Hypoxia-sensitive macrocycle inclusion complexes for targeted protein degradation

PROteolysis TArgeting Chimeras (PROTACs) have gained significant attention for targeted protein degradation in cancer therapy. However, their clinical application is limited by low bioavailability, poor tumor distribution, and potential off-target effects. This study presents NaC4A-PROTACs, a hypoxia-responsive host-guest drug delivery system where azo-modified calixarene derivative (Naph-SAC4A) acts as the host molecule, encapsulating PROTAC molecules as the guest. The PROTAC molecules are incorporated into the host cavity of Naph-SAC4A through reversible non-covalent interactions, forming well-defined supramolecular complexes, which, to our knowledge, represent the first supramolecular host-guest PROTAC delivery system. These complexes remain stable under normoxic physiological conditions. But in the hypoxic tumor microenvironment, Naph-SAC4A undergo enzyme-catalyzed azo bond cleavage, significantly reducing the host-guest binding affinity of the supramolecular complex. Subsequently, PROTAC molecules are efficiently released from the calixarene cavity to degrade bromodomain-containing protein 4 (BRD4) proteins. We demonstrate the efficacy of NaC4A-PROTACs for hypoxia-targeted therapy both in vitro and in vivo, showing significant enhancement of PROTACs bioavailability, improved tumor-specific delivery, and potent anti-tumor effects. Our study provides a simple, universal, and reproducible platform for the controlled release of PROTACs, which can effectively enhance the precision and efficacy of cancer therapy, providing a promising approach for the application of PROTACs in cancer treatment.