Improved Tumor Control Following Radiosensitization with Ultrasound-Sensitive Oxygen Microbubbles and Tumor Mitochondrial Respiration Inhibitors in a Preclinical Model of Head and Neck Cancer

Authors

Quezia Lacerda, Thomas Jefferson University
Hebah Falatah, Thomas Jefferson University
Ji-Bin Liu, Thomas Jefferson University
Corinne E. Wessner, Thomas Jefferson University
Brian Oeffinger, Drexel University
Ankit Rochani, St. John Fisher UniversityFollow
Dennis B. Leeper, Thomas Jefferson University
Flemming Forsberg, Thomas Jefferson University
Joseph M. Curry, Thomas Jefferson University
Gagan Kaushal, Thomas Jefferson University
Scott W. Keith, Thomas Jefferson University
Patrick O'Kane, Thomas Jefferson University
Margaret A. Wheatley, Drexel University
John R. Eisenbrey, Thomas Jefferson University

Document Type

Article

Publication Date

4-21-2023

Abstract

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.

DOI

https://doi.org/10.3390/pharmaceutics15041302

Publication Information

Lacerda, Quezia; Falatah, Hebah; Liu, Ji-Bin; Wessner, Corinne E.; Oeffinger, Brian; Rochani, Ankit; Leeper, Dennis B.; Forsberg, Flemming; Curry, Joseph M.; Kaushal, Gagan; Keith, Scott W.; O'Kane, Patrick; Wheatley, Margaret A.; and Eisenbrey, John R. (2023). "Improved Tumor Control Following Radiosensitization with Ultrasound-Sensitive Oxygen Microbubbles and Tumor Mitochondrial Respiration Inhibitors in a Preclinical Model of Head and Neck Cancer." Pharmaceutics 15.4.

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