Encapsulation of two anti-cancer experimental drugs within amphiphilic polymeric nanocarriers for the treatment of pediatric tumors of the Central Nervous System

Central nervous system (CNS) tumors are the second most common pediatric malignancy and the leading cause of childhood morbidity and mortality due to cancer. High percentage of the CNS tumors in children are diffuse intrinsic pontine gliomas (DIPG). DIPG is a tumor with likely fully conserved blood-brain barrier (BBB), the anatomical barrier that controls the trafficking of endogenous (e.g., nutrients) and exogenous molecules (e.g., drugs) from the systemic circulation into the CNS. The selection of the candidate drug for the treatment of DIPG is based on the recent progresses made in the biology of the disease. In this project, we investigate the encapsulation of two experimental drugs that inhibit two pathways upregulated in DIPG for their delivery to the CNS by the intranasal route: the anti-STAT3 agent WP1066 and the anti-ACVR1 LDN-212854. In this context, mixed mucoadhesive amphiphilic nanoparticles made of chitosan (CS) and poly(vinyl alcohol) (PVA) that were hydrophobized with poly(methyl methacrylate) (PMMA) blocks were synthesized and characterized. The size, size distribution and Zeta-potential of the nanoparticles was measured by dynamic light scattering and nanoparticles tracking analysis. Next, we investigated the intrinsic aqueous solubility and the encapsulation of both compounds within the nanoparticles. Finally, the interaction of these novel nanocarriers with patient-derived DIPG cells was characterized by means of confocal microscopy and the inhibitory concentration 50 (IC₅₀) of the free and encapsulated drugs was measured.

Acknowledgements. This work was funded by the Israel Science Foundation.