Drug Conjugation Affects Pharmacokinetics and Specificity of Kidney-Targeted Peptide Carriers

Abstract

Peptides play a crucial role as biological vectors for targeted drug delivery. In particular, in cases of specific receptor expression, peptides are highly potent carriers for drug targeting approaches. Kidney-targeted peptides require specific attention because of the necessity of fine-tuning their behavior with respect to extraction and retention in the complex architecture of the kidneys. To enable optimal carrier capacity and targeting specificity, this study focuses on pharmacokinetic profiles of different kidney-specific peptides and examines the impact of drug conjugation. γ-Scintigraphy was used to compare the pharmacokinetics and specificity prior to and after drug conjugation of the model drug α-lipoic acid. The results revealed that drug conjugation dramatically affects the targeting specificity, in the worst case leading to a total loss of kidney specificity. Nevertheless, efficient drug transport was achieved with the novel kidney carrier (KKEEE)K, even with a multiple-drug loading of α-lipoic acid after intraveous and intraperitoneal administration. In contrast to other peptidic molecules, (KKEEE)K demonstrated its significant potential as a promising carrier candidate for kidney-targeted drug delivery to proximal tubule cells, especially for the treatment of severe kidney diseases.

The effect of size, charge, and peptide ligand length on kidney targeting by small, organic nanoparticles

“…3 K peptide was found to target the kidney in part through megalin, a multiligand receptor that is present on the plasma membrane of proximal tubule cells, and the (KKEEE) 3 K peptide showed significantly reduced uptake in megalindeficient mice 19,20,[51][52][53]. As demonstrated by Vegt et al, megalin has been reported to associate with a library of peptides (octreotide, octreotate, minigastrin, exendin, and neurotensin) of varying charges 54.…”

A Pretargeted Imaging Strategy for EGFR Positive Colorectal Carcinoma via the Modulation of Tz-radioligand Pharmacokinetics

“…In addition, the authors found that uncharged Al[ 18 F]-NOTA-lysine-Tz was excreted mainly through the liver and intestines, while charged Al[ 18 F]-NOTA-(lysine) 2 -Tz (net charge: +1) and Al[ 18 F]-NOTA-(lysine) 3 -Tz (net charge: +2) were excreted mainly through the kidneys [26]. Besides, it has been reported that renal uptake and excretion may be related to the presence of lysine residues in the molecular structure [27,28].…”

A Pretargeted Imaging Strategy for EGFR Positive Colorectal Carcinoma via the Modulation of Tz-radioligand Pharmacokinetics

“…In a pharmacokinetic profile study including 25 different Tz derivatives radiolabeled with either Al[ 18 F] or 68 Ga, Meyer et al [30] observed that 68 Ga-NODA-Tz was excreted through renal pathway and Al (lysine) 3 -Tz (net charge: +2) were excreted mainly through the kidneys [30]. Besides, it has been reported that renal uptake and excretion may be related to the presence of lysine residues in the molecular structure [31,32].…”