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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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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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. |
format | Online Article Text |
id | pubmed-6523311 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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