DDEL-05. Intranasal delivery of dBET6 encapsulated in PDGFRA-immunopolymersome for the treatment of diffuse midline glioma

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. The infiltrative nature together with delicate tumor location in the brainstem precludes surgical resection, and the blood-brain barrier (BBB) limits distribution of systemically administered drugs to the brain. 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 formulation of the active metabolite of the DNA topoisomerase I inhibitor in orthotopic human DMG xenograft models. We recently employed polymersome, which improves mechanical stability and drug retention in compared to liposome. In addition, the specificity of polymersome (PS) can be enhanced by immunopolymersome formulation (iPS), which is coated the surface of polymersome wirh antibodies specific to tumor cells, leading to target drug delivery to the tumor cells and reduce toxicity to normal brain tissues. In this study, we used PDGFRA-conjugated iPS to facilitate selective drug delivery to PDGFRA-expressing DMGs. We test the anti-cell proliferative activity of PDGFRA-iPS-encapsulated PROPTAC - degrader of bromodomain-containing protein 4 (dBET6). dBET6 has large macromolecules and poor BBB-penetration. In PDGFRA-expressing DMG cell lines, PDGFRA-iPS-encapsulated dBET6 significantly reduced cell viability compared to control-PS-encapsulated dBET6 with using MTS assay and colony formation assay. The efficacy in vivo will be presented at the meeting. PDGFRA-iPS-dBET6 could represent a promising therapeutic approach for targeting PDGFRA-expressing DMG.