A Bioorthogonal Decaging Chemistry of N -Oxide and Silylborane for Prodrug Activation both In Vitro and In Vivo .

Bioorthogonal decaging chemistry with both fast kinetics and high efficiency is highly demanded for in vivo applications but remains very sporadic. Herein, we describe a new bioorthogonal decaging chemistry between N -oxide and silylborane. A simple replacement of "C" in boronic acid with "Si" was able to substantially accelerate the N -oxide decaging kinetics by 10 6 fold ( k 2 : up to 10 3 M -1 s -1 ). Moreover, a new N -oxide-masked self-immolative spacer was developed for the traceless release of various payloads upon clicking with silylborane with fast kinetics and high efficiency (>90%). Impressively, one such N -oxide-based self-assembled bioorthogonal nano-prodrug in combination with silylborane led to significantly enhanced tumor suppression effects as compared to the parent drug in a 4T1 mouse breast tumor model. In aggregate, this new bioorthogonal click-and-release chemistry is featured with fast kinetics and high efficiency and is perceived to find widespread applications in chemical biology and drug delivery.