Phage Display-Based Homing Peptide-Daunomycin Conjugates for Selective Drug Targeting to PANC-1 Pancreatic Cancer.

Levente E Dókus,Gitta Schlosser,Eszter Lajkó,Ivan Ranđelović,Diána Mező,László Kőhidai,József Tóvári,Gábor Mező

doi:10.3390/pharmaceutics12060576

Abstract

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.

Highlights

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most aggressive and dangerous cancerous diseases with a high mortality rate [1]
Five daunomycin-peptide conjugates were prepared for targeting PDAC cells
The potential homing peptide CKAAKN derived from phage display was modified by the replacement of Cys to Ser

Summary

Introduction

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most aggressive and dangerous cancerous diseases with a high mortality rate [1]. The main reason for the high mortality of pancreatic cancer patients could be very poor prognosis. Chemotherapy causes many side effects because of the low selectivity of the currently used drugs [5]. Targeted tumor therapy is based on targeting tumor-specific or overexpressed receptors or other cell surface compartments on tumor cells that can be recognized selectively by antibodies or small molecules like folic acid or peptides [9,10]. Drug molecules attached to these homing moieties can enter into tumor cells, resulting in selective toxicity without causing toxic side effects in healthy tissues. The application of small molecule drug conjugates (SMDCs) over antibody-drug conjugate (ADCs) may have an advantage in the treatment of PDAC because SMDCs have higher tissue permeability [11]

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