The Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most aggressive and dangerous
cancerous diseases, leading to a high rate of mortality. Therefore, the development
of new, more efficient treatment approaches is necessary to cure this illness. Peptide-based
drug targeting provides a new tool for this purpose. Previously, a hexapeptide Cys-Lys-Ala-Ala-Lys-Asn
(CKAAKN) was applied efficiently as the homing device for drug-loaded nanostructures
in PDAC cells. In this research, Cys was replaced by Ser in the sequence and this
new SKAAKN targeting moiety was used in conjugates containing daunomycin (Dau). Five
different structures were developed and tested. The results indicated that linear
versions with one Dau were not effective on PANC-1 cells in vitro; however, branched
conjugates with two Dau molecules showed significant antitumor activity. Differences
in the antitumor effect of the conjugates could be explained with the different cellular
uptake and lysosomal degradation. The most efficient conjugate was Dau=Aoa-GFLG-K(Dau=Aoa)SKAAKN-OH
(conjugate 4) that also showed significant tumor growth inhibition on s.c. implanted
PANC-1 tumor-bearing mice with negligible side effects. Our novel results suggest
that peptide-based drug delivery systems could be a promising tool for the treatment
of pancreatic cancers
