Microbubble encapsulation of monocarboxylate transporter 1 inhibitor AZD3965 for ultrasound mediated delivery to head and neck squamous cell carcinoma

Many solid tumors, including head and neck squamous cell carcinoma (HNSCC), are characterized by the dysregulation of metabolic functions, including accelerated glycolysis. This results in accumulation of intracellular lactate, which in turn leads to an increased expression of monocarboxylate transporters (MCT) family members to export lactate. The MCT 1 inhibitor AZD3965 has been developed as a targeted therapy, as it can increase intracellular lactate concentration resulting in tumor cell death, however translation into clinical trials has been challenging due to off target toxicity. The goal of this work was to develop a platform for targeted delivery of AZD3965 utilizing a surfactant stabilized microbubble (SE61) and ultrasound. AZD3965 was successfully loaded into SE61, resulting in a microbubble mean size of 1.58 +/- 0.08 mu m, a mean microbubble concentration of 5.58 +/- 1.44 x 108 microbubbles/mL and an average AZD3965 loading of 45.2 +/- 3.5 mu g/mL of SE61 microbubbles. The initial tolerability and ability to improve tumor control by ultrasound mediated microbubble delivery of the MCT 1 inhibitor to HNSCC tumor model was also evaluated in vivo. SE61 microbubbles loaded with AZD3965 were well tolerated, were imaged and successfully destroyed at tumor sites using ultrasound. Future studies will likely require a combination of multiple treatment doses, increased drug loading, and/or multiple inhibitors as no significant tumor response to treatment was observed in vivo. Overall, this study showed the feasibility of loading the MCT 1 inhibitor AZD3965 onto the SE61 microbubble platform for targeted ultrasound mediated delivery to HNSCC.