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

Abstract

Objectives-Hypoxic cancer cells have been shown to be more resistant to radiation therapy than normoxic cells. Hence, this study investigated whether ultrasound (US)-induced rupture of oxygen-carrying microbubbles (MBs) would enhance the response of breast cancer metastases to radiation.Methods-Nude mice (n = 15) received stereotactic injections of brain-seeking MDA-MB-231 breast cancer cells into the right hemisphere. Animals were randomly assigned into 1 of 5 treatment groups: no intervention, 10 Gy radiation using a small-animal radiation research platform, nitrogen-carrying MBs combined with US-mediated MB rupture immediately before 10 Gy radiation, oxygencarrying MBs immediately before 10 Gy radiation, and oxygen-carrying MBs with US-mediated MB rupture immediately before 10 Gy radiation. Tumor progression was monitored with 3-dimensional US, and overall survival was noted.Results-All groups except those treated with oxygen-carrying MB rupture and radiation had continued rapid tumor growth after treatment. Tumors treated with radiation alone showed a mean increase in volume AE SD of 337% AE 214% during the week after treatment. Tumors treated with oxygen-carrying MBs and radiation without MB rupture showed an increase in volume of 383% AE 226%. Tumors treated with radiation immediately after rupture of oxygen-carrying MBs showed an increase in volume of only 41% AE 1% (P = 0.045), and this group also showed a 1 week increase in survival time.Conclusions-Adding US-ruptured oxygen-carrying MBs to radiation therapy appears to delay tumor progression and improve survival in a murine model of metastatic breast cancer.B reast cancer is the most common of all cancers among women, projected to affect more than 12% of women in the United States. 1 Although several treatment options are available for early-stage breast cancer, they are more limited once the tumor becomes metastatic. This is particularly critical for metastasis to the brain, for which focused radiation therapy is the main treatment method. 2 It has been documented that metastasis is linked to tumor angiogenesis, especially in aggressive breast cancers. [3][4][5] The rapid and chaotic process of tumor angiogenesis

Recent Advances in Microbubble-Augmented Cancer Therapy

“…Additionally, the ultrasound-triggered oxygen microbubble destruction group experienced delayed tumor growth by 25-35 days and longer survival by 40-60 days than the other experimental groups. Comparable findings were reported using a murine model brain metastasis of breast cancer in mice [107]. These results show that increasing local oxygen levels sensitizes solid tumors to radiotherapy and the potential of microbubbles as efficient oxygen delivery vehicles.…”

Metabolite profiling reveals a connection between aldehyde dehydrogenase 1A3 and GABA metabolism in breast cancer metastasis

“…Indeed, MDA-MB-231 brain metastasis models follow two paradigms: (1) MDA-MB-231 cells are injected intracardially or (2) intracranially (El-Mabhouh et al, 2008 ; Gong et al, 2019 ; Kijewska et al, 2019 ; Sayyad et al, 2019 ). Even the “brain-seeking” MDA-MB-231BR cell line—derived from intracardiac-injected MDA-MB-231 cells which formed a brain lesion—must be injected intracranially to reliably form brain metastases (Delaney et al, 2019 ; Masiero et al, 2019 ; Yoneda et al, 2001 ). The increased systemic GABA or ALDH1A3 levels increased the permissiveness of the breast cancer cells to metastasize to the brain.…”

Opening doors with ultrasound and microbubbles: Beating biological barriers to promote drug delivery

“…Oxygen filled microbubbles have therefore been explored to restore tumor oxygenation and normalize malfunctioning blood vessels to prevent therapeutic resistance [302,[309][310][311]313]. Through microbubble cavitation, the dissolved oxygen encapsulated in the core of the microbubble is locally released in the tumor vasculature and can subsequently diffuse int the TME to support TME oxygenation [311,313,330]. Oxygen supply can sustain hypoxic cells for a longer period of time, thereby avoiding tumor necrosis [302].…”