Orally administered oxygen nanobubbles enhance tumor response to sonodynamic therapy

Suspensions of oxygen-filled bubbles are under active investigation as potential means of relieving tissue hypoxia. Intravenous administration of large quantities of bubbles is, however, undesirable. Previous work by the authors has demonstrated that tumor oxygen levels can be increased following oral administration of phospholipid stabilized oxygen nanobubbles. The aim of this study was to determine whether this would enhance the efficacy of sonodynamic therapy (SDT), which is known to be inhibited in hypoxic tissue. Experiments were conducted in a murine model of pancreatic cancer. Animals were treated with SDT (intratumoural injection of 1 mM Rose Bengal followed by exposure to 1 MHz ultrasound, 0.1 kHz pulse repetition frequency, 30% duty cycle, 3.5 W cm−2 for 3.5 minutes) either with or without a prior gavage of oxygen bubbles. A statistically significant reduction in the rate of tumor growth was observed in the groups receiving oxygen nanobubbles either 5 or 20 minutes before SDT. Separate measurements of tumor oxygen using a fiber optic probe and expression of hypoxia inducible factor (HIF)1α following tumor excision, confirmed the change in tumor oxygen levels. These findings offer a potentially promising new approach to relieving tissue hypoxia in order to facilitate cancer therapy

A single microbubble formulation carrying 5-fluorouridine, irinotecan and oxaliplatin to enable FOLFIRINOX treatment of pancreatic and colon cancer using ultrasound targeted microbubble destruction

FOLFIRINOX and FOLFOXIRI are combination chemotherapy treatments that incorporate the same drug cocktail (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) but exploit an altered dosing regimen when used in the management of pancreatic and colorectal cancer, respectively. Both have proven effective in extending life when used to treat patients with metastatic disease but are accompanied by significant adverse effects. To facilitate improved tumour-targeting of this drug combination, an ultrasound responsive microbubble formulation loaded with 5-fluorouridine, irinotecan and oxaliplatin (FIRINOX MB) was developed and its efficacy tested, together with the non-toxic folinic acid, in preclinical murine models of pancreatic and colorectal cancer. A significant improvement in tumour growth delay was observed in both models following ultrasound targeted microbubble destruction (UTMD) mediated FIRINOX treatment with pancreatic tumours 189% and colorectal tumours 82% smaller at the conclusion of the study when compared to animals treated with a standard dose of FOLFIRINOX. Survival prospects were also improved for animals in the UTMD mediated FIRINOX treatment group with an average survival of 22.17 ± 12.19 days (pancreatic) and 44.40 ± 3.85 days (colorectal) compared to standard FOLFIRINOX treatment (15.83 ± 4.17 days(pancreatic) and 37.50 ± 7.72 days (colon)). Notably, this improved efficacy was achieved using FIRINOX MB that contained 5-fluorouricil, irinotecan and oxaliplatin loadings that were 13.44-fold, 9.19-fold and 1.53-fold lower than used for the standard FOLFIRINOX treatment. These results suggest that UTMD enhances delivery of FIRINOX chemotherapy, making it significantly more effective at a substantially lower dose. In addition, the reduced systemic levels of 5-fluorouracil, irinotecan and oxaliplatin should also make the treatment more tolerable and reduce the adverse effects often associated with this treatment