Improved Tumor Control Following Radiosensitization with Ultrasound-Sensitive Oxygen Microbubbles and Tumor Mitochondrial Respiration Inhibitors in a Preclinical Model of Head and Neck Cancer
Quezia Lacerda,
Hebah Falatah,
Ji-Bin Liu,
Corinne E. Wessner,
Brian Oeffinger,
Ankit Rochani,
Dennis B. Leeper,
Flemming Forsberg,
Joseph M. Curry,
Gagan Kaushal,
Scott W. Keith,
Patrick O’Kane,
Margaret A. Wheatley,
John R. Eisenbrey
Affiliations
Quezia Lacerda
Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA
Hebah Falatah
Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA
Ji-Bin Liu
Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA
Corinne E. Wessner
Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA
Brian Oeffinger
School of Biomedical Engineering, Science and Health Systems Drexel University, Philadelphia, PA 19104, USA
Ankit Rochani
Department of Pharmaceutical Sciences, Thomas Jefferson University, Philadelphia, PA 19107, USA
Dennis B. Leeper
Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA 19107, USA
Flemming Forsberg
Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA
Joseph M. Curry
Department of Otolaryngology, Thomas Jefferson University, Philadelphia, PA 19107, USA
Gagan Kaushal
Department of Pharmaceutical Sciences, Thomas Jefferson University, Philadelphia, PA 19107, USA
Scott W. Keith
Division of Biostatistics, Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
Patrick O’Kane
Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA
Margaret A. Wheatley
School of Biomedical Engineering, Science and Health Systems Drexel University, Philadelphia, PA 19104, USA
John R. Eisenbrey
Department of Radiology, Thomas Jefferson University, Philadelphia, PA 19107, USA
Tumor hypoxia (oxygen deficiency) is a major contributor to radiotherapy resistance. Ultrasound-sensitive microbubbles containing oxygen have been explored as a mechanism for overcoming tumor hypoxia locally prior to radiotherapy. Previously, our group demonstrated the ability to encapsulate and deliver a pharmacological inhibitor of tumor mitochondrial respiration (lonidamine (LND)), which resulted in ultrasound-sensitive microbubbles loaded with O2 and LND providing prolonged oxygenation relative to oxygenated microbubbles alone. This follow-up study aimed to evaluate the therapeutic response to radiation following the administration of oxygen microbubbles combined with tumor mitochondrial respiration inhibitors in a head and neck squamous cell carcinoma (HNSCC) tumor model. The influences of different radiation dose rates and treatment combinations were also explored. The results demonstrated that the co-delivery of O2 and LND successfully sensitized HNSCC tumors to radiation, and this was also enhanced with oral metformin, significantly slowing tumor growth relative to unsensitized controls (p < 0.01). Microbubble sensitization was also shown to improve overall animal survival. Importantly, effects were found to be radiation dose-rate-dependent, reflecting the transient nature of tumor oxygenation.
