Abstract Diffuse midline glioma (DMG) is the most lethal pediatric brain tumor, with a median survival of less than 12 months. The blood-brain barrier (BBB) severely limits systemic drug delivery. Intranasal delivery (IND) bypasses the BBB, and immunoliposome (iLS) formulations enable receptor-targeted delivery to tumor cells while minimizing toxicity to normal tissues. This study developed and validated an IND strategy using PDGFRA-targeted immunoliposomes encapsulating SN-38 (PDGFRA-iLS-SN38) for selective DMG therapy.PDGFRA expression was assessed in DMG cell lines by Western blot, DIPG007 (PDGFRA-high) and SF8628 (PDGFRA-low) cells were selected for comparison. Cellular uptake of rhodamine-labeled PDGFRA-iLS was quantified by fluorescence microscopy. Anti-proliferative effects were measured using MTS viability, colony formation, BrdU incorporation, and Annexin V apoptosis assays. DNA damage (γH2AX, cleaved PARP) and DNA repair (BRCA1, RAD51) markers were analyzed by Western blot and immunocytochemistry. In vivo efficacy was evaluated in orthotopic DMG patient-derived xenograft (PDX) models using bioluminescence imaging and survival analysis.PDGFRA-iLS exhibited significantly enhanced cellular uptake in DIPG007 cells compared to non-targeted liposomes (LS), whereas minimal differential uptake was observed in SF8628 cells. In DIPG007 cells, PDGFRA-iLS-SN38 demonstrated greater anti-proliferative effects than LS-SN38, as evidenced by reduced cell viability and colony formation, suppression of S-phase progression, and increased apoptosis. PDGFRA-iLS-SN38 upregulated DNA damage markers (γH2AX, cleaved PARP) while downregulating DNA repair markers (BRCA1, RAD51) in DIPG007 cells.In orthotopic PDX models, IND of PDGFRA-iLS-SN38 significantly suppressed tumor growth and prolonged survival in PDGFRA-high DMG models compared to LS-SN38. Immunohistochemical analysis further revealed reduced Ki-67 proliferation and increased TUNEL-positive apoptosis in PDGFRA-high DMG models treated with PDGFRA-iLS-SN38.
Uchida et al. (Tue,) studied this question.