Facile synthesis of pH-responsive doxorubicin-loaded layered double hydroxide for efficient cancer therapy

Layered double hydroxides (LDHs) have attracted particular attention as drug delivery carriers due to their variable chemical composition, excellent biocompatibility, high anion exchange capacity and controlled drug release. However, their anion exchange capability only meets the requirement for encapsulating drugs with negative charge in aqueous media. Encapsulation of drugs with positive charge into LDHs still remains a big challenge. Herein, we report a facile strategy to obtain highly dispersible doxorubicin-loaded MgAl-LDH nanohybrids (DOX@MgAl-LDH). DOX@MgAl-LDH is stable under physiological conditions and releases DOX in response to an acidic tumor microenvironment. Intracellular tracking of DOX@MgAl-LDH confirms that after internalization into cancer cells via macropinocytosis, clathrin- and lipid raft/caveolae-mediated endocytosis, DOX@MgAl-LDH is transported to lysosomes and then releases DOX to the nucleus. Furthermore, DOX@MgAl-LDH exhibits good tumor targeting, enhanced cellular uptake and cytotoxicity against cancer cells compared with free DOX. In vivo anticancer experiments reveal that DOX@MgAl-LDH significantly inhibits tumor growth with decreased DOX-induced cardiotoxicity compared with free DOX. This study may provide a new approach for highly efficient DOX delivery in cancer therapy.