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Biological Evaluation of Naproxen–Dehydrodipeptide Conjugates with Self-Hydrogelation Capacity as Dual LOX/COX Inhibitors

The use of peptide–drug conjugates is emerging as a powerful strategy for targeted drug delivery. Previously, we have found that peptides conjugated to a non-steroidal anti-inflammatory drug (NSAID), more specifically naproxen–dehydrodipeptide conjugates, readily form nanostructured fibrilar supramo...

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Autores principales: Moreira, Rute, Jervis, Peter J., Carvalho, André, Ferreira, Paula M. T., Martins, José A., Valentão, Patrícia, Andrade, Paula B., Pereira, David M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076388/
https://www.ncbi.nlm.nih.gov/pubmed/32028608
http://dx.doi.org/10.3390/pharmaceutics12020122
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author Moreira, Rute
Jervis, Peter J.
Carvalho, André
Ferreira, Paula M. T.
Martins, José A.
Valentão, Patrícia
Andrade, Paula B.
Pereira, David M.
author_facet Moreira, Rute
Jervis, Peter J.
Carvalho, André
Ferreira, Paula M. T.
Martins, José A.
Valentão, Patrícia
Andrade, Paula B.
Pereira, David M.
author_sort Moreira, Rute
collection PubMed
description The use of peptide–drug conjugates is emerging as a powerful strategy for targeted drug delivery. Previously, we have found that peptides conjugated to a non-steroidal anti-inflammatory drug (NSAID), more specifically naproxen–dehydrodipeptide conjugates, readily form nanostructured fibrilar supramolecular hydrogels. These hydrogels were revealed as efficacious nano-carriers for drug delivery applications. Moreover, the incorporation of superparamagnetic iron oxide nanoparticles (SPIONs) rendered the hydrogels responsive to external magnetic fields, undergoing gel-to-solution phase transition upon remote magnetic excitation. Thus, magnetic dehydrodipeptide-based hydrogels may find interesting applications as responsive Magnetic Resonance Imaging (MRI) contrast agents and for magnetic hyperthermia-triggered drug-release applications. Supramolecular hydrogels where the hydrogelator molecule is endowed with intrinsic pharmacological properties can potentially fulfill a dual function in drug delivery systems as (passive) nanocariers for incorporated drugs and as active drugs themselves. In this present study, we investigated the pharmacological activities of a panel of naproxen–dehydrodipeptide conjugates, previously studied for their hydrogelation ability and as nanocarriers for drug-delivery applications. A focused library of dehydrodipeptides, containing N-terminal canonical amino acids (Phe, Tyr, Trp, Ala, Asp, Lys, Met) N-capped with naproxen and linked to a C-terminal dehydroaminoacid (ΔPhe, ΔAbu), were evaluated for their anti-inflammatory and anti-cancer activities, as well as for their cytotoxicity to non-cancer cells, using a variety of enzymatic and cellular assays. All compounds except one were able to significantly inhibit lipoxygenase (LOX) enzyme at a similar level to naproxen. One of the compounds 4 was able to inhibit the cyclooxygenase-2 (COX-2) to a greater extent than naproxen, without inhibiting cyclooxygenase-1 (COX-1), and therefore is a potential lead in the search for selective COX-2 inhibitors. This hydrogelator is a potential candidate for dual COX/LOX inhibition as an optimised strategy for treating inflammatory conditions.
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spelling pubmed-70763882020-03-24 Biological Evaluation of Naproxen–Dehydrodipeptide Conjugates with Self-Hydrogelation Capacity as Dual LOX/COX Inhibitors Moreira, Rute Jervis, Peter J. Carvalho, André Ferreira, Paula M. T. Martins, José A. Valentão, Patrícia Andrade, Paula B. Pereira, David M. Pharmaceutics Article The use of peptide–drug conjugates is emerging as a powerful strategy for targeted drug delivery. Previously, we have found that peptides conjugated to a non-steroidal anti-inflammatory drug (NSAID), more specifically naproxen–dehydrodipeptide conjugates, readily form nanostructured fibrilar supramolecular hydrogels. These hydrogels were revealed as efficacious nano-carriers for drug delivery applications. Moreover, the incorporation of superparamagnetic iron oxide nanoparticles (SPIONs) rendered the hydrogels responsive to external magnetic fields, undergoing gel-to-solution phase transition upon remote magnetic excitation. Thus, magnetic dehydrodipeptide-based hydrogels may find interesting applications as responsive Magnetic Resonance Imaging (MRI) contrast agents and for magnetic hyperthermia-triggered drug-release applications. Supramolecular hydrogels where the hydrogelator molecule is endowed with intrinsic pharmacological properties can potentially fulfill a dual function in drug delivery systems as (passive) nanocariers for incorporated drugs and as active drugs themselves. In this present study, we investigated the pharmacological activities of a panel of naproxen–dehydrodipeptide conjugates, previously studied for their hydrogelation ability and as nanocarriers for drug-delivery applications. A focused library of dehydrodipeptides, containing N-terminal canonical amino acids (Phe, Tyr, Trp, Ala, Asp, Lys, Met) N-capped with naproxen and linked to a C-terminal dehydroaminoacid (ΔPhe, ΔAbu), were evaluated for their anti-inflammatory and anti-cancer activities, as well as for their cytotoxicity to non-cancer cells, using a variety of enzymatic and cellular assays. All compounds except one were able to significantly inhibit lipoxygenase (LOX) enzyme at a similar level to naproxen. One of the compounds 4 was able to inhibit the cyclooxygenase-2 (COX-2) to a greater extent than naproxen, without inhibiting cyclooxygenase-1 (COX-1), and therefore is a potential lead in the search for selective COX-2 inhibitors. This hydrogelator is a potential candidate for dual COX/LOX inhibition as an optimised strategy for treating inflammatory conditions. MDPI 2020-02-03 /pmc/articles/PMC7076388/ /pubmed/32028608 http://dx.doi.org/10.3390/pharmaceutics12020122 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
Moreira, Rute
Jervis, Peter J.
Carvalho, André
Ferreira, Paula M. T.
Martins, José A.
Valentão, Patrícia
Andrade, Paula B.
Pereira, David M.
Biological Evaluation of Naproxen–Dehydrodipeptide Conjugates with Self-Hydrogelation Capacity as Dual LOX/COX Inhibitors
title Biological Evaluation of Naproxen–Dehydrodipeptide Conjugates with Self-Hydrogelation Capacity as Dual LOX/COX Inhibitors
title_full Biological Evaluation of Naproxen–Dehydrodipeptide Conjugates with Self-Hydrogelation Capacity as Dual LOX/COX Inhibitors
title_fullStr Biological Evaluation of Naproxen–Dehydrodipeptide Conjugates with Self-Hydrogelation Capacity as Dual LOX/COX Inhibitors
title_full_unstemmed Biological Evaluation of Naproxen–Dehydrodipeptide Conjugates with Self-Hydrogelation Capacity as Dual LOX/COX Inhibitors
title_short Biological Evaluation of Naproxen–Dehydrodipeptide Conjugates with Self-Hydrogelation Capacity as Dual LOX/COX Inhibitors
title_sort biological evaluation of naproxen–dehydrodipeptide conjugates with self-hydrogelation capacity as dual lox/cox inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076388/
https://www.ncbi.nlm.nih.gov/pubmed/32028608
http://dx.doi.org/10.3390/pharmaceutics12020122
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