Kidney-Targeted Epoxyeicosatrienoic Acid Analog, EET-F01, Reduces Inflammation, Oxidative Stress, and Cisplatin-Induced Nephrotoxicity

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.

Multi-Target Drugs for Kidney Diseases

“…66,67 Kidney targeting with folate conjugation has been successful demonstrated with EET analogs. 68 An alternative strategy small molecules that might limit unwanted side effects is to develop multi-target biologics and RNA-based therapies for kidney diseases. Biologics such as monoclonal antibodies and nanobodies that act on single target are advancing kidney diseases with improvements in bioavailability and tissue targeting.…”

Synthesis and Antitumor Activity of (3-Hydroxyacrylato-O,O′) Diammineplatinum(II)

“…The binding of the 3-hydroxyacrylate to platinum atoms as a bidentate ligand was confirmed by the shift of ν C¼O to lower frequencies and the absence of ν O-H absorption in IR spectra in the resulting complexes. 4 All complexes showed [M þ H] þ peaks, corresponding to their molecular weights, and had three typical protonated molecular ion peaks reflecting the platinum isotopes: 194 Pt(33%), 195 Pt (34%), and 196 Pt (25%). 1 H and 13 C NMR spectral peaks matched the chemical structures given in ►Fig.…”

“…1,2 However, it still has nonnegligible toxic and side effects such as nephrotoxicity, emetogenicity, and drug resistance, which cripple its overall effectiveness in cancer therapy. [3][4][5][6] For decades, thousands of platinum(II) complexes have been prepared in the hope of finding those with more tolerable toxicological profile and higher efficacy. 7 These efforts have brought several new drugs (carboplatin, oxaliplatin, nedaplatin, and lobaplatin) into market, [8][9][10] followed by several new complexes emerging in current clinical trials (►Fig.…”

Effects of Epoxyeicosatrienoic Acid-Enhancing Therapy on the Course of Congestive Heart Failure in Angiotensin II-Dependent Rat Hypertension: From mRNA Analysis towards Functional In Vivo Evaluation

“…Therefore, an alternative approach, which circumvents this limitation, consists of applying EETs-agonistic analogs designed to resist degradation. This new approach has not yet been adequately explored: the obtained results were not entirely consistent and not yet comprehensively evaluated in HF [20][21][22][23][24][25].…”