Characterisation of the cell and molecular biological effect of peptide-based daunorubicin conjugates developed for targeting pancreatic adenocarcinoma (PANC-1) cell line

Pancreatic adenocarcinoma is one of the tumours with the worst prognosis, with a 5-year survival rate of 5–10%. Our aim was to find and optimise peptide-based drug conjugates with daunorubicin (Dau) as the cytotoxic antitumour agent. When conjugated with targeting peptides, the side effect profile and pharmacokinetics of Dau can be improved. The targeting peptide sequences (e.g. GSSEQLYL) we studied were originally selected by phage display. By Ala-scan technique, we identified that position 6 in the parental sequence (Dau=Aoa-LRRY-GSSEQLYL-NH2, ConjA) could be modified without the loss of antitumour activity (Dau=Aoa-LRRY-GSSEQAYL-NH2, Conj03: 14. 9% viability). Our results showed that the incorporation of p-chloro-phenylalanine (Dau=Aoa-LRRY-GSSEQF(pCl)YL-NH2, Conj16) further increased the antitumour potency (10−5 M: 9.7% viability) on pancreatic adenocarcinoma cells (PANC-1). We found that conjugates containing modified GSSEQLYL sequences could be internalised to PANC-1 cells and induce cellular senescence in the short term and subsequent apoptotic cell death. Furthermore, the cardiotoxic effect of Dau was markedly reduced in the form of peptide conjugates. In conclusion, Conj16 had the most effective antitumor activity on PANC-1 cells, which makes this conjugate promising for developing new targeted therapies without cardiotoxic effects. [Display omitted] •The modification in position six with chlorination (Conj16) had the best outcome.•Conj16 is the most effective on the pancreas adenocarcinoma cell line (PANC-1).•Conjugation of daunorubicin to the targeting peptides reduced cardiotoxicity.•The three most promising conjugates act more selectively against PANC-1 cells.•Conj16 induced short-term senescence followed by apoptotic cell death.