Implementing losartan potassium-laden pegylated nanocubic vesicles as a novel nanoplatform to alleviate cisplatin-induced nephrotoxicity via blocking apoptosis and activating the wnt/β-catenin/TCF-4 pathway.

Autor: Salem HF; Pharmaceutics and Industrial Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt. Electronic address: heba.salim@pharm.bsu.edu.eg., Nafady MM; Pharmaceutics and Industrial Pharmacy Department, Faculty of Pharmacy, Nahda University Beni-Suef, Egypt. Electronic address: mohamed.abdelfatah@nub.edu.eg., Khallaf RA; Pharmaceutics and Industrial Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt. Electronic address: Rasha.mahmoud@pharm.bsu.edu.eg., Abdel-Sattar AR; Pharmacology and Toxicology Department, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt. Electronic address: asmaa.ramdan@nub.edu.eg., Abdel-Sattar HH; Pharmaceutics and Industrial Pharmacy Department, Faculty of Pharmacy, Nahda University Beni-Suef, Egypt. Electronic address: hend.abdelsatar@nub.edu.eg., Eissa EM; Pharmaceutics and Industrial Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt. Electronic address: essam.mohamed@pharm.bsu.edu.eg.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2024 Oct 01; Vol. 354, pp. 122955. Date of Electronic Publication: 2024 Aug 08.
DOI: 10.1016/j.lfs.2024.122955
Abstrakt: Aims: Losartan potassium-laden pegylated nanocubic vesicles (LP-NCVs-PEG) have an intriguing kidney-targeted nanoplatform for acute renal injury via blocking apoptosis and activating wnt/β-catenin pathway.
Main Methods: Utilizing a thin-film hydration methodology established on 4 2 full factorial design to produce LP loaded nanocubic formulations (LP-NCVs) which composed mainly from L-α-phosphatidylcholine and poloxamer. The optimization process was designed to select the formulation with maximum entrapment efficiency (EE %), maximum in-vitro drug release (Q 8h ), and minimum vesicle size (VS). The optimum formulation was then pegylated to obtain LP-NCVs-PEG formulation that shields NCVs from the harsh ecosystem of the stomach, improves their oral drug delivery performance and targets the proximal renal tubules with no systemic toxicity. Male albino rats were injected with Cisplatin (6 mg/kg, i.p.) alone or with LP-formulations (5 mg/kg/day). Kidney injury markers, inflammatory markers, apoptotic markers. Besides renal tissue expression of Wnt, β-Catenin, GSK-3β, renal RNA gene expression of TCF-4, LEF-1 and histopathology were also analyzed to display pharmacological study.
Key Findings: The pharmacokinetics studies demonstrated that LP-NCVs-PEG boosted LP bioavailability approximately 3.61 times compared to LP oral solution. Besides LP-NCVs-PEG may have an intriguing kidney-targeted nanoplatform for acute renal injury via decreased renal toxicity markers, renal expression of LEF-1, GSK3-β, caspase, TNF-α, NF-κB and TUNEL expression. Alternatively, increased renal tissue level of Bcl-2, wnt, β-catenin and TCF-4.
Significance: LP-NCVs-PEG improved LP pharmacokinetics targeting the kidney and improved injury by activating wnt/β-catenin/TCF-4 pathway, blocking apoptosis, inflammation and renal toxicity markers suggesting it might be successful nephroprotective adjuvant therapy.
Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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