title: A kidney-selective biopolymer for targeted drug delivery.
abstract: Improving drug delivery to the kidney using renal-targeted therapeutics is a promising but underdeveloped area. We aimed to develop a kidney-targeting construct for renal-specific drug delivery. Elastin-like polypeptides (ELPs) are nonimmunogenic protein-based carriers that can stabilize attached small-molecule and peptide therapeutics. We modified ELP at its NH2-terminus with a cyclic, seven-amino acid kidney-targeting peptide (KTP) and at its COOH-terminus with a cysteine residue for tracer conjugation. Comparative in vivo pharmacokinetics and biodistribution in rat and swine models and in vitro cell binding studies using human renal cells were performed. KTP-ELP had a longer plasma half-life than ELP in both animal models and was similarly accumulated in kidneys at levels fivefold higher than untargeted ELP, showing renal levels 15- to over 150-fold higher than in other major organs. Renal fluorescence histology demonstrated high accumulation of KTP-ELP in proximal tubules and vascular endothelium. Furthermore, a 14-day infusion of a high dose of ELP or KTP-ELP did not affect body weight, glomerular filtration rate, or albuminuria, or induce renal tissue damage compared with saline-treated controls. In vitro experiments showed higher binding of KTP-ELP to human podocytes, proximal tubule epithelial, and glomerular microvascular endothelial cells than untargeted ELP. These results show the high renal selectivity of KTP-ELP, support the notion that the construct is not species specific, and demonstrate that it does not induce acute renal toxicity. The plasticity of ELP for attachment of any class of therapeutics unlocks the possibility of applying ELP technology for targeted treatment of renal disease in future studies.
authors: Department of Neurology, University of Mississippi Medical Center, Jackson, Mississippi; gbidwell@umc.edu.|Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi.
authors: Gene L
authors: 0000-0001-9104-150X
authors: GL
authors: Bidwell
authors: Department of Neurology, University of Mississippi Medical Center, Jackson, Mississippi.
authors: Fakhri
authors: F
authors: Mahdi
authors: Department of Neurology, University of Mississippi Medical Center, Jackson, Mississippi.
authors: Qingmei
authors: Q
authors: Shao
authors: Department of Neurology, University of Mississippi Medical Center, Jackson, Mississippi.
authors: Omar C
authors: OC
authors: Logue
authors: Department of Neurology, University of Mississippi Medical Center, Jackson, Mississippi.
authors: Jamarius P
authors: JP
authors: Waller
authors: Belhaven University, Jackson, Mississippi; and.
authors: Caleb
authors: C
authors: Reese
authors: Departments of Physiology and Biophysics, Medicine, and Radiology, University of Mississippi Medical Center, Jackson, Mississippi.
authors: Alejandro R
authors: AR
authors: Chade
mesh_terms: D000818:Animals; D001704:Biopolymers / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D004549:Elastin / Q000378:metabolism*; D006207:Half-Life; D007668:Kidney / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D013552:Swine; D014018:Tissue Distribution / Q000502:physiology
chemical_list: D001704:Biopolymers; D010455:Peptides; D011506:Proteins; C103822:endozepine-like peptide ELP; D004549:Elastin
keywords: biopolymer; drug delivery; elastin-like polypeptide; kidney targeting peptide; renal disease