THER-15. FUNCTIONALIZED NANOPARTICLE TRAFFICKING ASSESSED IN A NOVEL MICROFLUIDIC MODEL OF THE BLOOD-BRAIN BARRIER WITH HIGH GRADE GLIOMA SPHEROIDS

High grade gliomas (HGG) are the most common malignant brain tumor in children, and remain effectively incurable with 5 year overall survival. We developed a library of functionalized nanoparticles (NPs) with ligands targeting BBB shuttle mechanisms. Using the layer-by-layer (LbL) platform to functionally ‘wrap’ polyelectrolytes around a NP core by iterative electrostatic adsorption, we can incorporate a wide range of drugs, modulate release kinetics, and add targeting moieties in a highly tunable system. In this study, we layered a liposomal core with alkyne-modified poly-L-aspartic acid or hyaluronic acid, and functionalized the surface with BBB ligands glutathione (GSH), angiopep-2 (AP2), or transferrin (Tf). Functionalization improved NP uptake in endothelial cells and lowered the IC50 of encapsulated cisplatin in HGG cells over control NPs. To investigate the ability of functionalized NPs to effectively cross the BBB and penetrate tumor cells, we incorporated HGG spheroids into a microfluidic model of co-cultured human astrocytes, pericytes, and induced pluripotent stem cell (iPSC) endothelial cells, which self-assemble into perfusable microvascular networks (µVNs) with properties comparable to the human BBB (Campisi et al. Biomaterials 2018). After perfusing fluorescent LbL NPs into µVNs with and without HGG spheroids, we quantified vascular permeability and found higher overall permeability in spheroid-containing networks. NPs functionalized with AP2 and Tf exhibited higher BBB transit than non-functionalized NPs in networks with and without HGG spheroids. In this work, we establish a new model for testing drug delivery across the BBB and identified promising functionalized drug carriers for HGG. Ongoing studies in murine models are underway to further validate this platform for clinical translation.