TY  - JOUR
A1  - Hoyer, Jan
A1  - Schatzschneider, Ulrich
A1  - Schulz-Siegmund, Michaela
A1  - Neundorf, Ines
T1  - Dimerization of a cell-penetrating peptide leads to enhanced cellular uptake and drug delivery
JF  - Beilstein Journal of Organic Chemistry
N2  - 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 IC\(_{50}\) 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.
KW  - peptides
KW  - internalization studies
KW  - drug delivery
KW  - cell-penetrating peptides
KW  - anti-tumor agents
KW  - organometallic complexes
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133933
VL  - 8
ER  -