Chemotherapy-induced organ toxicity mitigation
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PLGA-based nanoencapsulation enhanced the nephroprotective efficacy of OLM against MTX-induced nephrotoxicity and was associated with the modulation of the AT1R/ERK1/2 signaling axis.
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Background/Objectives: Methotrexate (MTX) is an effective antineoplastic and immunosuppressive agent whose clinical use can be limited by nephrotoxicity. Increasing evidence suggests that dysregulated angiotensin II-mediated signaling contributes to MTX-induced renal injury. Olmesartan (OLM), an angiotensin II type 1 receptor (AT1R) blocker, possesses renoprotective properties; however, its therapeutic efficacy may be limited by suboptimal pharmacokinetics and tissue deli\very. This study aimed to develop OLM-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (OLM-PLGA) and investigate their nephroprotective efficacy and underlying molecular mechanisms in MTX-induced nephrotoxicity. Methods: OLM-PLGA nanoparticles were prepared and evaluated for their physicochemical characteristics. The in vivo nephroprotective effects of OLM-PLGA were investigated in male Sprague–Dawley rats, which were allocated into four groups: OLM (10 mg/kg), OLM-PLGA (10 mg/kg), MTX-treated, and normal control. Renal function, oxidative stress, inflammation, apoptosis, and fibrosis were assessed, together with renal gene expression of AT1R and extracellular signal-regulated kinase 1/2 (ERK1/2). Results: Compared with free OLM, OLM-PLGA provided superior protection against MTX-induced renal dysfunction and oxidative stress, as evidenced by improved renal function and enhanced antioxidant defense. OLM-PLGA also exerted greater anti-inflammatory and anti-apoptotic effects and attenuated renal fibrotic changes, accompanied by reduced renal expression of α-smooth muscle actin and collagen. These protective effects were associated with decreased AT1R gene expression and suppression of downstream ERK1/2 signaling. Conclusions: PLGA-based nanoencapsulation enhanced the nephroprotective efficacy of OLM against MTX-induced nephrotoxicity and was associated with the modulation of the AT1R/ERK1/2 signaling axis. OLM-PLGA may therefore represent a promising nanotherapeutic approach for improving OLM delivery and renal protection during MTX treatment.
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@article{Alawad2026Olmesartan,
title = {Olmesartan-Loaded PLGA Nanoparticles Attenuate Methotrexate-Induced Kidney Injury: Association with the AT1R/ERK1/2 Signaling Axis},
author = {Omar M. Alawad and Norhan Tantawy and Soha Elsalhy and Asmaa A. Ahmed and Shahira Nofal and Eman M. Raafat},
journal = {Pharmaceuticals},
year = {2026},
doi = {10.3390/ph19091462},
url = {https://doi.org/10.3390/ph19091462}
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