A polymeric dexamethasone prodrug attenuates focal segmental glomerulosclerosis (FSGS) in an Adriamycin-induced mouse model with minimal glucocorticoid side effects
Focal segmental glomerulosclerosis (FSGS) is chronic renal injury characterized by proteinuria and podocyte injury with glomerulus scarring and tubulointerstitial fibrosis. Glucocorticoids (GCs) are the current first-line treatment. Long-term use of GCs, however, is associated with numerous off-targ...
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2025-03-01
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| author | Haochen Jiang Xin Fu Salma Althobaiti Braeden Pinkerton Shabnam Arash Xiaoqing Du Zhenshan Jia Fang Yu Kirk W. Foster Geoffrey M. Thiele Troy J. Plumb Dong Wang |
| author_facet | Haochen Jiang Xin Fu Salma Althobaiti Braeden Pinkerton Shabnam Arash Xiaoqing Du Zhenshan Jia Fang Yu Kirk W. Foster Geoffrey M. Thiele Troy J. Plumb Dong Wang |
| author_sort | Haochen Jiang |
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| description | Focal segmental glomerulosclerosis (FSGS) is chronic renal injury characterized by proteinuria and podocyte injury with glomerulus scarring and tubulointerstitial fibrosis. Glucocorticoids (GCs) are the current first-line treatment. Long-term use of GCs, however, is associated with numerous off-target adverse effects. Thus, there is an urgent unmet clinical need for novel FSGS therapies. Recognizing potent efficacy of GCs in managing FSGS, we proposed the use of a polyethylene glycol (PEG)-based nephrotropic dexamethasone (Dex) prodrug (ZSJ-0228 or PEG-Dex) to mitigate the GC side effects. The focus of the present study was to assess the therapeutic efficacy and safety of PEG-Dex in an Adriamycin-induced BALB/c mouse model of FSGS. A single dose of PEG-Dex treatment (35 mg/kg Dex dose equivalent) effectively reduced the proteinuria level, ameliorated FSGS lesions and restored kidney function when compared to the dose equivalent daily Dex treatment and Saline control. Additionally, PEG-Dex treatment also showed a much-improved safety profile than Dex with minimal adverse events detected. Collectively, these data suggest that PEG-Dex may be established as a promising drug candidate for more effective and safe clinical treatment of FSGS. |
| format | Article |
| id | doaj-art-803f2f401d794a22959422e3d2ae91b3 |
| institution | Kabale University |
| issn | 2590-1834 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | KeAi Communications Co., Ltd. |
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| series | Smart Materials in Medicine |
| spelling | doaj-art-803f2f401d794a22959422e3d2ae91b32025-08-20T03:44:35ZengKeAi Communications Co., Ltd.Smart Materials in Medicine2590-18342025-03-0161566610.1016/j.smaim.2025.02.003A polymeric dexamethasone prodrug attenuates focal segmental glomerulosclerosis (FSGS) in an Adriamycin-induced mouse model with minimal glucocorticoid side effectsHaochen Jiang0Xin Fu1Salma Althobaiti2Braeden Pinkerton3Shabnam Arash4Xiaoqing Du5Zhenshan Jia6Fang Yu7Kirk W. Foster8Geoffrey M. Thiele9Troy J. Plumb10Dong Wang11Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USADepartment of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE, 68198, USADepartment of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USADivision of Rheumatology and Immunology, Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Veterans Affairs (VA) Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USADivision of Nephrology, Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE, 68198, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USA; Corresponding author. Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 986125 Nebraska Medical Center, PDD 3020, Omaha, NE, 68198-6125, USA.Focal segmental glomerulosclerosis (FSGS) is chronic renal injury characterized by proteinuria and podocyte injury with glomerulus scarring and tubulointerstitial fibrosis. Glucocorticoids (GCs) are the current first-line treatment. Long-term use of GCs, however, is associated with numerous off-target adverse effects. Thus, there is an urgent unmet clinical need for novel FSGS therapies. Recognizing potent efficacy of GCs in managing FSGS, we proposed the use of a polyethylene glycol (PEG)-based nephrotropic dexamethasone (Dex) prodrug (ZSJ-0228 or PEG-Dex) to mitigate the GC side effects. The focus of the present study was to assess the therapeutic efficacy and safety of PEG-Dex in an Adriamycin-induced BALB/c mouse model of FSGS. A single dose of PEG-Dex treatment (35 mg/kg Dex dose equivalent) effectively reduced the proteinuria level, ameliorated FSGS lesions and restored kidney function when compared to the dose equivalent daily Dex treatment and Saline control. Additionally, PEG-Dex treatment also showed a much-improved safety profile than Dex with minimal adverse events detected. Collectively, these data suggest that PEG-Dex may be established as a promising drug candidate for more effective and safe clinical treatment of FSGS.http://www.sciencedirect.com/science/article/pii/S2590183425000055DexamethasoneGlucocorticoidsFocal segmental glomerulosclerosis (FSGS)Polymeric prodrugToxicity |
| spellingShingle | Haochen Jiang Xin Fu Salma Althobaiti Braeden Pinkerton Shabnam Arash Xiaoqing Du Zhenshan Jia Fang Yu Kirk W. Foster Geoffrey M. Thiele Troy J. Plumb Dong Wang A polymeric dexamethasone prodrug attenuates focal segmental glomerulosclerosis (FSGS) in an Adriamycin-induced mouse model with minimal glucocorticoid side effects Smart Materials in Medicine Dexamethasone Glucocorticoids Focal segmental glomerulosclerosis (FSGS) Polymeric prodrug Toxicity |
| title | A polymeric dexamethasone prodrug attenuates focal segmental glomerulosclerosis (FSGS) in an Adriamycin-induced mouse model with minimal glucocorticoid side effects |
| title_full | A polymeric dexamethasone prodrug attenuates focal segmental glomerulosclerosis (FSGS) in an Adriamycin-induced mouse model with minimal glucocorticoid side effects |
| title_fullStr | A polymeric dexamethasone prodrug attenuates focal segmental glomerulosclerosis (FSGS) in an Adriamycin-induced mouse model with minimal glucocorticoid side effects |
| title_full_unstemmed | A polymeric dexamethasone prodrug attenuates focal segmental glomerulosclerosis (FSGS) in an Adriamycin-induced mouse model with minimal glucocorticoid side effects |
| title_short | A polymeric dexamethasone prodrug attenuates focal segmental glomerulosclerosis (FSGS) in an Adriamycin-induced mouse model with minimal glucocorticoid side effects |
| title_sort | polymeric dexamethasone prodrug attenuates focal segmental glomerulosclerosis fsgs in an adriamycin induced mouse model with minimal glucocorticoid side effects |
| topic | Dexamethasone Glucocorticoids Focal segmental glomerulosclerosis (FSGS) Polymeric prodrug Toxicity |
| url | http://www.sciencedirect.com/science/article/pii/S2590183425000055 |
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