Cathepsin B-responsive prodrugs for cancer-targeted therapy: Recent advances and progress for clinical translation

The cathepsin B-responsive prodrugs are promising strategies to reduce the serious adverse effects of anticancer drugs by improving the cancer selectivity that can be specifically activated by overexpressed cathepsin B in targeted cancer cells. However, clinical translation of such therapeutic approaches has been restricted by low antitumor efficacy that is mainly attributable to undesirable pharmacokinetic profiles and inefficient tumor-targeting of cathepsin B-responsive prodrugs, due to their small-molecule structure. In recent decades, many researchers have widely investigated the drug delivery system (DDS) to improve the in vivo pharmacokinetic profiles and tumor-targeting efficiency of cathepsin B-responsive prodrugs via the application of polymers, dendrimers, antibodies, lipids, and inorganic nanoparticles as drug carriers. In addition, the potential therapeutic efficacy of DDS for cathepsin B-responsive prodrugs is demonstrated in multiple studies and combinatorial treatment with typical therapeutic modalities can effectively overcome the challenges of tumor heterogeneity and multidrug resistance. In this review, recent advances and progress of new DDS for cathepsin B-responsive prodrugs are outlined, and their clinical trials are discussed. Besides, potential challenges and the outlooks for clinical translation of cathepsin B-responsive prodrugs are highlighted.