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

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...

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Autores principales: Dókus, Levente E., Lajkó, Eszter, Ranđelović, Ivan, Mező, Diána, Schlosser, Gitta, Kőhidai, László, Tóvári, József, Mező, Gábor
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355684/
https://www.ncbi.nlm.nih.gov/pubmed/32580307
http://dx.doi.org/10.3390/pharmaceutics12060576
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author Dókus, Levente E.
Lajkó, Eszter
Ranđelović, Ivan
Mező, Diána
Schlosser, Gitta
Kőhidai, László
Tóvári, József
Mező, Gábor
author_facet Dókus, Levente E.
Lajkó, Eszter
Ranđelović, Ivan
Mező, Diána
Schlosser, Gitta
Kőhidai, László
Tóvári, József
Mező, Gábor
author_sort Dókus, Levente E.
collection PubMed
description 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.
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spelling pubmed-73556842020-07-23 Phage Display-Based Homing Peptide-Daunomycin Conjugates for Selective Drug Targeting to PANC-1 Pancreatic Cancer Dókus, Levente E. Lajkó, Eszter Ranđelović, Ivan Mező, Diána Schlosser, Gitta Kőhidai, László Tóvári, József Mező, Gábor Pharmaceutics Article 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. MDPI 2020-06-22 /pmc/articles/PMC7355684/ /pubmed/32580307 http://dx.doi.org/10.3390/pharmaceutics12060576 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dókus, Levente E.
Lajkó, Eszter
Ranđelović, Ivan
Mező, Diána
Schlosser, Gitta
Kőhidai, László
Tóvári, József
Mező, Gábor
Phage Display-Based Homing Peptide-Daunomycin Conjugates for Selective Drug Targeting to PANC-1 Pancreatic Cancer
title Phage Display-Based Homing Peptide-Daunomycin Conjugates for Selective Drug Targeting to PANC-1 Pancreatic Cancer
title_full Phage Display-Based Homing Peptide-Daunomycin Conjugates for Selective Drug Targeting to PANC-1 Pancreatic Cancer
title_fullStr Phage Display-Based Homing Peptide-Daunomycin Conjugates for Selective Drug Targeting to PANC-1 Pancreatic Cancer
title_full_unstemmed Phage Display-Based Homing Peptide-Daunomycin Conjugates for Selective Drug Targeting to PANC-1 Pancreatic Cancer
title_short Phage Display-Based Homing Peptide-Daunomycin Conjugates for Selective Drug Targeting to PANC-1 Pancreatic Cancer
title_sort phage display-based homing peptide-daunomycin conjugates for selective drug targeting to panc-1 pancreatic cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355684/
https://www.ncbi.nlm.nih.gov/pubmed/32580307
http://dx.doi.org/10.3390/pharmaceutics12060576
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