Search

CA-3273067-C - NANOPLATFORM FOR TARGETING INFLAMMATORY MACROPHAGES AND COMPOSITION FOR PREVENTING OR TREATING INFLAMMATORY DISEASES CONTAINING THE SAME

CA3273067CCA 3273067 CCA3273067 CCA 3273067CCA-3273067-C

Abstract

The present invention relates to a nanoplatform for targeting an inflammatory macrophage and a composition for preventing or treating inflammatory diseases using the same. The nanoplatform for targeting the inflammatory macrophage according to the present invention can selectively target the inflammatory macrophage with a conjugated glucosyl group as a transmitter. Furthermore, it can suppress inflammatory responses in damaged cells or tissues, restore mitochondrial function, and inhibit cell death, making it an effective composition for preventing or treating inflammatory diseases, particularly kidney diseases.

Inventors

  • Yun Sang Lee
  • Ji Yong Park
  • Ran Ji YOO
  • Tae Hyeon CHOI
  • Seung Hee Yang
  • Yon Su Kim
  • DON KI KIM
  • Jung Nam An

Assignees

  • CLICHEMBIO, INC.

Dates

Publication Date
20260505
Application Date
20231127
Priority Date
20221125

Claims (1)

  1. 29 【CLAIMS】 【Claim 1】 A nanoplatform for targeting an inflammatory macrophage, obtained by a click chemistry reaction between albumin conjugated with an azide (N3) or cyclooctyne functional group and a transmitter conjugated with an azide (N3) or cyclooctyne functional group, wherein the transmitter comprises a glucosyl group, and when the albumin is conjugated with the azide functional group, the transmitter is conjugated with the cyclooctyne functional group, and when the albumin is conjugated with the cyclooctyne functional group, the transmitter is conjugated with the azide functional group. 【Claim 2】 The nanoplatform for targeting the inflammatory macrophage of claim 1, wherein the azide or cyclooctyne functional group introduced into the albumin ranges from 1 to 14. 【Claim 3】 The nanoplatform for targeting the inflammatory macrophage of claim 1, wherein the nanoplatform comprises 4 to 8 glucosyl groups. 【Claim 4】 The nanoplatform for targeting the inflammatory macrophage of claim 1, wherein the azide or cyclooctyne functional group is conjugated to the 6th carbon of the glucosyl group. 【Claim 5】 The nanoplatform for targeting the inflammatory macrophage of claim 1, wherein the transmitter further comprises a radioactive isotope, and the radioactive isotope is one or more selected from the group consisting of 3H, 11C, 18F, 14Cl, 32P, 35S, 36Cl, 45Ca, 51Cr, 57Co, 58Co, 59F,30 64Cu, 67Ga, 68Ga, 89Zr, 90Y, 99Mo, 99mTc, 111In, 131I, 125I, 124I, 123I, 186Re, 188Re, 225Ac, 212Pb, 117mSn and 177Lu. 【Claim 6】 The nanoplatform for targeting the inflammatory macrophage of claim 5, wherein the radioactive isotope is labeled by a chelating agent, and the chelating agent is one or more selected from the group consisting of NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DFO (3-[6,17-dihyroxy- 7,10,18,21-tetraoxo-27-[N-acetylhydroxylamino)-6,11,17,22-tetraazaheptaeicosane]thiourea), DTPA (diethylenetriaminepentaacetic acid), N2S2 (diaminedithiol), p-SCN-Bn-NOTA (2-(4'- isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid), NODAGA (1,4,7- triazacyclononane,1-glutaric acid-4,7-acetic acid), p-SCN-Bn-DOTA (2-(4'- isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), p-SCN-Bn-DTPA (2-(4- isothiocyanatobenzyl)-diethylenetriaminepentaacetic acid), p-SCN-Bn-DFO (1-(4- isothiocyanatophenyl)-3-[6,17-dihyroxy-7,10,18,21-tetraoxo-27-[N-acetylhydroxylamino)- 6,11,17,22-tetraazaheptaeicosane]thiourea) and HYNIC (hydrazinonicotinic acid). 【Claim 7】 The nanoplatform for targeting the inflammatory macrophage of claim 1, wherein the transmitter further comprises a fluorescent material, and the fluorescent material is one or more selected from the group consisting of FNR (Ferrodoxin NADP(+) reductase), cyanine-based fluorescent material, TAMRA (tetramethylrhodamine-5-maleimide), Flamma® fluorescent material and ICG (indocyanine green). 【Claim 8】31 The nanoplatform for targeting the inflammatory macrophage of claim 1, wherein the nanoplatform selectively targets a macrophage with overexpressed GLUT (Glucose Transporter). 【Claim 9】 A pharmaceutical composition for preventing or treating an inflammatory disease, comprising the nanoplatform for targeting the inflammatory macrophage of any one of claims 1 to 8 as an active ingredient. 【Claim 10】 The pharmaceutical composition of claim 9, wherein the nanoplatform for targeting the inflammatory macrophage selectively targets a damaged tissue. 【Claim 11】 The pharmaceutical composition of claim 9, wherein the nanoplatform for targeting the inflammatory macrophage restores mitochondrial function within the damaged tissue and suppresses cell death. 【Claim 12】 The pharmaceutical composition of claim 9, wherein the inflammatory disease is one or more selected from the group consisting of sepsis, septic shock, inflammatory bowel disease (IBD), peritonitis, inflammatory kidney disease, acute bronchitis, chronic bronchitis, osteoarthritis, enteropathic spondylitis, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, acute lung injury and bronchopulmonary dysplasia. 【Claim 13】32 A pharmaceutical composition for preventing or treating a kidney disease, comprising the nanoplatform for targeting the inflammatory macrophage of any one of claims 1 to 8 as an active ingredient. 【Claim 14】 The pharmaceutical composition of claim 13, wherein the kidney disease is one or more selected from the group consisting of nephritis, pyelonephritis, nephrotic syndrome, kidney cancer, acute pyelonephritis, chronic pyelonephritis, renal tuberculosis, urinary tract infection, urolithiasis, ureteral calculus, acute renal failure, chronic renal failure, diabetic nephropathy, renal fibrosis, chronic glomerulonephritis, rapidly progressive glomerulonephritis, nephrotic syndrome, focal segmental glomerulosclerosis, membranous nephropathy and membranoproliferative glomerulonephritis.

Description

1 【DESCRIPTION】 【Invention Title】 NANOPLATFORM FOR TARGETING INFLAMMATORY MACROPHAGES AND COMPOSITION FOR PREVENTING OR TREATING INFLAMMATORY DISEASES CONTAINING THE SAME 【Technical Field】 [0001] The present invention relates to a nanoplatform for targeting an inflammatory macrophage and a composition for preventing or treating inflammatory diseases using the same. 【Background Art】 [0002] Inflammation refers to the expression of the body's defense mechanism against internal and external stimuli such as external infections and endogenous metabolic by-products through various pathways. Various intracellular inflammatory regulatory factors act as mediators in this process, contributing to the causes of various diseases such as allergies, atopy, arthritis, kidney disease, brain disorders, circulatory disorders, and even cancer. [0003] Generally, the inflammatory response is a biological defense process aimed at repairing and regenerating damage caused by invasions that bring about structural changes to the body's cells or tissues. In this process, local blood vessels, various tissue cells in bodily fluids and immune cells are involved. While an inflammatory response induced by external invading pathogens serves as a defense system to protect the body under normal conditions, an abnormally excessive inflammatory response can lead to various diseases, which are collectively referred to as inflammatory diseases. [0004] The onset of many inflammation-related diseases is associated with the activation of macrophages and the consequent excessive production of inflammation-related factors. Representative inflammatory factors include interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and nitrogen oxide (NO). [0005] The kidney is an organ responsible for excreting waste products and maintaining2 homeostasis in the body. Kidney diseases occur due to a reduction in the filtration function of the glomeruli, the main structural units of the kidney, and can be broadly classified into acute kidney injury (AKI) and chronic kidney disease (CKD) based on the rate of kidney function impairment. [0006] Acute kidney injury (AKI) refers to a rapid decline in kidney function occurring over a short period, such as a few hours or days. The prevalence of AKI is increasing annually regardless of gender or age and is observed in approximately 10% of hospitalized patients. Even if AKI patients recover, they may progress to chronic kidney disease (CKD) or end-stage renal disease (ESRD). If recovery does not occur, the risk of permanent kidney damage or mortality significantly increases. Chronic kidney disease (CKD) is a condition in which the glomerular filtration function gradually declines, ultimately leading to irreversible loss of kidney function. According to data tracked by the U.S. National Institutes of Health (NIH) until 2008, the risk of developing CKD increases in individuals with other illnesses. For instance, it has been reported that 1 in 3 diabetic patients and 1 in 5 hypertensive patients are affected by CKD. [0007] Additionally, the number of patients with end-stage renal disease (ESRD) has shown a sharp increase over the past 20 years. In South Korea, the number of dialysis patients rose significantly from 64,679 in 2014 to 87,720 in 2019. ESRD patients impose a substantial burden on the healthcare system and society due to their high mortality rate and medical expenses. [0008] Kidney fibrosis, a type of kidney disease, is considered the final common pathway. While early detection of the causes of kidney disease may allow recovery through appropriate treatment, if moderate or more severe chronic kidney disease (CKD) develops, it often progresses to end-stage renal disease (ESRD) or leads to death due to cardiovascular complications. [0009] Proximal tubular epithelial cells, which are key components of kidney function, are3 characterized by a high density of mitochondria. In the pathophysiological background of kidney diseases such as acute kidney injury (AKI) and chronic kidney disease (CKD), mitochondrial alterations, damage, and dysfunction have been implicated. In particular, excessive activation of macrophages triggers inflammatory responses that can lead to mitochondrial damage. Prolonged mitochondrial damage induces oxidative stress, which in turn causes damage to proteins, lipids, and DNA in kidney cells, ultimately resulting in cellular apoptosis. [0010] Given the growing recognition of the importance of mitochondria in kidney diseases, there is a pressing need to develop fundamental therapeutics capable of regulating the progression of kidney diseases by improving mitochondrial homeostasis and function. 【Disclosure】 【Technical Problem】 [0011] Object of the present invention is to provide an albumin-based nanoplatform that selectively targets inflammatory macrophages. [0012] Another objective of the present invention is to provide a composition for preventing or treating inflammatory diseases, containing a na