Abstract

Over the past 20 years, cell-penetrating peptides (CPPs) have gained tremendous interest due to their ability to deliver a variety of therapeutically active molecules that would otherwise be unable to cross the cellular membrane due to their size or hydrophilicity. Recently, we reported on the identification of a novel CPP, sC18, which is derived from the C-terminus of the 18 kDa cationic antimicrobial protein. Furthermore, we demonstrated successful application of sC18 for the delivery of functionalized cyclopentadienyl manganese tricarbonyl (cymantrene) complexes to tumor cell lines, inducing high cellular toxicity. In order to increase the potential of the organometallic complexes to kill tumor cells, we were looking for a way to enhance cellular uptake. Therefore, we designed a branched dimeric variant of sC18, (sC18)2, which was shown to have a dramatically improved capacity to internalize into various cell lines, even primary cells, using flow cytometry and fluorescence microscopy. Cell viability assays indicated increased cytotoxicity of the dimer presumably caused by membrane leakage; however, this effect turned out to be dependent on the specific cell type. Finally, we could show that conjugation of a functionalized cymantrene with (sC18)2 leads to significant reduction of its IC50 value in tumor cells compared to the respective sC18 conjugate, proving that dimerization is a useful method to increase the drug-delivery potential of a cell-penetrating peptide.

Highlights

  • A substantial problem concerning promising drug candidates is often their incapacity to reach their full therapeutic potential due to limited bioavailability and cellular uptake

  • Cell-penetrating peptides (CPPs) emerged as an encouraging tool to overcome this obstacle owing to their ability to autonomously cross the cellular membrane in a receptor-independent manner

  • Endocytic and non-endocytic processes have been proposed to be involved in cellular uptake; the exact mechanism triggering internalization is still under debate and was shown to depend on several factors such as structure and concentration of the cell-penetrating peptides (CPPs) as well as the cargo to be transported and the specific cell line [7]

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Summary

Introduction

A substantial problem concerning promising drug candidates is often their incapacity to reach their full therapeutic potential due to limited bioavailability and cellular uptake. At least for HEK-293 and MCF-7, this effect seemed to be in no way related to different intracellular amounts of peptide since both cell lines showed equal propensity to take up (sC18)2 as was shown above.

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