Drug Targeting of Self-Assembled Polymeric Nanocarriers Through the Blood Brain Barrier to a Patient-Derived Model of Pediatric Brain Tumor

Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric cancer in the central nervous system (CNS). In DIPG, the blood brain barrier (BBB) remains intact, thus cells proliferate and migrate without disrupting the anatomical structures until the disease reaches advanced stages. SN-38 is a topoisomerase I inhibitor and it has demonstrated potent anti-DIPG activity in vitro, though limited in vivo due to low bioavailability in the central nervous system (CNS). In addition, SN-38 undergoes hydrolysis in the biological milieu to its inactive carboxylate.

We hypothesized that the intravenous administration of SN-38-loaded amphiphilic polymeric nanocarrier with sizes in the 150-300 nm range would improve the delivery of the drug to the CNS. In this context, a novel type of self-assembled polymeric nanoparticle was synthesized by the hydrophobization of a chitosan backbone with poly(methyl methacrylate) (PMMA) and poly(acrylic acid) (PAAc). Chitosan has been demonstrated to disrupt the tight junctions in different epithelia and endothelia and increase the permeability of nanoparticulate matter. PMMA serves as the hydrophobe that induces self-assembly to produce the nanoparticles, while PAAc generates a slightly acid microenvironment to preserve the active cargo in its active lactonic form. Amphiphilic chitosan-PMMA-PAAc copolymers were synthesized and their aggregation, size, size distribution and zeta-potential characterized by dynamic light scattering. Then, we optimized the encapsulation of SN-38 and the conditions for the physical stabilization of the nanoparticles by ionotropic crosslinking. Finally, we studied the interaction of these novel nanocarriers with a patient-derived DIPG cell culture model and a BBB cell line in vitro.