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 (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.

Automated summary

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.