Abstract Pediatric high-grade glioma is the leading cause of cancer-related death in children, with diffuse midline glioma (DMG) being the most malignant and devastating. Its anatomical location in the brainstem, infiltrative nature, and the blood-brain barrier (BBB) limit surgical resection and distribution of systemically administered drugs. Intranasal delivery (IND) is a non-invasive drug delivery system that bypasses the BBB by exploiting the unique anatomical connections of the olfactory and trigeminal pathways to the brain. We have previously demonstrated IND efficacy of nanoliposomal (LS) formulation of the active metabolite of the DNA topoisomerase I inhibitor irinotecan, LS-SN-38, in orthotopic human DMG xenograft models. In contrast to liposome, polymersome improves mechanical stability and drug retention in vivo. In addition, the specificity of polymersome (PS) can be enhanced with antibodies specific to tumor cells, resulting in targeted drug delivery and reduced toxicity to normal brain tissues. In this study, we used platelet-derived growth factor receptor alpha (PDGFRA)-conjugated immunopolymersome (iPS) to facilitate selective drug delivery to PDGFRA-expressing DMGs. The cellular uptake of Alexa568-labeled PDGFRA-iPS was confirmed by fluorescence microscopy. We test the anti-cell proliferative activity of PDGFRA-iPS-encapsulated degrader of bromodomain-containing protein 4 (dBET6) in vitro and in vivo. dBET6 has large macromolecules and poor BBB penetration. The efficacy will be presented at the meeting. PDGFRA-iPS could represent a promising therapeutic approach for targeting PDGFRA-expressing DMG.
Mineji et al. (Fri,) studied this question.