In Vivo Imaging of Small Molecular Weight Peptides for Targeted Renal Drug Delivery: A Study in Normal and Polycystic Kidney Diseased Mice

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a leading monogenetic cause of end-stage renal disease with limited therapeutic repertoire. A targeted drug delivery strategy that directs a small molecule to renal niches around cysts could increase the safety margins of agents that slow the progression of ADPKD but are poorly tolerated due to extrarenal toxicity. Herein, we determined whether previously characterized lysine-based and glutamic acid-based megalin-binding peptides can achieve renal-specific localization in the juvenile cystic kidney (JCK) mouse model of polycystic kidney disease and whether the distribution is altered compared with control mice. We performed in vivo optical and magnetic resonance imaging studies using peptides conjugated to the VivoTag 680 dye and demonstrated that megalin-interacting peptides distributed almost exclusively to the kidney cortex in both normal and JCK mice. Confocal analysis demonstrated that the peptide-dye conjugate distribution overlapped with megalin-positive renal proximal tubules. However, in the JCK mouse, the epithelium of renal cysts did not retain expression of the proximal tubule markers aquaporin 1 and megalin, and therefore these cysts did not retain peptide-dye conjugates. Furthermore, human kidney tumor tissues were evaluated by immunohistochemistry and revealed significant megalin expression in tissues from patients with renal cell carcinoma, raising the possibility that these tumors could be treated using this drug delivery strategy. Taken together, our data suggest that linking a small-molecule drug to these carrier peptides could represent a promising opportunity to develop a new platform for renal enrichment and targeting in the treatment of ADPKD and certain renal carcinomas.

Renal Artery Catheterization for Microcapsules’ Targeted Delivery to the Mouse Kidney

“…Firstly, the capsules’ administration through the renal artery provided a significantly greater fluorescence in the target kidney compared to the opposite during 24 h of observation, while 3 h after the free conjugate injection, the fluorescent signal in both kidneys became the equal. Several papers presented the results of an effective increase in the concentration of intravenously administered delivery systems based on polypeptides [ 78 , 79 ], nanoparticles [ 80 , 81 ], triblock amphiphilic polymers [ 82 ], micelles [ 83 ], and macrophage microvesicles [ 84 ]. However, the administered carriers are distributed equally in the both kidneys, which may not be desirable if only one kidney needs therapy.…”

Functional megalin is expressed in renal cysts in a mouse model of adult polycystic kidney disease

“…Megalin-mediated endocytosis has previously been explored experimentally in mice for kidney-specific drug delivery using peptide-based ligands, showing peptides accumulating almost exclusively within the kidneys [ 13 , 24 ], although megalin is also expressed in other absorptive epithelia [ 12 ]. While the above findings may suggest a similar capability of megalin to facilitate uptake of ADPKD-specific agents in renal cysts, our findings have some important limitations that must be considered.…”

Novel Drug Delivery Technologies and Targets for Renal Disease

“…The same peptide was also used for delivery to cysts in a model of polycystic kidney disease, where it targeted a fluorophore to the kidneys with very high renal specificity and colocalized with aquaporin in healthy and polycystic kidney disease kidneys. 92…”

“…The same peptide was also used for delivery to cysts in a model of polycystic kidney disease, where it targeted a fluorophore to the kidneys with very high renal specificity and colocalized with aquaporin in healthy and polycystic kidney disease kidneys. 92 The G3-C12 peptide (ANTPCGPYTHDCPVKR) was also shown to be effective for kidney targeting. 93 When fused peptide to captopril via a disulfide bond, the conjugate accumulated in the kidney via tubular reabsorption and released captopril, resulting in improved ACE inhibition relative to the untargeted drug.…”