Cascade-responsive nano-PROTACs for tumor-specific ALK protein degradation and enhanced cancer therapy

PROteolysis TArgeting Chimeras (PROTACs), as a promising therapeutic modality, have been exploited to degrade specific pathogenic proteins. However, the in vivo antitumor efficacy of PROTACs is seriously impaired by its poor pharmacokinetics and insufficient tumor distribution, consequently restricting their clinical applications. Herein, we report a pH/enzyme cascade-responsive nano-PROTACs (CRNPs) by integrating the cathepsin B-cleavable Gly-Phe-Leu-Gly (GFLG) linked PROTAC onto ultra-pH-sensitive (UPS) nanoplatform for enhanced tumor-specific ALK degradation and precise cancer therapy. The CRNPs exhibit a stable nanostructure with a diameter of 33 nm under physiological conditions, while rapidly dissociate at pH 6.0 and are subsequently cleaved by cathepsins B to effectively release the PROTAC payload. This further results in efficient ALK degradation, p-ALK reduction, G0/G1 phase cell cycle arrest, and suppression of tumor cells proliferation. Moreover, the cascade-responsive design dramatically improves the in vivo pharmacokinetics via prolonged circulation lifetime as well as enhanced tumor specific accumulation and release of PROTAC. Consequently, CRNPs significantly augment the antitumor efficacy, achieving with over 94 % suppression in Karpas299 tumor models, while demonstrating good biocompatibility in vivo. These findings highlight the potential of cascade-responsive nanocarriers for delivering PROTACs to combat a wide range of cancers by attacking their pathogenic proteins.