A new nanomedicine platform to deliver a carnitine palmitoyl-transferase 1 (CPT1) inhibitor into glioma cells and neurons

Obesity and glioblastoma multiforme (GB) are two unmet medical needs where effective therapies are lacking. Carnitine palmitoyl transferase 1 (CPT1), an enzyme catalyzing the rate-lim- iting step in fatty acid oxidation (FAO), is a viable target for both diseases. C75, a fatty acid synthase (FAS) in...

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Autores: Paraiso, West Kristian D., García-Chica, Jesús, Ariza Piquer, Xavier, García Gómez, Jordi, Kataoka, Kazunori, Rodríguez Rodríguez, Rosalía, Quader, Sabina
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2020
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositório:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/177653
Acesso em linha:https://hdl.handle.net/2445/177653
Access Level:Acceso aberto
Palavra-chave:Nanomedicina
Obesitat
Càncer
Nanomedicine
Obesity
Cancer
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spelling A new nanomedicine platform to deliver a carnitine palmitoyl-transferase 1 (CPT1) inhibitor into glioma cells and neuronsParaiso, West Kristian D.García-Chica, JesúsAriza Piquer, XavierGarcía Gómez, JordiKataoka, KazunoriRodríguez Rodríguez, RosalíaQuader, SabinaNanomedicinaObesitatCàncerNanomedicineObesityCancerObesity and glioblastoma multiforme (GB) are two unmet medical needs where effective therapies are lacking. Carnitine palmitoyl transferase 1 (CPT1), an enzyme catalyzing the rate-lim- iting step in fatty acid oxidation (FAO), is a viable target for both diseases. C75, a fatty acid synthase (FAS) inhibitor, forms an adduct with coenzyme A (CoA) to form C75-CoA, which is a strong com- petitive inhibitor to CPT1 that is selective in its target. However, it is polar and charged, having low cell membrane permeability, and therefore needing a delivery system for intracellular transport. (±)-C75-CoA and its enantio-separated forms (+)- and (−)-C75-CoA were used to form poly-ion com- plex (PIC) micelles with the cationic block co-polymer PEG-PAsp(DET). The drug and polymer were mixed in a 1:1 anion/cation ratio to give 50-70 nm micelles with a unimodal size profile and narrow polydispersity. Size was maintained upon introduction of physiological saline. Micellar (±)-, (+)-, and (−)-C75-CoA were all significantly more cytotoxic compared to the respective free drugs in U87MG. We examined whether C75-CoA inhibits FAO by measuring ATP concentrations in U87MG and GT1-7. ATP generation was found to be hampered after adding C75-CoA in both cell types, with micelle-treated cells producing significantly lower ATP than those treated with free drug, suggesting that the effective intracellular delivery of C75-CoA leads to a more pronounced FAO inhibition. A fluorescent CoA derivative, Fluor-CoA, also yielded monodisperse micelles sim- ilar to C75-CoA. Micellar internalization was significantly greater than that of the free dye. Uptake of both increased with time, with this effect is more pronounced in U87MG than GT1-7. The %Fluor- CoA+ cells were also expressively higher for the micelle across cell lines. From this data, it can be convincingly concluded that neuronal and glioma cellular uptake of micelles is superior to that of the free dye, validating the need for cellular delivery systems for anionic, CoA-type molecules. The micellar form neutralized the negative charge of the cargo, promoting transport into the cell. These outcomes strongly support the effectiveness of using a PIC micelle-type system to deliver anionic small molecules into glioma cells and neurons meant to inhibit enzymes such as CPT1, for future applications in diseases like obesity and cancer.MDPI2021202120202021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/177653Articles publicats en revistes (Química Inorgànica i Orgànica)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.3390/IOCN2020-07986Materials Proceedings, 2020, vol. 4, num. 58https://doi.org/10.3390/IOCN2020-07986cc-by (c) Paraiso, West Kristian D. et al., 2020https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1776532026-05-29T05:05:01Z
dc.title.none.fl_str_mv A new nanomedicine platform to deliver a carnitine palmitoyl-transferase 1 (CPT1) inhibitor into glioma cells and neurons
title A new nanomedicine platform to deliver a carnitine palmitoyl-transferase 1 (CPT1) inhibitor into glioma cells and neurons
spellingShingle A new nanomedicine platform to deliver a carnitine palmitoyl-transferase 1 (CPT1) inhibitor into glioma cells and neurons
Paraiso, West Kristian D.
Nanomedicina
Obesitat
Càncer
Nanomedicine
Obesity
Cancer
title_short A new nanomedicine platform to deliver a carnitine palmitoyl-transferase 1 (CPT1) inhibitor into glioma cells and neurons
title_full A new nanomedicine platform to deliver a carnitine palmitoyl-transferase 1 (CPT1) inhibitor into glioma cells and neurons
title_fullStr A new nanomedicine platform to deliver a carnitine palmitoyl-transferase 1 (CPT1) inhibitor into glioma cells and neurons
title_full_unstemmed A new nanomedicine platform to deliver a carnitine palmitoyl-transferase 1 (CPT1) inhibitor into glioma cells and neurons
title_sort A new nanomedicine platform to deliver a carnitine palmitoyl-transferase 1 (CPT1) inhibitor into glioma cells and neurons
dc.creator.none.fl_str_mv Paraiso, West Kristian D.
García-Chica, Jesús
Ariza Piquer, Xavier
García Gómez, Jordi
Kataoka, Kazunori
Rodríguez Rodríguez, Rosalía
Quader, Sabina
author Paraiso, West Kristian D.
author_facet Paraiso, West Kristian D.
García-Chica, Jesús
Ariza Piquer, Xavier
García Gómez, Jordi
Kataoka, Kazunori
Rodríguez Rodríguez, Rosalía
Quader, Sabina
author_role author
author2 García-Chica, Jesús
Ariza Piquer, Xavier
García Gómez, Jordi
Kataoka, Kazunori
Rodríguez Rodríguez, Rosalía
Quader, Sabina
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Nanomedicina
Obesitat
Càncer
Nanomedicine
Obesity
Cancer
topic Nanomedicina
Obesitat
Càncer
Nanomedicine
Obesity
Cancer
description Obesity and glioblastoma multiforme (GB) are two unmet medical needs where effective therapies are lacking. Carnitine palmitoyl transferase 1 (CPT1), an enzyme catalyzing the rate-lim- iting step in fatty acid oxidation (FAO), is a viable target for both diseases. C75, a fatty acid synthase (FAS) inhibitor, forms an adduct with coenzyme A (CoA) to form C75-CoA, which is a strong com- petitive inhibitor to CPT1 that is selective in its target. However, it is polar and charged, having low cell membrane permeability, and therefore needing a delivery system for intracellular transport. (±)-C75-CoA and its enantio-separated forms (+)- and (−)-C75-CoA were used to form poly-ion com- plex (PIC) micelles with the cationic block co-polymer PEG-PAsp(DET). The drug and polymer were mixed in a 1:1 anion/cation ratio to give 50-70 nm micelles with a unimodal size profile and narrow polydispersity. Size was maintained upon introduction of physiological saline. Micellar (±)-, (+)-, and (−)-C75-CoA were all significantly more cytotoxic compared to the respective free drugs in U87MG. We examined whether C75-CoA inhibits FAO by measuring ATP concentrations in U87MG and GT1-7. ATP generation was found to be hampered after adding C75-CoA in both cell types, with micelle-treated cells producing significantly lower ATP than those treated with free drug, suggesting that the effective intracellular delivery of C75-CoA leads to a more pronounced FAO inhibition. A fluorescent CoA derivative, Fluor-CoA, also yielded monodisperse micelles sim- ilar to C75-CoA. Micellar internalization was significantly greater than that of the free dye. Uptake of both increased with time, with this effect is more pronounced in U87MG than GT1-7. The %Fluor- CoA+ cells were also expressively higher for the micelle across cell lines. From this data, it can be convincingly concluded that neuronal and glioma cellular uptake of micelles is superior to that of the free dye, validating the need for cellular delivery systems for anionic, CoA-type molecules. The micellar form neutralized the negative charge of the cargo, promoting transport into the cell. These outcomes strongly support the effectiveness of using a PIC micelle-type system to deliver anionic small molecules into glioma cells and neurons meant to inhibit enzymes such as CPT1, for future applications in diseases like obesity and cancer.
publishDate 2020
dc.date.none.fl_str_mv 2020
2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/177653
url https://hdl.handle.net/2445/177653
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3390/IOCN2020-07986
Materials Proceedings, 2020, vol. 4, num. 58
https://doi.org/10.3390/IOCN2020-07986
dc.rights.none.fl_str_mv cc-by (c) Paraiso, West Kristian D. et al., 2020
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Paraiso, West Kristian D. et al., 2020
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv Articles publicats en revistes (Química Inorgànica i Orgànica)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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