Abstract
Systemic therapies for brain tumors are complicated by dose-limiting extraneural toxicity, serum protein binding and restricted blood-brain barrier (BBB) permeability. For patients with SHH-subgroup medulloblastoma, SHH-pathway inhibition may be more effective and less toxic than current non-targeted therapy. However, vismodegib, which effectively targets SHH-driven basal cell carcinoma, has limited benefit for patients with SHH-driven medulloblastoma. Formulating vismodegib in poly(2-oxazoline) micelles (POx-vismo) improved delivery and efficacy, using medulloblastoma-prone hGFAP-Cre/SmoM2 (G-Smo) mice for a preclinical model. Compared to conventional vismodegib (c-vismo), POx-vismo increased maximum tolerated dose (MTD), tumor:serum ratio and penetration to brain and tumor. Further studies have shown the ability of POx micelles to load CDK4/6 inhibitor. Loading into POx micelles improved MTD and efficacy of palbociclib. Taken together, our results show the potential for poly(2-oxazoline) micelles delivery to make failed brain tumor treatments newly effective. This work was supported by the NCI Alliance for Nanotechnology in Cancer (U54CA198999, Carolina Center of Cancer Nanotechnology Excellence), by NINDS (R01NS088219, R01NS102627) and by the St. Baldrick’s Foundation. References: (1) H. Bader et al. Angew. Macromol. Chem. 1984, 123/124:457; A. Kabanov et al. FEBS Lett. 1989, 258:343; M. Yokoyama et al. Cancer Res. 1990, 50:1693. (2) M. Yokoyama et al. J. Exp. Clin. Med. 2011, 3:8. (3) T. Lorson et al. Biomaterials. 2018, 178:204. (4) R. Luxenhofer et al. Biomaterials 2010, 31:4972; A. Schulz et al. ACS Nano 2014, 8 (3):2686; Z. He et al. Biomaterials 2016, 101:296