Smart Magnetic Nanocarriers for Codelivery of Nitric Oxide and Doxorubicin for Enhanced Apoptosis in Cancer Cells

[Image: see text] Extremely short half-life therapeutic molecule nitric oxide (NO) plays significant roles in the functioning of various physiological and pathological processes in the human body, whereas doxorubicin hydrochloride (DOX) is a clinically important anticancer drug widely used in cancer chemotherapy. Thus, the intracellular delivery of these therapeutic molecules is tremendously important to achieve their full potential. Herein, we report a novel approach for the development of highly water-dispersible magnetic nanocarriers for codelivery of NO and DOX. Primarily, bifunctional magnetic nanoparticles enriched with carboxyl and thiol groups were prepared by introducing cysteine onto the surface of citrate-functionalized Fe(3)O(4) nanoparticles. DOX was electrostatically conjugated onto the surface of bifunctional nanoparticles via carboxyl moieties, whereas the thiol group was further nitrosated to provide NO-releasing molecules. The developed magnetic nanocarrier exhibited good aqueous colloidal stability, protein resistance behavior, and high encapsulation efficacy for NO (65.5%) and DOX (85%), as well as sustained release characteristics. Moreover, they showed superior cytotoxicity toward cancer (A549 and MCF-7) cells via apoptosis induction over normal (WI26VA4) cells. Specifically, we have developed magnetic nanocarriers having the capability of dual delivery of NO and DOX, which holds great potential for combinatorial cancer treatment.