Abstract
Although epoxyeicosatrienoic acid (EET) analogs have performed well in several acute and chronic kidney disease models, targeted delivery of EET analogs to the kidney can be reasonably expected to reduce the level of drug needed to achieve a therapeutic effect and obviate possible side effects. For EET analog kidney-targeted delivery, we conjugated a stable EET analog to folic acid via a PEG-diamine linker. Next, we compared the kidney targeted EET analog, EET-F01, to a well-studied EET analog, EET-A. EET-A or EET-F01 was infused i.v. and plasma and kidney tissue collected. EET-A was detected in the plasma but was undetectable in the kidney. On the other hand, EET-F01 was detected in the plasma and kidney. Experiments were conducted to compare the efficacy of EET-F01 and EET-A for decreasing cisplatin nephrotoxicity. Cisplatin was administered to WKY rats treated with vehicle, EET-A (10 mg/kg i.p.) or EET-F01 (20 mg/kg or 2 mg/kg i.p.). Cisplatin increased kidney injury markers, viz., blood urea nitrogen (BUN), N-acetyl-β-(D)-glucosaminidase (NAG), kidney injury molecule-1 (KIM-1), and thiobarbituric acid reactive substances (TBARS). EET-F01 was as effective as EET-A in decreasing BUN, NAG, KIM-1, TBARS, and renal histological injury caused by cisplatin. Despite its almost 2×-greater molecular weight compared with EET-A, EET-F01 was comparably effective in decreasing renal injury at a 10-fold w/w lower dose. EET-F01 decreased cisplatin nephrotoxicity by reducing oxidative stress and inflammation. These data demonstrate that EET-F01 targets the kidney, allows for a lower effective dose, and combats cisplatin nephrotoxicity. In conclusion, we have developed a kidney targeted EET analog, EET-F01, that demonstrates excellent potential as a therapeutic for kidney diseases.
Highlights
Renal disease in cancer patients and survivors has emerged as a major healthcare issue and continues to escalate sharply [1,2,3]
Nephrotoxicity that involves acute kidney injury that progresses to chronic kidney disease is the most common and severe organ toxicity associated with cisplatin therapy [4,5,6,17]
Cisplatin nephrotoxicity occurs because epithelial cells uptake cisplatin which results in renal inflammation, oxidative stress, and tubular damage [4,5,6,17]
Summary
Renal disease in cancer patients and survivors has emerged as a major healthcare issue and continues to escalate sharply [1,2,3]. Anti-cancer drugs, vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFRI) and platinum derivatives can cause severe renal injury that significantly compromises their effective and safe use [3,4,5]. There is a significant clinical need for novel therapies to effectively treat and stop kidney disease in cancer patients. This healthcare issue has led to the development, evolution, and emergence of a subspecialty, OncoNephrology [5]. Our ongoing research is attacking this emerging cancer arena and we are focused on developing epoxyeicosatrienoic acid (EET)
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