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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...

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Autores principales: Zhang, Yumiao, Song, Wentao, Geng, Jumin, Chitgupi, Upendra, Unsal, Hande, Federizon, Jasmin, Rzayev, Javid, Sukumaran, Dinesh K., Alexandridis, Paschalis, Lovell, Jonathan F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
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.
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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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