Dual-sensitive dual-prodrug nanoparticles with light-controlled endo/lysosomal escape for synergistic photoactivated chemotherapy

The clinical application of conventional chemotherapeutic agents, represented by cisplatin, is limited by severe side effects. So, it is essential to explore more safer and controlled drug delivery systems for synergistic chemotherapy. In this work, we designed dual-sensitive dual-prodrug nanoparticles (DDNPs) for photoactivated platinum-based synergistic chemotherapy. With photosensitivity, DDNPs could be photoactivated from inert Pt(IV) to toxic Pt(II) under safe UVA light in a spatiotemporally controlled manner. Concurrently, mild could be generated from DDNPs to assist the endo/lysosomal escape of DDNPs for better photoactivated chemotherapy (PACT). Furthermore, with acid-sensitivity, demethylcantharidin (DMC), a protein phosphatase 2A (PP2A) inhibitor, was released to block the DNA repair pathway and thereby could sensitize platinum-based chemotherapy in intracellular acidic microenvironments. Along with a precise ratio (Pt : DMC = 1 : 2), DDNPs had a powerful synergistic anti-cancer effect in vitro and in vivo. In the future, DDNPs have great potential as a safe and multifunctional drug delivery system for precise nanomedicine in clinical treatments.