Hybrid lipidic and fluorinated polymer microbubbles for blood-brain barrier opening: a comparative study with SonoVue

Abstract

Microbubble-mediated focused ultrasound is a promising strategy for transient and localized blood-brain barrier (BBB) permeabilization, enabling drug delivery to the brain. Optimizing microbubble stability and acoustic response is essential to maximize treatment efficiency and minimize potential damage. This study introduces an innovative microbubble formulation with a phospholipid-fluoropolymer shell (LIP-POL), designed to enhance circulation persistence while maintaining a low cavitation threshold. The physicochemical and acoustic properties of LIP-POL microbubbles were systematically compared with phospholipid-shell microbubbles (LIP) and the commercial agent SonoVue®. Both SonoVue and LIP-POL microbubbles have similar concentrations and sizes (approximately 5 × 10⁸ bubbles/mL, mean size of 2.5-2.7 µm), whereas LIP microbubbles are around 100 times more concentrated (7.3 × 10¹⁰ bubbles/mL) and slightly smaller (1.9 µm). In vitro, ultra-harmonics appeared at 120 kPa for LIP, 150 kPa for LIP-POL, and 200 kPa for SonoVue (fc = 1 MHz, PRF = 10 kHz, 40 cycles). Consistent with microbubbles’ acoustic signature, the BBB opening threshold (fc = 1.5 MHz) occurred at lower Mechanical Indices (MI) for LIP and LIP-POL microbubbles (MI = 0.16) compared to SonoVue (MI = 0.20). Stability of circulating microbubbles was assessed using BBB permeabilization protocol at various time points post microbubble-injection. LIP-POL microbubbles remained effective for up to 15 min post-injection, compared to 7.5 min for LIP and 5 min for SonoVue (2 × 10⁷ microbubbles injected). The prolonged efficacy of LIP-POL microbubbles (three times longer than SonoVue) opens the possibility for extended ultrasound treatments, particularly for BBB permeabilization across larger areas in large animal models or humans.