Pharmaceutical nanoformulation strategies to spatiotemporally manipulate oxidative stress for improving cancer therapies — exemplified by polyunsaturated fatty acids and other ROS-modulating agents

Chronic oxidative stress and inflammation promote tumorigenesis and tumor progression, while certain chemotherapeutic drugs and radiation are applied to produce free radicals against cancer cells. To reduce tumor-promoting oxidative stress and protect normal tissue from chemotherapy and radiation-associated toxicity, dietary antioxidants, such as omega-3 polyunsaturated fatty acids (PUFA), have been combined with cancer therapies. However, the results of clinical studies are mixed with little to no benefit to therapeutic effect, and even exacerbated adverse effects. PUFA can function as a double-edged sword as an anti- or pro-oxidant depending on when and where it appears. Recent publications indicate that nano-formulations can enhance therapeutic benefit of PUFA and other free-radical generating cytotoxic drugs during chemotherapy by controlling oxidative stress within a nanoscale vicinity. This article critically evaluates the concurrent use of dietary omega-3 PUFA as an adjuvant to cancer therapies, reviews the findings in studies using nanoparticle formulations, and delineates the importance of spatiotemporal manipulation of oxidative stress by pharmaceutical nanotechnology for improving outcomes with cancer therapies using various examples. We hope this review will shed light on rational design of nano-formulations to turn harmful pathological oxidative stress into useful pharmacological modalities by manipulating the location and timing of free-radical generation. Graphical abstract