Improved treatment of head and neck cancer using 3-D focused ultrasound-mediated cetuximab drug delivery

Head and neck squamous cell carcinoma (HNSCC) is a common form of cancer with more than 54,000 cases expected in the United States in 2022. It is known that advanced disease correlates with an overexpression of epidermal growth factor receptor (EGFR) and leads to a poor prognosis and less favorable outcomes. Cetuximab is a monoclonal antibody that targets the extracellular domain of EGFR. However, the therapeutic effect of cetuximab is in part limited by the physical barriers of the tumor microenvironment. One promising technique that overcomes these challenges is focused ultrasound (FUS) therapy, which safely and temporarily increases microvascular permeability and drug extravasation. This study investigated the use of a novel three-dimensional (3-D) FUS approach to improve cetuximab delivery and treatment of HNSCC. HNSCC-bearing mice were divided into three groups: control and drug $\pm$ FUS. Prior to therapy, each mouse received a bolus injection of saline and microbubbles (50 $\mu \mathbf{L}$, Definity, Lantheus Medical Imaging) via a tail vein inj ection. FUS therapy was performed using a customizable ultrasound image-guided scanner (HIFUPlex-06, Verasonics Inc). For the drug dosed mice, IRDye750 (Li-COR Biosciences) was conjugated to cetuximab and administered as a single dose of 3.30 mg. $\text{kg}^{-1}$. In vivo optical imaging (Pearl Trilogy, LI-COR Biosciences) was used to measure drug accumulation at $0 \ \mathbf{d}$ (baseline) and again at 1, 3, and 7 $\mathbf{d}$. Optical imaging found mice treated with drug + FUS exhibited signal intensity increases of 143.9 and 83.0 % over mice treated with drug alone at 1 and 3 $\mathbf{d}$, respectively $(p < 0.01)$. This combined treatment of drug + FUS improved survival by 40 % compared to mice dosed with cetuximab alone $(p=0.04)$.