Propagation of Cell Death Programs in Cancer Using Targeted Ultrasmall Silica Nanoparticles

S.E. Kim, L. Zhang, K.M.M. Riegman, F. Chen, S. Monette, T. Quinn, U. Wiesner, M. Overholtzer, and M.S. Bradbury
Memorial Sloan Kettering Cancer Center,
United States

Keywords: silica nanoparticles, cancer care

Summary:

Cancer cells can spontaneously undergo cell death or be induced into cell death programs that demonstrate necrotic features, usually in the presence of cytotoxic agents. Such agents are often small hydrophobic molecules plagued by poor water solubility, non-specific biodistribution, and off-target toxicities. As a result, the use of these agents has often led to problematic dose-limiting toxicities with resulting narrow therapeutic indices and limited clinical benefit. The shortcomings often associated with these traditional formulations have accelerated development of alternative therapeutic systems offering key advantages over traditional formulations to overcome technical and regulatory hurdles. One such alternative treatment focuses on the use of “self-therapeutic” nanoparticles to induce an iron- and reactive oxygen species (ROS)-dependent cell death program – ferroptosis - without the need for conjugated and highly toxic compounds. This mechanism renders cells highly susceptible to cell death by promoting metabolic dysregulation and damage to membrane lipids. We have shown high-dose induction of ferroptosis in cancerous tissues for the first time using a class of targeted ultrasmall hybrid organic-inorganic silica nanoparticles, termed Cornell dots (C′ dots), under metabolically deprived conditions. Under such conditions, ingestion of targeted C′ dots killed cancer cells and inhibited tumor growth. The discovery of nanoparticle-induced ferroptosis as a redox modulator of cell fate, as well as a mediator of tumor regression and growth inhibition, suggests that this process may be exploited therapeutically in the clinic to synchronously and selectively kill those cancers most susceptible to this mechanism.