Beyond Internalization: Target Binding as the Trigger.

Targeted drug conjugates often rely on receptor-mediated internalization and intracellular trafficking for payload release. This requirement limits the range of tumor-associated targets that can be effectively exploited and has motivated the development of strategies for extracellular drug release. Wen and colleagues introduce a binding-to-release (BTR) strategy in which target engagement itself serves as the trigger for payload release. The authors used ligand-directed chemistry to develop phosphorus(V)-phenol exchange (PhoPEx) chemistry that exploits proximity between an electrophilic linker and a nucleophilic tyrosine residue within the binding pocket of the target to initiate target-triggered payload release. Through optimization of the phenol-based scaffold, the authors evaluated 15 PhoPEx compounds to balance hydrolytic stability and reaction kinetics. The authors then used fibroblast activation protein, a poorly internalizing stromal target, to test the BTR strategy using a membrane-permeable payload, resulting in improved tumor drug exposure and antitumor activity in preclinical models. The BTR strategy was further extended to imaging applications and other targets, including programmed death-ligand 1. Although demonstrated primarily with small-molecule conjugates, BTR introduces an alternative approach for targeted drug delivery of poorly internalizing targets in which target binding could be exploited as a trigger, potentially expanding the landscape of tumor-associated targets accessible to targeted therapeutics.