Nanocarrier Drug Release and Blood-Brain Barrier Penetration at Post-Stroke Microthrombi Monitored by Real-Time Förster Resonance Energy Transfer-Based Detection System (FedEcs)

Abstract

Nanotechnology holds great promise to improve delivery of therapeutics to the brain. Current experimental approaches are, however, hampered by the lack of tools to dynamically monitor cargo delivery in vivo. We developed highly fluorescent lipid nanodroplets (LNDs) that carry a F&oumlrster-resonance energy transfer (FRET)-based drug delivery detection system able to monitor cargo release (FedEcs) in vivo. We investigated the distribution, stability, and cargo release of FedEcs-LNDs in the healthy and ischemic mouse brain by intravital multiphoton microscopy. We dynamically observed that LNDs accumulated within cerebral microclots after ischemia, caused by magnetic nanoparticles (Nano-stroke), and released their cargo. Furthermore, the blood-brain barrier (BBB) became permeable at sites of microclots thereby allowing FedEcs-LNDs to cross the BBB and to deliver their cargo to the brain parenchyma. Consequently, FedEcs represents a novel tool to quantitatively investigate the nanocarriers biodistribution and cargo release using intravital microscopy and may thus tremendously ease their translational validation.