Nanocatalase-Based Oxygen-Generating Nanocarriers for Active Oxygen Delivery to Relieve Hypoxia in Pancreatic Cancer

Hypoxia of the tumor microenvironment has the potential to give rise to significant radiation and drug resistance that can contribute to tumor recurrence and or low treatment efficacy. If hypoxia can be mitigated, successive treatments can be more efficacious. Herein, we propose a dual oxygen supply strategy afforded by oxygen generation utilizing dextran sulfate-modified catalase as an enzyme in a nano bioreactor that will react with the overexpressed hydrogen peroxide in the tumor microenvironment to generate oxygen. Meanwhile, oxygen loaded onto these nanoparticles could diffuse out of the nanocarriers to deliver a second stage of oxygenation. Our dual oxygen supply platform was found to release oxygen at a sustained rate for over 6 h in PANC-1 pancreatic cancer cells. We further extended our studies to evaluating hypoxia mitigation efficacy in three-dimensional (3D) tumor spheroids fabricated with a flip well plate method. Gene expression studies revealed that the expression of several hypoxia-related genes in both two-dimensional (2D) and 3D culture systems could be restored upon oxygenation to normal levels. The dual oxygen supply platform was synthesized using safe reagents by "green" synthesis and with Food and Drug Administration (FDA)-approved reagents and is expected to have a broad appeal in mitigating hypoxia in cancers as well as in other diseases.