Lymph‐Directed Self‐Immolative Nitric Oxide Prodrug for Inhibition of Intractable Metastatic Cancer

Abstract There has been a significant clinical demand for lymph‐directed anti‐metastatic therapy as tumor‐draining lymph nodes play pivotal roles in cancer metastasis which accounts for more than 90% of tumor‐related deaths. Despite the high potential of nitric oxide (NO) in anti‐cancer therapy owing to its biocompatibility and tumor cell‐specific cytotoxicity, the poor stability and lack of target specificity of present NO donors and delivery systems have limited its clinical applications. Herein, a redox‐triggered self‐immolative NO prodrug that can be readily conjugated to various materials containing free thiol groups such as albumin, is reported. The prodrug and its conjugates demonstrate smart release of NO donor via intramolecular cyclization under reductive conditions, followed by spontaneously generating NO in physiological conditions. The albumin‐prodrug conjugate inhibits tumor metastasis by inducing cytotoxicity preferentially on tumor cells after efficiently draining into lymph nodes. This novel prodrug can contribute to the development of on‐demand NO delivery systems for anti‐metastatic therapy and other treatments.