SURG-01. Fucoidan nanoparticle encapsulation of targeted therapies facilitates BBB penetration and tumor-specific localization in DMG

The blood-brain barrier (BBB) is one of the greatest barriers for the effective treatment of H3K27-altered diffuse midline glioma (DMG), a near universally fatal childhood brain cancer. EZH2 inhibitor EPZ-6438 (Tazemetostat) has emerged as a promising targeted therapeutic for DMG but has limited BBB penetration. We have developed a clinically-compatible fucoidan (Fi) nanoparticle that homes to P-selectin on tumor vasculature after low-dose radiation (RT) to breach the BBB through active caveolin-1-dependent transcytosis and deliver several classes of targeted therapies. In previous studies using a transgenic mouse model of SHH-driven medulloblastoma with an intact BBB, our approach with Fi-encapsulated Vismodegib significantly improved survival while eliminating on-target systemic toxicities. We have now applied this drug delivery technology to DMG using RCAS-TVA based transgenic mouse models with a relatively intact BBB. We are able to fucoidan encapsulate EPZ-6438 (Fi-EPZ) together with a biocompatible excipient near-infrared dye (indocyanine green) through a nanoprecipitation reaction using hydrophobic forces and simple vortexing with high drug loading efficiency (∼70% drug content). Fi-EPZ nanoparticles are uniform (average size distribution by AFM of 88±5nm), stable (-30 mV zeta potential), and amenable to lyophilization for at least three months to facilitate storage and transport. We have confirmed that our RCAS DMG tumor vasculature expresses P-selectin, and that expression is enhanced in a time-dependent manner by a single low-dose (2 Gy) fraction of ionizing radiation. Importantly, this RT-primed approach permits tumor localization of Fi-EPZ while sparing non-tumor brain regions. We are working to confirm drug target inhibition, PK, biodistribution, and survival benefit. Our findings will provide the foundation for this P-selectin targeting nanomedicine approach to be evaluated in clinical trials for children with this lethal cancer.