Oxygen microbubbles improve radiotherapy tumor control in a rat fibrosarcoma model – A preliminary study

Abstract

Cancer affects 39.6% of Americans at some point during their lifetime. Solid tumor microenvironments are characterized by a disorganized, leaky vasculature that promotes regions of low oxygenation (hypoxia). Tumor hypoxia is a key predictor of poor treatment outcome for all radiotherapy (RT), chemotherapy and surgery procedures, and is a hallmark of metastatic potential. In particular, the radiation therapy dose needed to achieve the same tumor control probability in hypoxic tissue as in normoxic tissue can be up to 3 times higher. Even very small tumors (<2–3 mm3) comprise 10–30% of hypoxic regions in the form of chronic and/or transient hypoxia fluctuating over the course of seconds to days. We investigate the potential of recently developed lipid-stabilized oxygen microbubbles (OMBs) to improve the therapeutic ratio of RT. OMBs, but not nitrogen microbubbles (NMBs), are shown to significantly increase dissolved oxygen content when added to water in vitro and increase tumor oxygen levels in vivo in a rat fibrosarcoma model. Tumor control is significantly improved with OMB but not NMB intra-tumoral injections immediately prior to RT treatment and effect size is shown to depend on initial tumor volume on RT treatment day, as expected.

Conventional dose rate spatially-fractionated radiation therapy (SFRT) treatment response and its association with dosimetric parameters—A preclinical study in a Fischer 344 rat model

“…Forty-two eight-week-old female Fischer 344 rats from Charles River Labs and rat fibrosarcoma tumor allografts were used [23]. The rat fibrosarcoma (FSA) allograft model has been well characterized in several radiotherapy response studies by our and collaborator labs [23][24][25]. Rat FSA is characterized as a local, non-metastasizing tumor that is highly vascular and oxygen dependent.…”

Breast Cancer Brain Metastasis Response to Radiation After Microbubble Oxygen Delivery in a Murine Model

“…UCA cavitation for localized delivery of gases, specifically oxygen, is less studied but represents a potentially viable delivery platform. Groups have proposed using nano‐ and micro‐sized UCAs stabilized with chitosan, dextran, protein, and lipid‐based shells to deliver oxygen …”

Phospholipid Oxygen Microbubbles for Image-Guided Therapy

“…On the topic of oxygen delivery for radiotherapy, Fix et al has previously shown that a 30% increase in tumoral hemoglobin saturation is sufficient to achieve a ~30% reduction in tumor growth rate by injection of ~3×10 10 OMBs/kg directly into the tumor [29]. For intravenous, as opposed to intratumoral administration, we see a constraint on OMB concentration (<5×10 8 OMB/mL) due to handling considerations related to excessive viscosity at high OMB concentrations.…”

“…In 2016, Owen et al showed that orally administered OMB can reduce tumor hypoxia [3]. In 2018, Fix et al showed that intra-tumoral injection lipid-coated OMB Ivyspring International Publisher can increase tumor oxygen levels and tumor control in a fibrosarcoma rat model [4]. In the same year, Eisenbrey et al showed that intravenous injection of surfactant-coated OMB can increase tumor oxygen and control in a breast cancer model [5,6].…”