Development, formulation, and cellular mechanism of a lipophilic copper chelator for the treatment of Wilson's disease
Copyright © 2021 Elsevier B.V. All rights reserved..
Copper homeostasis is finely regulated in human to avoid any detrimental impact of free intracellular copper ions. Upon copper accumulation, biliary excretion is triggered in liver thanks to trafficking of the ATP7B copper transporter to bile canaliculi. However, in Wilson's disease this protein is mutated leading to copper accumulation. Current therapy uses Cu chelators acting extracellularly and requiring a life-long treatment with side effects. Herein, a new Cu(I) pro-chelator was encapsulated in long-term stable nanostructured lipid carriers. Cellular assays revealed that the pro-chelator protects hepatocytes against Cu-induced cell death. Besides, the cellular stresses induced by moderate copper concentrations, including protein unfolding, are counteracted by the pro-chelator. These data showed the pro-chelator efficiency to deliver intracellularly an active chelator that copes with copper stress and surpasses current and under development chelators. Although its biological activity is more mitigated, the pro-chelator nanolipid formulation led to promising results. This innovative approach is of outmost importance in the quest of better treatments for Wilson's disease.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:609 |
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| Enthalten in: |
International journal of pharmaceutics - 609(2021) vom: 20. Nov., Seite 121193 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gauthier, Laura [VerfasserIn] |
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| Links: |
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| Themen: |
789U1901C5 |
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| Anmerkungen: |
Date Completed 09.11.2021 Date Revised 31.05.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ijpharm.2021.121193 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM332133508 |
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| 520 | |a Copyright © 2021 Elsevier B.V. All rights reserved. | ||
| 520 | |a Copper homeostasis is finely regulated in human to avoid any detrimental impact of free intracellular copper ions. Upon copper accumulation, biliary excretion is triggered in liver thanks to trafficking of the ATP7B copper transporter to bile canaliculi. However, in Wilson's disease this protein is mutated leading to copper accumulation. Current therapy uses Cu chelators acting extracellularly and requiring a life-long treatment with side effects. Herein, a new Cu(I) pro-chelator was encapsulated in long-term stable nanostructured lipid carriers. Cellular assays revealed that the pro-chelator protects hepatocytes against Cu-induced cell death. Besides, the cellular stresses induced by moderate copper concentrations, including protein unfolding, are counteracted by the pro-chelator. These data showed the pro-chelator efficiency to deliver intracellularly an active chelator that copes with copper stress and surpasses current and under development chelators. Although its biological activity is more mitigated, the pro-chelator nanolipid formulation led to promising results. This innovative approach is of outmost importance in the quest of better treatments for Wilson's disease | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Copper chelator | |
| 650 | 4 | |a Hepatocytes | |
| 650 | 4 | |a Nanolipid formulation | |
| 650 | 4 | |a Wilson’s disease | |
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| 700 | 1 | |a Texier, Isabelle |e verfasserin |4 aut | |
| 700 | 1 | |a Gateau, Christelle |e verfasserin |4 aut | |
| 700 | 1 | |a Deniaud, Aurélien |e verfasserin |4 aut | |
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