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Time-Prolonged Release of Tumor-Targeted Protein–MMAE Nanoconjugates from Implantable Hybrid Materials

The sustained release of small, tumor-targeted cytotoxic drugs is an unmet need in cancer therapies, which usually rely on punctual administration regimens of non-targeted drugs. Here, we have developed a novel concept of protein–drug nanoconjugates, which are packaged as slow-releasing chemically h...

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Autores principales: Serna, Naroa, Falgàs, Aïda, García-León, Annabel, Unzueta, Ugutz, Núñez, Yáiza, Sánchez-Chardi, Alejandro, Martínez-Torró, Carlos, Mangues, Ramón, Vazquez, Esther, Casanova, Isolda, Villaverde, Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8777625/
https://www.ncbi.nlm.nih.gov/pubmed/35057088
http://dx.doi.org/10.3390/pharmaceutics14010192
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author Serna, Naroa
Falgàs, Aïda
García-León, Annabel
Unzueta, Ugutz
Núñez, Yáiza
Sánchez-Chardi, Alejandro
Martínez-Torró, Carlos
Mangues, Ramón
Vazquez, Esther
Casanova, Isolda
Villaverde, Antonio
author_facet Serna, Naroa
Falgàs, Aïda
García-León, Annabel
Unzueta, Ugutz
Núñez, Yáiza
Sánchez-Chardi, Alejandro
Martínez-Torró, Carlos
Mangues, Ramón
Vazquez, Esther
Casanova, Isolda
Villaverde, Antonio
author_sort Serna, Naroa
collection PubMed
description The sustained release of small, tumor-targeted cytotoxic drugs is an unmet need in cancer therapies, which usually rely on punctual administration regimens of non-targeted drugs. Here, we have developed a novel concept of protein–drug nanoconjugates, which are packaged as slow-releasing chemically hybrid depots and sustain a prolonged secretion of the therapeutic agent. For this, we covalently attached hydrophobic molecules (including the antitumoral drug Monomethyl Auristatin E) to a protein targeting a tumoral cell surface marker abundant in several human neoplasias, namely the cytokine receptor CXCR4. By this, a controlled aggregation of the complex is achieved, resulting in mechanically stable protein–drug microparticles. These materials, which are mimetics of bacterial inclusion bodies and of mammalian secretory granules, allow the slow leakage of fully functional conjugates at the nanoscale, both in vitro and in vivo. Upon subcutaneous administration in a mouse model of human CXCR4(+) lymphoma, the protein–drug depots release nanoconjugates for at least 10 days, which accumulate in the tumor with a potent antitumoral effect. The modification of scaffold cell-targeted proteins by hydrophobic drug conjugation is then shown as a novel transversal platform for the design of slow releasing protein–drug depots, with potential application in a broad spectrum of clinical settings.
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spelling pubmed-87776252022-01-22 Time-Prolonged Release of Tumor-Targeted Protein–MMAE Nanoconjugates from Implantable Hybrid Materials Serna, Naroa Falgàs, Aïda García-León, Annabel Unzueta, Ugutz Núñez, Yáiza Sánchez-Chardi, Alejandro Martínez-Torró, Carlos Mangues, Ramón Vazquez, Esther Casanova, Isolda Villaverde, Antonio Pharmaceutics Article The sustained release of small, tumor-targeted cytotoxic drugs is an unmet need in cancer therapies, which usually rely on punctual administration regimens of non-targeted drugs. Here, we have developed a novel concept of protein–drug nanoconjugates, which are packaged as slow-releasing chemically hybrid depots and sustain a prolonged secretion of the therapeutic agent. For this, we covalently attached hydrophobic molecules (including the antitumoral drug Monomethyl Auristatin E) to a protein targeting a tumoral cell surface marker abundant in several human neoplasias, namely the cytokine receptor CXCR4. By this, a controlled aggregation of the complex is achieved, resulting in mechanically stable protein–drug microparticles. These materials, which are mimetics of bacterial inclusion bodies and of mammalian secretory granules, allow the slow leakage of fully functional conjugates at the nanoscale, both in vitro and in vivo. Upon subcutaneous administration in a mouse model of human CXCR4(+) lymphoma, the protein–drug depots release nanoconjugates for at least 10 days, which accumulate in the tumor with a potent antitumoral effect. The modification of scaffold cell-targeted proteins by hydrophobic drug conjugation is then shown as a novel transversal platform for the design of slow releasing protein–drug depots, with potential application in a broad spectrum of clinical settings. MDPI 2022-01-14 /pmc/articles/PMC8777625/ /pubmed/35057088 http://dx.doi.org/10.3390/pharmaceutics14010192 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Serna, Naroa
Falgàs, Aïda
García-León, Annabel
Unzueta, Ugutz
Núñez, Yáiza
Sánchez-Chardi, Alejandro
Martínez-Torró, Carlos
Mangues, Ramón
Vazquez, Esther
Casanova, Isolda
Villaverde, Antonio
Time-Prolonged Release of Tumor-Targeted Protein–MMAE Nanoconjugates from Implantable Hybrid Materials
title Time-Prolonged Release of Tumor-Targeted Protein–MMAE Nanoconjugates from Implantable Hybrid Materials
title_full Time-Prolonged Release of Tumor-Targeted Protein–MMAE Nanoconjugates from Implantable Hybrid Materials
title_fullStr Time-Prolonged Release of Tumor-Targeted Protein–MMAE Nanoconjugates from Implantable Hybrid Materials
title_full_unstemmed Time-Prolonged Release of Tumor-Targeted Protein–MMAE Nanoconjugates from Implantable Hybrid Materials
title_short Time-Prolonged Release of Tumor-Targeted Protein–MMAE Nanoconjugates from Implantable Hybrid Materials
title_sort time-prolonged release of tumor-targeted protein–mmae nanoconjugates from implantable hybrid materials
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8777625/
https://www.ncbi.nlm.nih.gov/pubmed/35057088
http://dx.doi.org/10.3390/pharmaceutics14010192
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