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Increasing Brain Permeability of PHA-767491, a Cell Division Cycle 7 Kinase Inhibitor, with Biodegradable Polymeric Nanoparticles

A potent cell division cycle 7 (CDC7) kinase inhibitor, known as PHA-767491, has been described to reduce the transactive response DNA binding protein of 43 KDa (TDP-43) phosphorylation in vitro and in vivo, which is one of the main proteins found to aggregate and accumulate in the cytoplasm of moto...

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Autores principales: Rojas-Prats, Elisa, Tosat-Bitrián, Carlota, Martínez-González, Loreto, Nozal, Vanesa, Pérez, Daniel I., Martínez, Ana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912371/
https://www.ncbi.nlm.nih.gov/pubmed/33525757
http://dx.doi.org/10.3390/pharmaceutics13020180
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author Rojas-Prats, Elisa
Tosat-Bitrián, Carlota
Martínez-González, Loreto
Nozal, Vanesa
Pérez, Daniel I.
Martínez, Ana
author_facet Rojas-Prats, Elisa
Tosat-Bitrián, Carlota
Martínez-González, Loreto
Nozal, Vanesa
Pérez, Daniel I.
Martínez, Ana
author_sort Rojas-Prats, Elisa
collection PubMed
description A potent cell division cycle 7 (CDC7) kinase inhibitor, known as PHA-767491, has been described to reduce the transactive response DNA binding protein of 43 KDa (TDP-43) phosphorylation in vitro and in vivo, which is one of the main proteins found to aggregate and accumulate in the cytoplasm of motoneurons in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. However, the main drawback of this compound is its low permeability to the central nervous system (CNS), limiting its use for the treatment of neurological conditions. In this context, the use of drug delivery systems like nanocarriers has become an interesting approach to improve drug release to the CNS. In this study, we prepared and characterized biodegradable nanoparticles in order to encapsulate PHA-767491 and improve its permeability to the CNS. Our results demonstrate that poly (lactic-co-glycolic acid) (PLGA) nanoparticles with an average radius between 145 and 155 nm could be used to entrap PHA-767491 and enhance the permeability of this compound through the blood–brain barrier (BBB), becoming a promising candidate for the treatment of TDP-43 proteinopathies such as ALS.
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spelling pubmed-79123712021-02-28 Increasing Brain Permeability of PHA-767491, a Cell Division Cycle 7 Kinase Inhibitor, with Biodegradable Polymeric Nanoparticles Rojas-Prats, Elisa Tosat-Bitrián, Carlota Martínez-González, Loreto Nozal, Vanesa Pérez, Daniel I. Martínez, Ana Pharmaceutics Article A potent cell division cycle 7 (CDC7) kinase inhibitor, known as PHA-767491, has been described to reduce the transactive response DNA binding protein of 43 KDa (TDP-43) phosphorylation in vitro and in vivo, which is one of the main proteins found to aggregate and accumulate in the cytoplasm of motoneurons in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. However, the main drawback of this compound is its low permeability to the central nervous system (CNS), limiting its use for the treatment of neurological conditions. In this context, the use of drug delivery systems like nanocarriers has become an interesting approach to improve drug release to the CNS. In this study, we prepared and characterized biodegradable nanoparticles in order to encapsulate PHA-767491 and improve its permeability to the CNS. Our results demonstrate that poly (lactic-co-glycolic acid) (PLGA) nanoparticles with an average radius between 145 and 155 nm could be used to entrap PHA-767491 and enhance the permeability of this compound through the blood–brain barrier (BBB), becoming a promising candidate for the treatment of TDP-43 proteinopathies such as ALS. MDPI 2021-01-28 /pmc/articles/PMC7912371/ /pubmed/33525757 http://dx.doi.org/10.3390/pharmaceutics13020180 Text en © 2021 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
Rojas-Prats, Elisa
Tosat-Bitrián, Carlota
Martínez-González, Loreto
Nozal, Vanesa
Pérez, Daniel I.
Martínez, Ana
Increasing Brain Permeability of PHA-767491, a Cell Division Cycle 7 Kinase Inhibitor, with Biodegradable Polymeric Nanoparticles
title Increasing Brain Permeability of PHA-767491, a Cell Division Cycle 7 Kinase Inhibitor, with Biodegradable Polymeric Nanoparticles
title_full Increasing Brain Permeability of PHA-767491, a Cell Division Cycle 7 Kinase Inhibitor, with Biodegradable Polymeric Nanoparticles
title_fullStr Increasing Brain Permeability of PHA-767491, a Cell Division Cycle 7 Kinase Inhibitor, with Biodegradable Polymeric Nanoparticles
title_full_unstemmed Increasing Brain Permeability of PHA-767491, a Cell Division Cycle 7 Kinase Inhibitor, with Biodegradable Polymeric Nanoparticles
title_short Increasing Brain Permeability of PHA-767491, a Cell Division Cycle 7 Kinase Inhibitor, with Biodegradable Polymeric Nanoparticles
title_sort increasing brain permeability of pha-767491, a cell division cycle 7 kinase inhibitor, with biodegradable polymeric nanoparticles
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912371/
https://www.ncbi.nlm.nih.gov/pubmed/33525757
http://dx.doi.org/10.3390/pharmaceutics13020180
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