Abstract
Pediatric central nervous system tumors are the leading cause of cancer death in children. Promising therapeutics have been identified, but the ability to deliver an effective concentration to the tumor without causing excessive systemic toxicity remains a challenge. To address this, we leveraged a tunable nanocarrier platform to design a brain-penetrant nanocarrier with preferential uptake into tumor cells over healthy brain cells. First, we used the layer-by-layer technique to iteratively coat liposomes with nanometers-thick layers of oppositely charged polyelectrolytes. To investigate the influence of surface chemistry on cellular trafficking, a panel of layered liposomes was tested for interactions with cancer cell lines, identifying poly-L-aspartic acid and hyaluronic acid as the highest-performing formulations across brain tumor lines. To facilitate nanocarrier transit across the blood-brain barrier (BBB), we developed a click chemistry platform to functionalize the nanocarrier with BBB shuttle ligands. To investigate trafficking in vitro, we utilized a microfluidic brain microvascular model comprising endothelial cells, astrocytes, pericytes, and glioma cells that self-assemble into a perfusable vascular network. We found that nanocarrier size influenced vascular transport, and the addition of BBB shuttle ligands improved transport in the presence of a glioma spheroid. To investigate in vivo nanocarrier trafficking, we performed intravital imaging through a cranial window in anesthetized mice. After intravenous administration, nanocarrier transit across intact brain capillaries was visualized using two photon microscopy, and vessel permeability was quantified over time. Ongoing studies in mice bearing patient-derived xenograft medulloblastoma and glioma tumors are being conducted to further characterize trafficking across tumor-associated vasculature.
Cerebromicrovascular endothelial cells are resistant to l-glutamate