Multi-modality imaging for precise intra-arterial delivery of mRNA, AAVs, and antibodies to the head and neck area in mice

The intra-arterial (IA) route offers several advantages over systemic infusion for drug administration, enabling selective delivery to target organs, achieving higher local drug concentrations, and minimizing off-target toxicity. However, its clinical adoption remains limited, with only a few IA-based therapies routinely used in patients. While IA chemotherapy for head and neck cancer has been explored, results remain conflicting. With the rapid rise of biologics, we investigated the efficacy of IA delivery for three key classes-mRNA, adeno-associated viruses (AAVs), and monoclonal antibodies-targeting the head and neck region in mice. We infused firefly luciferase-encoding mRNA (Luc mRNA), adeno-associated virus encoding luciferase (AAV9-Luc), and radiolabeled anti-VEGF monoclonal antibody (bevacizumab) via the external carotid artery and compared results with IV administration. Bioluminescence imaging revealed robust expression of Luc mRNA and AAV9-Luc in the head and neck region following IA infusion, with negligible expression after IV delivery. qPCR analysis further confirmed significantly higher Luc mRNA expression in targeted tissues (salivary gland, temporal muscle, and tongue) following IA administration. In contrast, after IV administration, Luc mRNA expression was detected only in the salivary gland at a level 100-fold lower, with no detectable expression in the temporal muscle or tongue. For quantitative assessment of antibody biodistribution, we radiolabeled bevacizumab with Zirconium-89 (⁸⁹Zr) and performed positron emission tomography (PET) imaging following IA vs. IV infusion. PET imaging revealed significantly increased uptake of bevacizumab in the neck following IA delivery (mean standardized uptake values: 0.65 vs. 0.29, IA vs. IV), corroborated by ex vivo biodistribution analysis, which confirmed higher accumulation of bevacizumab in targeted structures of the head and neck. In summary, our findings demonstrate the feasibility and superiority of the IA route for the delivery of biologics to the head and neck territory. This study provides compelling evidence supporting the translational potential of IA administration as a highly effective strategy for precise biologic delivery in head and neck disorders and cancers.