Drug‐Sponge Lipid Nanocarrier for in Situ Cargo Loading and Release Using Dynamic Covalent Chemistry

Currently, drug‐delivery strategies using nanocarriers (NCs) deal with encapsulation of cargo or its covalently modified prodrug. Herein, we propose a concept of reversible pH‐controlled capture and delivery of active cargo based on dynamic covalent chemistry inside lipid nano‐droplets (nanoemulsion...

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Bibliographic Details
Published in:Angewandte Chemie 2021-03, Vol.133 (12), p.6647-6654
Main Authors: Liu, Fei, Niko, Yosuke, Bouchaala, Redouane, Mercier, Luc, Lefebvre, Olivier, Andreiuk, Bohdan, Vandamme, Thierry, Goetz, Jacky G., Anton, Nicolas, Klymchenko, Andrey
Format: Article
Language:English
Subjects:
Cargo handling
Chemistry
controlled release
Covalence
Cytotoxicity
Detoxification
Doxorubicin
Dyes
dynamic covalent bonds
fluorescence
Fluorescent dyes
Fluorescent indicators
Hydrazones
Ketones
Lipids
Lipophilic
Lipophilicity
Nanoemulsions
nanotechnology
pH effects
prodrugs
Toxicity
Tumor cell lines
Xenografts
Xenotransplantation
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Summary:Currently, drug‐delivery strategies using nanocarriers (NCs) deal with encapsulation of cargo or its covalently modified prodrug. Herein, we propose a concept of reversible pH‐controlled capture and delivery of active cargo based on dynamic covalent chemistry inside lipid nano‐droplets (nanoemulsions), coined as “drug sponge”. We designed a highly lipophilic hydrazide (LipoHD) capable of reacting with a free cargo‐ketone (fluorescent dye and doxorubicin drug) directly inside lipid NCs, yielding a lipophilic hydrazone prodrug efficiently captured in the oil core. LipoHD‐loaded NCs spontaneously accumulated cargo‐ketones, yielding formulations stable against cargo leakage at pH 7.4, and further released their dye/drug cargo at low pH range (5.0–6.8) in solution and live cells. Doxorubicin‐loaded drug‐sponge NCs showed cytotoxicity in four cancer cell lines and capacity to inhibit tumor growth in subcutaneous xenografts of mice. Finally, unprecedented extraction of dye/drug cargos directly from cells and tissues (i.e. detoxification) was realized by the drug‐sponge NCs. A drug‐sponge nanocarrier that reversibly captures and releases drugs or contrast agents under pH control is developed using dynamic covalent chemistry. Inside this lipid droplet nano‐reactor, lipophilic capture molecules transform free cargo‐ketones into encapsulated hydrazone prodrugs, enabling the controlled release of active cargos and also their extraction from cells and tissues for detoxification.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.202014259