Oxygen generating nanoparticles for improved photodynamic therapy of hypoxic tumours

• Published in: Journal of controlled release Vol. 264; pp. 333 - 340
• Main Authors: Sheng, Yingjie, Nesbitt, Heather, Callan, Bridgeen, Taylor, Mark A., Love, Mark, McHale, Anthony P., Callan, John F.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 28.10.2017
• Subjects: Animals; Calcium peroxide; Cell Line, Tumor; Humans; Hypoxia; Hypoxia - metabolism; Male; Mice, SCID; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Nanoparticles - therapeutic use; Oxygen - chemistry; Oxygen - therapeutic use; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Peroxides - administration & dosage; Peroxides - chemistry; Peroxides - therapeutic use; Photochemotherapy; Photodynamic therapy; Calcium peroxide; Hypoxia; Photodynamic therapy; Pancreatic cancer
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2017.09.004

Photodynamic therapy (PDT) is a clinically approved anti-cancer treatment that involves the activation of an otherwise inactive sensitiser drug with light, which in the presence of molecular oxygen, generates cytotoxic reactive oxygen species (ROS). As oxygen is a key requirement for the generation of ROS in PDT and given the fact that hypoxia is a characteristic of most solid cancerous tumours, treating hypoxic tumours using PDT can be a challenge. In this manuscript, we have prepared a CaO2 nanoparticle (NP) formulation coated with a pH-sensitive polymer to enable the controlled generation of molecular oxygen as a function of pH. The polymer coat was designed to protect the particles from decomposition while in circulation but enable their activation at lower pH values in hypoxic regions of solid tumours. The oxygen generating capability of the polymer coated NPs was demonstrated in aqueous solution with minimal oxygen produced at pH7.4, whereas it increased significantly when the pH was reduced to 6.2. The polymer coated CaO2 NPs were also observed to significantly increase tumour pO2 levels (p<0.05) in mice bearing ectopic human xenograft MIA PaCa-2 pancreatic tumours with an average increase in tumour pO2 of 6.5mmHg in the period 10–30min following administration. A statistically significant improvement in PDT mediated efficacy (p<0.001) was also observed when the particles were administered to mice bearing the same tumours 20min prior to PDT treatment. These results suggest that the polymer coated CaO2 NP formulation offers significant potential as an in situ method for oxygen generation to enhance the efficacy of treatments that depend on the presence of oxygen to elicit a cytotoxic effect. pH responsive polymer coated CaO2 NPs elevate tumour oxygen levels and improve PDT mediated efficacy in mice bearing pancreatic cancer tumours. [Display omitted]