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Therapeutic surfactant-stripped frozen micelles
Injectable hydrophobic drugs are typically dissolved in surfactants and non-aqueous solvents which can induce negative side-effects. Alternatives like ‘top-down' fine milling of excipient-free injectable drug suspensions are not yet clinically viable and ‘bottom-up' self-assembled delivery...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874033/ https://www.ncbi.nlm.nih.gov/pubmed/27193558 http://dx.doi.org/10.1038/ncomms11649 |
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author | Zhang, Yumiao Song, Wentao Geng, Jumin Chitgupi, Upendra Unsal, Hande Federizon, Jasmin Rzayev, Javid Sukumaran, Dinesh K. Alexandridis, Paschalis Lovell, Jonathan F. |
author_facet | Zhang, Yumiao Song, Wentao Geng, Jumin Chitgupi, Upendra Unsal, Hande Federizon, Jasmin Rzayev, Javid Sukumaran, Dinesh K. Alexandridis, Paschalis Lovell, Jonathan F. |
author_sort | Zhang, Yumiao |
collection | PubMed |
description | Injectable hydrophobic drugs are typically dissolved in surfactants and non-aqueous solvents which can induce negative side-effects. Alternatives like ‘top-down' fine milling of excipient-free injectable drug suspensions are not yet clinically viable and ‘bottom-up' self-assembled delivery systems usually substitute one solubilizing excipient for another, bringing new issues to consider. Here, we show that Pluronic (Poloxamer) block copolymers are amenable to low-temperature processing to strip away all free and loosely bound surfactant, leaving behind concentrated, kinetically frozen drug micelles containing minimal solubilizing excipient. This approach was validated for phylloquinone, cyclosporine, testosterone undecanoate, cabazitaxel and seven other bioactive molecules, achieving sizes between 45 and 160 nm and drug to solubilizer molar ratios 2–3 orders of magnitude higher than current formulations. Hypertonic saline or co-loaded cargo was found to prevent aggregation in some cases. Use of surfactant-stripped micelles avoided potential risks associated with other injectable formulations. Mechanistic insights are elucidated and therapeutic dose responses are demonstrated. |
format | Online Article Text |
id | pubmed-4874033 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-48740332016-06-02 Therapeutic surfactant-stripped frozen micelles Zhang, Yumiao Song, Wentao Geng, Jumin Chitgupi, Upendra Unsal, Hande Federizon, Jasmin Rzayev, Javid Sukumaran, Dinesh K. Alexandridis, Paschalis Lovell, Jonathan F. Nat Commun Article Injectable hydrophobic drugs are typically dissolved in surfactants and non-aqueous solvents which can induce negative side-effects. Alternatives like ‘top-down' fine milling of excipient-free injectable drug suspensions are not yet clinically viable and ‘bottom-up' self-assembled delivery systems usually substitute one solubilizing excipient for another, bringing new issues to consider. Here, we show that Pluronic (Poloxamer) block copolymers are amenable to low-temperature processing to strip away all free and loosely bound surfactant, leaving behind concentrated, kinetically frozen drug micelles containing minimal solubilizing excipient. This approach was validated for phylloquinone, cyclosporine, testosterone undecanoate, cabazitaxel and seven other bioactive molecules, achieving sizes between 45 and 160 nm and drug to solubilizer molar ratios 2–3 orders of magnitude higher than current formulations. Hypertonic saline or co-loaded cargo was found to prevent aggregation in some cases. Use of surfactant-stripped micelles avoided potential risks associated with other injectable formulations. Mechanistic insights are elucidated and therapeutic dose responses are demonstrated. Nature Publishing Group 2016-05-19 /pmc/articles/PMC4874033/ /pubmed/27193558 http://dx.doi.org/10.1038/ncomms11649 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Zhang, Yumiao Song, Wentao Geng, Jumin Chitgupi, Upendra Unsal, Hande Federizon, Jasmin Rzayev, Javid Sukumaran, Dinesh K. Alexandridis, Paschalis Lovell, Jonathan F. Therapeutic surfactant-stripped frozen micelles |
title | Therapeutic surfactant-stripped frozen micelles |
title_full | Therapeutic surfactant-stripped frozen micelles |
title_fullStr | Therapeutic surfactant-stripped frozen micelles |
title_full_unstemmed | Therapeutic surfactant-stripped frozen micelles |
title_short | Therapeutic surfactant-stripped frozen micelles |
title_sort | therapeutic surfactant-stripped frozen micelles |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874033/ https://www.ncbi.nlm.nih.gov/pubmed/27193558 http://dx.doi.org/10.1038/ncomms11649 |
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