Endovascular administration and magnetic retention of nanocapsules for improved brain delivery in large cerebral vascular models

Brain delivery remains a challenge for the clinical translation of therapeutic nanomedicines, particularly in focal diseases with specific delivery needs, such as stroke. In this scenario, clinically relevant endovascular interventions are recently being proposed as strategies to enhance delivery into specific cerebral vascular territories. In this study, we assess the feasibility of endovascular delivery and magnetic retention of biocompatible magnetic nanocapsules (NCs) in cerebral circulation models that better predict human responses. More specifically, polymeric NCs synthesized with magnetic properties (superparamagnetic oxide nanoparticles, SPIONs) and fluorescent (Cy5) moieties were infused into pigs via a femoral microcatheter reaching the brain vasculature and showing greater efficacy in targeting the ipsilateral brain hemisphere with preferential accumulation in microvessels when compared to intravenous administration which resulted in very little accumulation. Transient adverse effects related to hemodynamic instability upon nanocapsule administration were observed in both administration groups related to acute complement activation. Successful endovascular brain NC delivery is further demonstrated in a 3D-vascular model of the human large arterial vessel brain supply, with successful NC accumulation in the target arterial segment (the proximal middle cerebral artery) with sensible enhancement when using local magnetic fields. This study demonstrates the feasibility of endovascular NC delivery for focal brain nanotargeting via clinically relevant and minimally invasive procedures and proves the advantages of using magnetized nanomaterials to improve local vascular NC retention. Further safety and efficacy studies, including drug nanocapsule formulations, are needed to establish the clinical relevance of the proposed approach.