Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 60, Issue 12, Pages 6573-6580Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202014259
Keywords
controlled release; dynamic covalent bonds; fluorescence; nanotechnology; prodrugs
Categories
Funding
- European Research Council [BrightSens 648528]
- SATT Conectus
- INSERM
- CNRS
- University of Strasbourg
- China Scholarship council (CSC)
- JSPS Fellowship for Research Abroad
- LabEx Chimie des Systemes Complexes
- Region Alsace
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This study introduces a drug delivery strategy that involves reversible pH-controlled capture and release of active cargo based on dynamic covalent chemistry within lipid nano-droplets, termed as drug sponge. This approach effectively encapsulates fluorescent dyes and doxorubicin drugs, allowing for stable formulations at neutral pH and controlled release in acidic environments. The drug-sponge nanoemulsions exhibit cytotoxicity in cancer cells and inhibit tumor growth in mouse xenograft models, as well as enable unprecedented extraction of dye/drug cargos directly from cells and tissues.
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.
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