pH-sensitive doxorubicin-tocopherol succinate prodrug encapsulated in docosahexaenoic acid-based nanostructured lipid carriers: An effective strategy to improve pharmacokinetics and reduce toxic effects

Side effects often limit the use of doxorubicin (DOX) in cancer treatment. We have recently developed a nanostructured lipid carrier (NLC) formulation for synergistic chemotherapy, encapsulating DOX and the anticancer adjuvants docosahexaenoic acid (DHA) and α-tocopherol succinate (TS). Hydrophobic...

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Autores principales:	Eduardo Burgarelli Lages, Renata Salgado Fernandes, Marina Mol Sena Andrade, Nitchawat Paiyabhroma, Renata Barbosa de Oliveira, Christian Fernandes, Geovanni Dantas Cassali, Pierre Sicard, Sylvain Richard, André Luís Branco de Barros, Lucas Antônio Miranda Ferreira
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Doxorubicin Nanomedicine Ion-pairing Amide Hydrazone Antitumor activity Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/ab30badd949049e1a663721747a3b7e3
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spelling	oai:doaj.org-article:ab30badd949049e1a663721747a3b7e32021-11-14T04:30:25ZpH-sensitive doxorubicin-tocopherol succinate prodrug encapsulated in docosahexaenoic acid-based nanostructured lipid carriers: An effective strategy to improve pharmacokinetics and reduce toxic effects0753-332210.1016/j.biopha.2021.112373https://doaj.org/article/ab30badd949049e1a663721747a3b7e32021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221011574https://doaj.org/toc/0753-3322Side effects often limit the use of doxorubicin (DOX) in cancer treatment. We have recently developed a nanostructured lipid carrier (NLC) formulation for synergistic chemotherapy, encapsulating DOX and the anticancer adjuvants docosahexaenoic acid (DHA) and α-tocopherol succinate (TS). Hydrophobic ion-pairing with TS allowed a high DOX entrapment in the nanocarrier. In this work, we investigated the pharmacokinetics of this formulation after intravenous administration in mice. The first data obtained led us to propose synthesizing covalent DOX-TS conjugates to increase DOX retention in the NLC. We successfully conjugated DOX to TS via an amide or hydrazone bond. In vitro studies in 4T1 tumor cells indicated low cytotoxicity of the amide derivative, while the hydrazone conjugate was effective in killing cancer cells. We encapsulated the hydrazone derivative in a DHA-based nanocarrier (DOX-hyd-TS/NLC), which had reduced particle size and high drug encapsulation efficiency. The pH-sensitive hydrazone bond allowed controlled DOX release from the NLC, with increased drug release at acidic conditions. In vivo studies revealed that DOX-hyd-TS/NLC had a better pharmacokinetic profile than free DOX and attenuated the short-term cardiotoxic effects caused by DOX, such as QT prolongation and impaired left ventricular systolic function. Moreover, this formulation showed excellent therapeutic performance by reducing tumor growth in 4T1 tumor-bearing mice and decreasing DOX-induced toxicity to the heart and liver, demonstrated by hematologic, biochemical, and histologic analyses. These results indicate that DOX-hyd-TS/NLC may be a promising nanocarrier for breast cancer treatment.Eduardo Burgarelli LagesRenata Salgado FernandesMarina Mol Sena AndradeNitchawat PaiyabhromaRenata Barbosa de OliveiraChristian FernandesGeovanni Dantas CassaliPierre SicardSylvain RichardAndré Luís Branco de BarrosLucas Antônio Miranda FerreiraElsevierarticleDoxorubicinNanomedicineIon-pairingAmideHydrazoneAntitumor activityTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 144, Iss , Pp 112373- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Doxorubicin Nanomedicine Ion-pairing Amide Hydrazone Antitumor activity Therapeutics. Pharmacology RM1-950
spellingShingle	Doxorubicin Nanomedicine Ion-pairing Amide Hydrazone Antitumor activity Therapeutics. Pharmacology RM1-950 Eduardo Burgarelli Lages Renata Salgado Fernandes Marina Mol Sena Andrade Nitchawat Paiyabhroma Renata Barbosa de Oliveira Christian Fernandes Geovanni Dantas Cassali Pierre Sicard Sylvain Richard André Luís Branco de Barros Lucas Antônio Miranda Ferreira pH-sensitive doxorubicin-tocopherol succinate prodrug encapsulated in docosahexaenoic acid-based nanostructured lipid carriers: An effective strategy to improve pharmacokinetics and reduce toxic effects
description	Side effects often limit the use of doxorubicin (DOX) in cancer treatment. We have recently developed a nanostructured lipid carrier (NLC) formulation for synergistic chemotherapy, encapsulating DOX and the anticancer adjuvants docosahexaenoic acid (DHA) and α-tocopherol succinate (TS). Hydrophobic ion-pairing with TS allowed a high DOX entrapment in the nanocarrier. In this work, we investigated the pharmacokinetics of this formulation after intravenous administration in mice. The first data obtained led us to propose synthesizing covalent DOX-TS conjugates to increase DOX retention in the NLC. We successfully conjugated DOX to TS via an amide or hydrazone bond. In vitro studies in 4T1 tumor cells indicated low cytotoxicity of the amide derivative, while the hydrazone conjugate was effective in killing cancer cells. We encapsulated the hydrazone derivative in a DHA-based nanocarrier (DOX-hyd-TS/NLC), which had reduced particle size and high drug encapsulation efficiency. The pH-sensitive hydrazone bond allowed controlled DOX release from the NLC, with increased drug release at acidic conditions. In vivo studies revealed that DOX-hyd-TS/NLC had a better pharmacokinetic profile than free DOX and attenuated the short-term cardiotoxic effects caused by DOX, such as QT prolongation and impaired left ventricular systolic function. Moreover, this formulation showed excellent therapeutic performance by reducing tumor growth in 4T1 tumor-bearing mice and decreasing DOX-induced toxicity to the heart and liver, demonstrated by hematologic, biochemical, and histologic analyses. These results indicate that DOX-hyd-TS/NLC may be a promising nanocarrier for breast cancer treatment.
format	article
author	Eduardo Burgarelli Lages Renata Salgado Fernandes Marina Mol Sena Andrade Nitchawat Paiyabhroma Renata Barbosa de Oliveira Christian Fernandes Geovanni Dantas Cassali Pierre Sicard Sylvain Richard André Luís Branco de Barros Lucas Antônio Miranda Ferreira
author_facet	Eduardo Burgarelli Lages Renata Salgado Fernandes Marina Mol Sena Andrade Nitchawat Paiyabhroma Renata Barbosa de Oliveira Christian Fernandes Geovanni Dantas Cassali Pierre Sicard Sylvain Richard André Luís Branco de Barros Lucas Antônio Miranda Ferreira
author_sort	Eduardo Burgarelli Lages
title	pH-sensitive doxorubicin-tocopherol succinate prodrug encapsulated in docosahexaenoic acid-based nanostructured lipid carriers: An effective strategy to improve pharmacokinetics and reduce toxic effects
title_short	pH-sensitive doxorubicin-tocopherol succinate prodrug encapsulated in docosahexaenoic acid-based nanostructured lipid carriers: An effective strategy to improve pharmacokinetics and reduce toxic effects
title_full	pH-sensitive doxorubicin-tocopherol succinate prodrug encapsulated in docosahexaenoic acid-based nanostructured lipid carriers: An effective strategy to improve pharmacokinetics and reduce toxic effects
title_fullStr	pH-sensitive doxorubicin-tocopherol succinate prodrug encapsulated in docosahexaenoic acid-based nanostructured lipid carriers: An effective strategy to improve pharmacokinetics and reduce toxic effects
title_full_unstemmed	pH-sensitive doxorubicin-tocopherol succinate prodrug encapsulated in docosahexaenoic acid-based nanostructured lipid carriers: An effective strategy to improve pharmacokinetics and reduce toxic effects
title_sort	ph-sensitive doxorubicin-tocopherol succinate prodrug encapsulated in docosahexaenoic acid-based nanostructured lipid carriers: an effective strategy to improve pharmacokinetics and reduce toxic effects
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/ab30badd949049e1a663721747a3b7e3
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pH-sensitive doxorubicin-tocopherol succinate prodrug encapsulated in docosahexaenoic acid-based nanostructured lipid carriers: An effective strategy to improve pharmacokinetics and reduce toxic effects

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