COG133 peptide-conjugated lipid nanoparticles sensitize medulloblastoma to radiation therapy in mice.

Medulloblastoma (MB) is a malignant brain tumor that often arises in the cerebellum and has a propensity for spreading to the spinal cord or other parts of the central nervous system (CNS). Craniospinal irradiation (CSI) has long been a cornerstone in the treatment of MB, especially for patients with high-risk or metastatic disease. However, CSI often leads to long-term neurocognitive deficits, including learning disabilities, and growth abnormalities, especially in children. In this study, we aimed to decrease the dose of irradiation and the proliferation of MB by using Volasertib (VSB), a Polo-like kinase 1 (PLK1) specific inhibitor. VSB was highly potent in-vitro with an IC of 27.43 nM and 13 nM in HDMB03 and DAOY cells, respectively. However, in the orthotopic MB mouse model, VSB as a free drug did not improve overall survival or decrease tumor burden. Hence, we encapsulated VSB in COG133-conjugated lipid nanoparticles (COG133-LNPs) to circumvent the blood-brain barrier (BBB). We observed that COG-133-LNPs loaded with VSB increased the biodistribution of VSB by three folds than the non-targeted LNPs in the brain. Furthermore, COG133-LNPs along with irradiation decreased tumor burden significantly as compared to VSB or radiation alone. To our observation, COG133-LNPs display high potency in killing MB cells and sensitizing them toward radiation therapy.