by coating a natural neutrophil membrane on the outermost layer.
  2. 2. The method according to claim 1, wherein the prevention and/or treatment of rheumatoid arthritis is characterized by at least one of the following: 1) Improving the clinical symptoms of rheumatoid arthritis; 2) Improving pathological damage of joint tissues caused by rheumatoid arthritis; 3) Improving bone loss caused by rheumatoid arthritis; 4) Improving the infiltration quantity of Ly6G + neutrophils in the synovium caused by rheumatoid arthritis; 5) Inhibiting the formation of MPO + NETs in synovium caused by rheumatoid arthritis; 6) Inhibiting M1 type macrophage increase caused by rheumatoid arthritis, and inhibiting M2 type macrophage decrease caused by rheumatoid arthritis.
  3. 3. The use according to claim 2, wherein said improving the clinical symptoms of rheumatoid arthritis comprises at least one of a 1) improving the clinical score of arthritis, b 1) improving joint redness and swelling.
  4. 4. The method according to claim 2, wherein said ameliorating pathological damage to joint tissue caused by rheumatoid arthritis comprises at least one of a 2) ameliorating synovitis, b 2) ameliorating synovial hyperplasia, c 2) ameliorating articular cartilage damage.
  5. 5. The use according to claim 2, wherein said improving bone loss caused by rheumatoid arthritis comprises at least one of a 3) improving Bone Mineral Density (BMD) and b 3) improving bone trabecular thickness.
  6. 6. The use according to any one of claims 1 to 5, wherein the PADI4 inhibitor-loaded liposome is prepared from a steroid, a PEG lipid and a PADI4 inhibitor, wherein the PEG end of the PEG lipid is modified with a group reactive with a group in a CD177 targeting peptide; such PADI4 inhibitors include, but are not limited to, GSK199, GSK484, cl-amidine; the mass ratio of the PEG lipid to the steroid is 10:1.
  7. 7. The method according to claim 1 to 6, wherein the CD177 targeting peptide has the amino acid sequence CGGGTIRLNPMPKYFD; and/or the mass ratio of the CD177 targeting peptide to the PEG lipid is 1 (1-1.5); and/or the mass ratio of total lipid in the PADI4 inhibitor-loaded liposome to the natural neutrophil membrane is 11:1.
  8. 8. A medicament for preventing and/or treating rheumatoid arthritis, the active ingredient of which comprises the membrane-modified liposome targeting CD177 positive neutrophils according to any one of claims 1-7.
  9. 9. The pharmaceutical composition of claim 8, wherein a pharmaceutically acceptable carrier material is further added.
  10. 10. A method of treating and/or preventing a disease or disorder in a subject, comprising administering to a subject in need thereof the medicament of claim 8 or 9; Wherein the disease is rheumatoid arthritis, and the disease is caused by the rheumatoid arthritis.

Description

Application of CD177 targeted membrane modified liposome in preparation of medicine for preventing and/or treating rheumatoid arthritis Technical Field The invention belongs to the field of biological medicine, and in particular relates to an application of a CD177 targeting membrane modified liposome in preparing a medicine for preventing and/or treating rheumatoid arthritis. Background Rheumatoid Arthritis (RA) is a chronic progressive autoimmune disease characterized by chronic inflammation of synovium, degradation of articular cartilage and bone erosion, and its pathological mechanism involves multiple immune cell dysfunction such as neutrophil, T-cell, macrophage, etc., and abnormal activation of multiple inflammatory pathways such as JAK-STAT, NF- κb, etc. The current clinical treatment means comprise oral administration of traditional disease-improving antirheumatic drugs (DMARDs such as methotrexate), glucocorticoids and biological agents (such as anti-TNF-alpha antibodies), and although the inflammatory progress can be controlled to a certain extent, the traditional drugs have the common limitations that the traditional drugs lack of cell and tissue specificity, the long-term use is easy to cause side effects such as liver and kidney function injury, infection risk rise and bone marrow suppression, and part of biological agents face the problems of uneven response rate of patients, attenuation of curative effects along with the course of disease, high treatment cost and the like. Therefore, the development of a novel therapeutic strategy with high targeting, strong curative effect and high safety is a core technical demand for breaking through the dilemma of clinical treatment of RA. Recent studies have demonstrated that neutrophils and their released Neutrophil Extracellular Traps (NETs) are key cores in driving RA joint inflammation and structural destruction. NETs are composed of DNA released after neutrophil activation, citrullinated histone, myeloperoxidase (MPO) and other components, and a large amount of NETs accumulate in RA synovial tissue to cause double pathogenic effects, wherein on one hand, NETs are used as injury related molecular patterns (DAMPs) and can directly activate synovial fibroblasts and macrophages to induce the same to secrete IL-1 beta, IL-6, TNF-alpha and other pro-inflammatory cytokines, and simultaneously promote the release of Matrix Metalloproteinases (MMPs) and accelerate the degradation of cartilage and bone tissues, and on the other hand, citrullinated proteins in NETs can be used as self antigens to trigger B cells to generate anti-cyclic citrullinated peptide antibodies (ACPA) and further activate adaptive immune responses to form malignant circulation of NETs-inflammatory factor-autoantibodies, so that chronic joint inflammation and irreversible structural injury are caused. Intensive studies have found that abnormal microenvironments in RA patients (e.g. synovial local high concentrations of IL-8, CXCL 1) can continuously activate neutrophils, putting them in a "pre-activated" state, significantly increasing susceptibility to netois (net formation process). More importantly, the heterogeneity of neutrophils shows definite functional specificity in RA, that a subset of CD177 positive (CD 177 +) neutrophils significantly expand in peripheral blood and synovial tissue of patients in proportion positively correlated with disease activity score (DAS 28), blood sedimentation (ESR), and that this subset has significantly greater ability to produce NETs after stimulation in vitro than CD177 - neutrophils, being the primary source of pathological NETs in RA synovium. This finding suggests that CD177 + neutrophils are a precise target for intervention in RA nes-associated pathological pathways. Among the molecular mechanisms of NETs formation, peptidyl arginine deiminase 4 (PADI 4) is an indispensable key rate limiting enzyme. PADI4 catalyzes the citrullination of the arginine residue of histone H3, destroying the structural stability of chromatin, providing a necessary condition for the release of NETs. Thus, inhibition of PADI4 activity is an effective technological pathway to block pathological nes, and related inhibitors (such as GSK 199) have shown significant inhibition of nes in vitro experiments. However, the clinical transformation of the existing PADI4 inhibitor faces two technical bottlenecks, namely that systemic administration lacks cell specificity and cannot be accurately enriched in CD177 + neutrophils, so that not only is effective treatment concentration difficult to achieve at a synovial inflammation part, but also physiological functions of PADI4 in normal tissues (such as participation in apoptosis regulation) can be possibly interfered to cause potential off-target toxicity, and the inhibitor is easy to be subjected to enzymolysis or renal clearance in vivo, has low bioavailability and is difficult to continuously act on a joint part with chronic