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

• Published in: Life sciences (1973) Vol. 354; p. 122955
• Main Authors: Salem, Heba F., Nafady, Mohamed M., Khallaf, Rasha A., Abdel-Sattar, Asmaa Ramadan, Abdel-Sattar, Hend Hassan, Eissa, Essam M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.10.2024
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - drug therapy; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Acute Kidney Injury - prevention & control; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; beta Catenin - metabolism; Cisplatin; Drug Liberation; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidney injury; Losartan - pharmacology; Losartan potassium; Male; Nanoparticles - chemistry; Polyethylene Glycols - chemistry; Rats; Rats, Wistar; TCF-4; Transcription Factor 4 - metabolism; Wnt; Wnt Signaling Pathway - drug effects; TCF-4; Losartan potassium; Wnt; Kidney injury; Cisplatin; Apoptosis
• ISSN: 0024-3205; 1879-0631; 1879-0631
• DOI: 10.1016/j.lfs.2024.122955

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. Utilizing a thin-film hydration methodology established on 42 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 (Q8h), 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. 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. 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. [Display omitted]