A Trifunctional Self-Immolative Spacer Enables Drug Release with Two Non-Sequential Enzymatic Cleavages

Cyclative cleavage of an amine-carbamate self-immolative spacer to deliver a hydroxyl cargo was inhibited by the spacer derivatisation with a phosphate monoester handle. This trifunctional spacer was installed in a model anticancer prodrug which showed a fast drug release only when incubated with both a protease and a phosphatase enzymes.