Nanomedicines for Reactive Oxygen Species Mediated Approach: An Emerging Paradigm for Cancer Treatment.

Growth in the knowledge of cancer biology has led to the emergence and evolution of cancer nanomedicines by providing the rationale for leveraging nanotechnology to develop better treatment options. The discovery of nanometer-sized intercellular openings in the defective angiogenic tumor vasculature contributed to the development of an idea for the well-known cancer passive targeting regime, enhanced permeability and retention (EPR) effect, of the nanomedicines. Recently, reactive oxygen species (ROS) have been highlighted as one of the key players that underlie the acquisition of the various hallmarks of cancer. As ROS are associated with all stages of cancer, their applications in cancer treatment based on the following concentration-dependent implications have attracted much attention: (1) low to moderate levels of ROS as key signaling molecules, (2) elevated levels of ROS in cancer cells as one of the unique characteristics of cancer, and (3) excessive levels of ROS as cytotoxic agents. Considering ROS from a different point of view, various cancer nanomedicines have been designed to achieve spatiotemporal control of therapeutic action, the main research focus in this area. This Account includes our efforts and preclinical achievements in development of nanomedicines for a range of ROS-mediated cancer therapies. It begins with general background regarding cancer nanomedicines, the significance of ROS in cancer, and a brief overview of ROS-mediated approaches for cancer therapy. Then, this Account highlights the two key roles of ROS that define therapeutic purposes of cancer nanomedicines: (1) ROS as drug delivery enhancers and (2) ROS as cell death inducers. The former inspired us to develop nitric oxide-generating nanoparticles for improved EPR effect, endogenous ROS-responsive polymeric micelles for enhanced intracellular drug delivery, and exogenous ROS-activated micelles for subcellular localization via photochemical internalization. While refining conventional chemotherapy, recent researches also have focused on the latter, the cytotoxic ROS, to advance alternative treatment modalities such as oxidation therapy, photodynamic therapy (PDT), and sonodynamic therapy (SDT). In particular, we have been motivated to develop polymeric nanoreactors containing enzymes to produce H2O2 for oxidation therapy, photosensitizer-loaded gold-nanoclustered polymeric nanoassemblies for photothermally activated PDT overcoming the oxygen dependency of PDT, and hydrophilized TiO2 nanoparticles and Au-TiO2 nanocomposites as novel sonosensitizers for improved SDT efficiency. The integration of nanomedicine and ROS-mediated therapy has emerged as the new paradigm in the treatment of cancer, based on promising proof-of-concept demonstrations in preclinical studies. Further efforts to ensure clinical translation along with more sophisticated cancer nanomedicines to address relevant challenges are expected to be made in the coming years.