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Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug Delivery

Cryptophycins are potent tubulin polymerization inhibitors with picomolar antiproliferative potency in vitro and activity against multidrug-resistant (MDR) cancer cells. Because of neurotoxic side effects and limited efficacy in vivo, cryptophycin-52 failed as a clinical candidate in cancer treatmen...

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Autores principales: Borbély, Adina, Figueras, Eduard, Martins, Ana, Esposito, Simone, Auciello, Giulio, Monteagudo, Edith, Di Marco, Annalise, Summa, Vincenzo, Cordella, Paola, Perego, Raffaella, Kemker, Isabell, Frese, Marcel, Gallinari, Paola, Steinkühler, Christian, Sewald, Norbert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523311/
https://www.ncbi.nlm.nih.gov/pubmed/30939768
http://dx.doi.org/10.3390/pharmaceutics11040151
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author Borbély, Adina
Figueras, Eduard
Martins, Ana
Esposito, Simone
Auciello, Giulio
Monteagudo, Edith
Di Marco, Annalise
Summa, Vincenzo
Cordella, Paola
Perego, Raffaella
Kemker, Isabell
Frese, Marcel
Gallinari, Paola
Steinkühler, Christian
Sewald, Norbert
author_facet Borbély, Adina
Figueras, Eduard
Martins, Ana
Esposito, Simone
Auciello, Giulio
Monteagudo, Edith
Di Marco, Annalise
Summa, Vincenzo
Cordella, Paola
Perego, Raffaella
Kemker, Isabell
Frese, Marcel
Gallinari, Paola
Steinkühler, Christian
Sewald, Norbert
author_sort Borbély, Adina
collection PubMed
description Cryptophycins are potent tubulin polymerization inhibitors with picomolar antiproliferative potency in vitro and activity against multidrug-resistant (MDR) cancer cells. Because of neurotoxic side effects and limited efficacy in vivo, cryptophycin-52 failed as a clinical candidate in cancer treatment. However, this class of compounds has emerged as attractive payloads for tumor-targeting applications. In this study, cryptophycin was conjugated to the cyclopeptide c(RGDfK), targeting integrin α(v)β(3), across the protease-cleavable Val-Cit linker and two different self-immolative spacers. Plasma metabolic stability studies in vitro showed that our selected payload displays an improved stability compared to the parent compound, while the stability of the conjugates is strongly influenced by the self-immolative moiety. Cathepsin B cleavage assays revealed that modifications in the linker lead to different drug release profiles. Antiproliferative effects of Arg-Gly-Asp (RGD)–cryptophycin conjugates were evaluated on M21 and M21-L human melanoma cell lines. The low nanomolar in vitro activity of the novel conjugates was associated with inferior selectivity for cell lines with different integrin α(v)β(3) expression levels. To elucidate the drug delivery process, cryptophycin was replaced by an infrared dye and the obtained conjugates were studied by confocal microscopy.
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spelling pubmed-65233112019-06-04 Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug Delivery Borbély, Adina Figueras, Eduard Martins, Ana Esposito, Simone Auciello, Giulio Monteagudo, Edith Di Marco, Annalise Summa, Vincenzo Cordella, Paola Perego, Raffaella Kemker, Isabell Frese, Marcel Gallinari, Paola Steinkühler, Christian Sewald, Norbert Pharmaceutics Article Cryptophycins are potent tubulin polymerization inhibitors with picomolar antiproliferative potency in vitro and activity against multidrug-resistant (MDR) cancer cells. Because of neurotoxic side effects and limited efficacy in vivo, cryptophycin-52 failed as a clinical candidate in cancer treatment. However, this class of compounds has emerged as attractive payloads for tumor-targeting applications. In this study, cryptophycin was conjugated to the cyclopeptide c(RGDfK), targeting integrin α(v)β(3), across the protease-cleavable Val-Cit linker and two different self-immolative spacers. Plasma metabolic stability studies in vitro showed that our selected payload displays an improved stability compared to the parent compound, while the stability of the conjugates is strongly influenced by the self-immolative moiety. Cathepsin B cleavage assays revealed that modifications in the linker lead to different drug release profiles. Antiproliferative effects of Arg-Gly-Asp (RGD)–cryptophycin conjugates were evaluated on M21 and M21-L human melanoma cell lines. The low nanomolar in vitro activity of the novel conjugates was associated with inferior selectivity for cell lines with different integrin α(v)β(3) expression levels. To elucidate the drug delivery process, cryptophycin was replaced by an infrared dye and the obtained conjugates were studied by confocal microscopy. MDPI 2019-04-01 /pmc/articles/PMC6523311/ /pubmed/30939768 http://dx.doi.org/10.3390/pharmaceutics11040151 Text en © 2019 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
Borbély, Adina
Figueras, Eduard
Martins, Ana
Esposito, Simone
Auciello, Giulio
Monteagudo, Edith
Di Marco, Annalise
Summa, Vincenzo
Cordella, Paola
Perego, Raffaella
Kemker, Isabell
Frese, Marcel
Gallinari, Paola
Steinkühler, Christian
Sewald, Norbert
Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug Delivery
title Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug Delivery
title_full Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug Delivery
title_fullStr Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug Delivery
title_full_unstemmed Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug Delivery
title_short Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug Delivery
title_sort synthesis and biological evaluation of rgd–cryptophycin conjugates for targeted drug delivery
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523311/
https://www.ncbi.nlm.nih.gov/pubmed/30939768
http://dx.doi.org/10.3390/pharmaceutics11040151
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