SURG-03. LAYER-BY-LAYER CORE-SHELL NANOPARTICLES FOR THE DELIVERY OF HDAC INHIBITORS TO THE CENTRAL NERVOUS SYSTEM

Diffuse midline gliomas (DMGs) present unique challenges in pediatric cancer care. The location of DMGs often renders the tumor inoperable and radiation produces only a temporary effect. One promising approach in DMG treatment is histone deacetylase (HDAC) inhibitors. However, HDAC inhibitors are difficult to deliver to primary central nervous system (CNS) tumors because of low blood-brain barrier (BBB) permeability and poor accumulation in tumor tissues. The BBB permeability is particularly restricting for DMGs, which maintain a relatively intact BBB. To overcome these delivery challenges, we developed a new polymer-lipid core-shell nanoformulation for the delivery of HDAC inhibitors to the CNS that does not rely on polyethylene glycol (PEG) for colloidal stability. Removing PEG allows for surface charge manipulation to generate charged nanoparticles amenable to layer-by-layer assembly with alternately charged polyelectrolytes. This modular platform allows the addition of targeting moieties to enhance the delivery of HDAC inhibitor core-shell nanoparticles across the BBB and into DMG cells. HDAC inhibitors panobinostat and quisinostat were loaded into core-shell nanoparticles comprised of a poly(lactide-co-glycolide) (PLGA) core and a phospholipid shell. Nanoparticles were characterized using dynamic light scattering and transmission electron microscopy exhibiting favorable properties for in vivo delivery (panobinostat nanoparticle diameter 91.6 ± 1.0 nm, polydispersity index 0.115 ± 0.013). The release of HDAC inhibitors from layered and unlayered core-shell nanoparticles was investigated using high-performance liquid chromatography. The deacetylating activity of nanoencapsulated agents was confirmed in vitro in patient-derived DMG neurosphere models. CNS pharmacokinetic parameters are currently being investigated after intravenous delivery of drug-loaded nanoparticles in non-tumor-bearing mice, including cerebrospinal fluid and brain tissue concentrations of the encapsulated agents. Future studies will investigate brain biodistribution of core-shell HDAC inhibitor nanoparticles in orthotopic DMG tumor-bearing mice, comparing intravenous and local delivery strategies.