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Repurposing Heparin as Antimalarial: Evaluation of Multiple Modifications Toward In Vivo Application

Heparin is a promising antimalarial drug due to its activity in inhibiting Plasmodium invasion of red blood cells and to the lack of resistance evolution by the parasite against it, but its potent anticoagulant activity is preventing the advance of heparin along the clinical pipeline. We have determ...

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Autores principales: Lantero, Elena, Aláez-Versón, Carlos Raúl, Romero, Pilar, Sierra, Teresa, Fernàndez-Busquets, Xavier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557421/
https://www.ncbi.nlm.nih.gov/pubmed/32872434
http://dx.doi.org/10.3390/pharmaceutics12090825
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author Lantero, Elena
Aláez-Versón, Carlos Raúl
Romero, Pilar
Sierra, Teresa
Fernàndez-Busquets, Xavier
author_facet Lantero, Elena
Aláez-Versón, Carlos Raúl
Romero, Pilar
Sierra, Teresa
Fernàndez-Busquets, Xavier
author_sort Lantero, Elena
collection PubMed
description Heparin is a promising antimalarial drug due to its activity in inhibiting Plasmodium invasion of red blood cells and to the lack of resistance evolution by the parasite against it, but its potent anticoagulant activity is preventing the advance of heparin along the clinical pipeline. We have determined, in in vitro Plasmodium falciparum cultures, the antimalarial activity of heparin-derived structures of different origins and sizes, to obtain formulations having a good balance of in vitro safety (neither cytotoxic nor hemolytic), low anticoagulant activity (≤23 IU/mL according to activated partial thromboplastin time assays), and not too low antimalarial activity (IC50 at least around 100 µg/mL). This led to the selection of five chemically modified heparins according to the parameters explored, i.e., chain length, sulfation degree and position, and glycol-split, and whose in vivo toxicity indicated their safety for mice up to an intravenous dose of 320 mg/kg. The in vivo antimalarial activity of the selected formulations was poor as a consequence of their short blood half-life. The covalent crosslinking of heparin onto the surface of polyethylene glycol-containing liposomes did not affect its antimalarial activity in vitro and provided higher initial plasma concentrations, although it did not increase mean circulation time. Finding a suitable nanocarrier to impart long blood residence times to the modified heparins described here will be the next step toward new heparin-based antimalarial strategies.
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spelling pubmed-75574212020-10-20 Repurposing Heparin as Antimalarial: Evaluation of Multiple Modifications Toward In Vivo Application Lantero, Elena Aláez-Versón, Carlos Raúl Romero, Pilar Sierra, Teresa Fernàndez-Busquets, Xavier Pharmaceutics Article Heparin is a promising antimalarial drug due to its activity in inhibiting Plasmodium invasion of red blood cells and to the lack of resistance evolution by the parasite against it, but its potent anticoagulant activity is preventing the advance of heparin along the clinical pipeline. We have determined, in in vitro Plasmodium falciparum cultures, the antimalarial activity of heparin-derived structures of different origins and sizes, to obtain formulations having a good balance of in vitro safety (neither cytotoxic nor hemolytic), low anticoagulant activity (≤23 IU/mL according to activated partial thromboplastin time assays), and not too low antimalarial activity (IC50 at least around 100 µg/mL). This led to the selection of five chemically modified heparins according to the parameters explored, i.e., chain length, sulfation degree and position, and glycol-split, and whose in vivo toxicity indicated their safety for mice up to an intravenous dose of 320 mg/kg. The in vivo antimalarial activity of the selected formulations was poor as a consequence of their short blood half-life. The covalent crosslinking of heparin onto the surface of polyethylene glycol-containing liposomes did not affect its antimalarial activity in vitro and provided higher initial plasma concentrations, although it did not increase mean circulation time. Finding a suitable nanocarrier to impart long blood residence times to the modified heparins described here will be the next step toward new heparin-based antimalarial strategies. MDPI 2020-08-29 /pmc/articles/PMC7557421/ /pubmed/32872434 http://dx.doi.org/10.3390/pharmaceutics12090825 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
Lantero, Elena
Aláez-Versón, Carlos Raúl
Romero, Pilar
Sierra, Teresa
Fernàndez-Busquets, Xavier
Repurposing Heparin as Antimalarial: Evaluation of Multiple Modifications Toward In Vivo Application
title Repurposing Heparin as Antimalarial: Evaluation of Multiple Modifications Toward In Vivo Application
title_full Repurposing Heparin as Antimalarial: Evaluation of Multiple Modifications Toward In Vivo Application
title_fullStr Repurposing Heparin as Antimalarial: Evaluation of Multiple Modifications Toward In Vivo Application
title_full_unstemmed Repurposing Heparin as Antimalarial: Evaluation of Multiple Modifications Toward In Vivo Application
title_short Repurposing Heparin as Antimalarial: Evaluation of Multiple Modifications Toward In Vivo Application
title_sort repurposing heparin as antimalarial: evaluation of multiple modifications toward in vivo application
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557421/
https://www.ncbi.nlm.nih.gov/pubmed/32872434
http://dx.doi.org/10.3390/pharmaceutics12090825
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