Despite favorable advancements in
therapy cancer is still not curative in many cases, which is often due to inadequate specificity for
tumor cells. In this study derivatives of a short cationic
peptide derived from the human
host defense peptide lactoferricin were optimized in their selective toxicity towards
cancer cells. We proved that the target of these
peptides is the negatively charged
membrane lipid phosphatidylserine (PS), specifically exposed on the surface of
cancer cells. We have studied the membrane interaction of three
peptides namely LF11-322, its N-acyl derivative 6-methyloctanoyl-LF11-322 and its retro repeat derivative R(etro)-DIM-P-LF11-322 with
liposomes mimicking cancerous and non-cancerous cell membranes composed of PS and
phosphatidylcholine (PC), respectively. Calorimetric and permeability studies showed that N-acylation and even more the repeat derivative of LF11-322 leads to strongly improved interaction with the
cancer mimic PS, whereas only the N-acyl derivative also slightly affects PC.
Tryptophan fluorescence of selective
peptide R-DIM-P-LF11-322 revealed specific
peptide penetration into the PS membrane interface and circular dichroism showed change of its secondary structure by increase of proportion of β-sheets just in the presence of the
cancer mimic. Data correlated with in vitro studies with cell lines of human
melanomas, their
metastases and melanocytes, revealing R-DIM-P-LF11-322 to exhibit strongly increased specificity for
cancer cells. This indicates the need of high affinity to the target PS, a minimum length and net positive charge, an adequate but moderate hydrophobicity, and capability of adoption of a defined structure exclusively in presence of the target membrane for high antitumor activity.