Tumor-specific release of copper-incorporated diethyldithiocarbamate from an optimized apoferritin scaffold enables both potent and safe anti-cancer therapy

Here we successfully resolved both off-target toxicity and multidrug resistance (MDR) problems, which remain a major challenge in traditional cancer chemotherapy, by adopting an optimized scaffold-conjugated drug - copper ion-incorporated diethyldithiocarbamate (Cu-DDC₂) with both permeability-glycoprotein inhibiting- and anti-cancer activities. Cu-DDC₂ molecules were loaded onto a human apoferritin-derived, optimized scaffold (AF) in a large quantity (∼120 molecules/AF), which simultaneously enables 1) targeted delivery of the loaded Cu-DDC₂ to tumor cells and 2) toxification of Cu-DDC₂ only inside tumor cells to eliminate off-target toxicity, the latter being based on tumor cell-specific, proteolytic release of Cu-DDC₂ from the AF. Consequently, the AF-conjugated Cu-DDC₂ led to notable repression of both human pancreatic and gastric cancer growth in xenograft mice without causing pathological abnormalities in normal tissues/cells. This approach is expected to open up a novel, attractive clinical route for both potent and safe cancer therapy.