Abstract
Development of a single combinatorial nano-platform technology to target cancer cells has been an unprecedented reality in boosting synergistic anti-tumor activities and in reducing off-target effects. We have designed a novel anti-tumor delivery system using a chemotherapy drug and a tumor target molecule covalently linked to cerium oxide nanoparticles (nanoceria). Nanoceria have a unique redox activity in that they possess antioxidant activity at physiological pH but have an intrinsic oxidase activity at acidic pH. Our system is integrated with (1) extracellular pH responsive functionality, (2) tumor cell targetable (CXC chemokine receptor 4, CXCR4 receptor specific) antagonist, (3) reactive oxygen species (ROS) inducible nanoceria, and (4) chemotherapeutic doxorubicin (DOX). These combinatorial nanoparticles (AMD-GCCNPs-DOX) are not only sensitive to the extracellular acidic pH conditions and targeted tumor cells but can also instantaneously induce ROS and release DOX intracellularly to enhance the chemotherapeutic activity in retinoblastoma cells (WERI-Rb-1 and Y79) and in xenograft (Y79/GFP-luc grafted) and genetic p107s (Rb Lox/lox , p107 +/- , p130 -/- ) orthotopic mice models. Together we introduce a lucidly engineered combinatorial nano-construct that offers a viable and simple strategy for delivering a cocktail of therapeutics into tumor cells under acidosis, exhibiting a promising new future for clinical therapeutic opportunities.