Redox-responsive nanoparticles enhance radiation therapy by altering multifaceted radio-resistance mechanisms in human castration-resistant prostate cancer cells and xenografts.

INTRODUCTION: Radiation therapy (RT) is a major modality for the treatment of prostate cancer (PCa), especially castration-resistant PCa (CRPC). However, hypoxia, often seen in PCa tumors, leads to radiation-resistance. This work investigates the effect of a novel oxygen-generating polymer-lipid manganese dioxide nanoparticle (PLMDs) on improving RT outcomes in CRPC xenograft models by modulating the tumor microenvironment (TME) both before and after RT. MATERIALS AND METHODS: Human PC3 and DU145 PCa cells were used to investigate clonogenic inhibition and DNA repair pathways in vitro. Tumor hypoxia and post-RT angiogenesis were evaluated in a PC3-bearing SCID mouse model. PC3 and DU145 xenografts were used to study the efficacy of PLMD in combination with single or fractionated RT. RESULTS: PLMD plus RT significantly inhibited clonogenic potential, increased DNA double-strand breaks, and reduced DNA damage repair in hypoxic PC3 and DU145 cells as compared to RT alone. PLMD significantly reduced hypoxia-positive areas, hypoxia induced factor 1α (HIF-1α) expression, and protein carbonyl levels (a measure of oxidative stress). Application of PLMD with RT decreased RT-induced angiogenic biomarkers by up to 3-fold. Treatment of the human CRPC xenografts with PLMD plus RT (single or fractionated doses) significantly prolonged median survival of the host compared to RT alone resulting in up to a 40% curative rate. CONCLUSION: PLMD treatment modulated TME and sensitized hypoxic human CRPC cells to RT thus enhancing the efficacy of RT. These results confirmed the potential of PLMD as an adjuvant to RT for the treatment of hypoxic CRPC.

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.