Improving Brain Arteriovenous Malformation Cure with Local Injectable Anti-Angiogenic Nanoparticle Embolization Biomaterials

ACTION BRAIN aims at developing an innovative Safe-and-Sustainable-by-Design (SSbd), open science and anticipatory innovation governance, to advance in novel injectable biomaterial for therapeutical micro-embolization of for example brain malformations considering its full LCA, including societal and economical LC. The material is based on current clinical micro-embolization materials enhanced with ionizable lipid nanoparticles (iLNPs) carrying rapamycin/trametinib for the slow and local release of anti-agiogenic drugs, and cerium oxide nanoparticles (CeO2NPs) as safe and radio-protective contrast agent for radio-guided application. This has to be applied to brain arteriovenous malformations (bAVM) are tangles of dysplastic cerebral arteries and veins that converge at a vascular nidus without normal cerebral parenchyma. High blood flow in dysplastic vessels increases the risk of rupture, causing hemorrhagic stroke, particularly in young individuals, often resulting in poor outcomes since no therapeutic approach is entirely efficacious without associated complications. Recent discoveries show altered expression of proliferation-regulating signaling molecules, including mTOR and KRAS pathways, meaning that targeted therapies modulating those pathways could potentially reverse the abnormal vascular growth. Despite the efficacy of rapamycin and trametinib in inducing apoptosis in cultured cells from bAVM patients, their clinical application is limited due to their systemic side effects. Oral or intravenous formulations are not recommended. Additionally, currently employed embolization polymers contain microparticles of tantalum to provide CT X ray contrast essential to guide the direct injection of embolic liquid through a microcatheter into the AVM. We propose to substitute it for cerium oxide nanoparticles what will reduce dose, increase resolution, and produce also anti-inflammatory and anti-angiogenic effects.