Layer‐by‐Layer Core–Shell Nanoparticles Encapsulate HDAC Inhibitors and Reduce Diffuse Midline Glioma Neurosphere Proliferation

ABSTRACT

Diffuse midline glioma (DMG) is a central nervous system (CNS) tumor that is often surgically inaccessible and radiation‐resistant. Preclinical studies have suggested the utility of histone deacetylase (HDAC) inhibitors for this challenging disease. However, clinical trials with the HDAC inhibitor panobinostat have not demonstrated a survival benefit, largely due to insufficient drug concentration at the tumor site after oral administration. The blood‐brain barrier limits the CNS penetration of the drug, and off‐target drug toxicity precludes increasing systemic doses. The present study develops a lipid‐polymer nanoparticle (NP) for targeted HDAC inhibitor delivery to DMG tumor cells. NPs with an acid‐terminated PLGA core and a soy PC and POPG lipid shell were found to display suitable properties for systemic administration and efficiently encapsulate panobinostat and quisinostat. Layer‐by‐layer modification with electrostatically charged layers of poly‐L‐arginine, followed by hyaluronate (HA) significantly increased NP association with patient‐derived DMG tumor neurospheres in vitro. Furthermore, HA‐layered panobinostat NPs retained HDAC inhibition activity and reduced the proliferation of DMG neurospheres. These results demonstrate the potential of this optimized NP for targeted delivery of HDAC inhibitors to DMG with an improved tumor exposure‐to‐off‐target toxicity ratio.