Intraarterial microbubble delivery enhances focused ultrasound induced blood brain barrier opening in the murine substantia nigra

Focused ultrasound (FUS) combined with microbubbles facilitates blood-brain barrier (BBB) opening to enhance therapeutic delivery to the substantia nigra for Parkinson's disease treatment. While intravenous (IV) microbubble administration is commonly used, the efficacy of intra-arterial (IA) delivery remains unclear. This study compared IA versus IV administration of low (2.80 × 10⁸/kg) and high (1.12 × 10⁹/kg) microbubble doses for FUS-induced BBB opening in the murine substantia nigra. FUS was applied at a BBB-opening threshold (mechanical index: 0.42; 1 Hz; 60 s; 1% duty cycle; bregma - 3.16 mm). BBB permeability was assessed using Evans blue (EB) dye extravasation and IgG immunohistochemistry. EB staining of peripheral organs evaluated systemic off-target effects. At the low dose, Near-Infrared Fluorescence imaging on the LI-COR Odyssey system showed lower EB signals in the stomach and liver (both P = 0.01) in the IA group versus the IV low-dose MB group. Notably, high-dose IA administration led to greater IgG extravasation in deep brain regions, including thalamus (P = 0.002) and substantia nigra (P = 0.0001), and reduced off-target effects in the stomach (P = 0.004), lung (P = 0.04), liver (P = 0.004), and spleen (P = 0.02) compared to the IV high-dose group. IA delivery offers enhanced BBB opening but requires safety considerations.