| Popis: |
Medulloblastoma (MB) is the most common malignant pediatric brain tumor with ~30% mediated by Sonic hedgehog (SHH) signaling. While SHH effector Smoothened inhibition is promising, therapeutic index is reduced by high systemic doses required for sufficient intracranial drug concentrations. Treatment-related toxicities associated with radiation therapy result in lifelong morbidity, and SHH pathway inhibition in children notably results in permanent bone defects. Here, we found that nanoparticle-mediated P-selectin targeting on tumor vasculature induces caveolin-1-dependent transcellular passage across the blood-brain barrier. A vismodegib nanocarrier that targets P-selectin exhibited striking efficacy and markedly reduced both bone-related toxicities and drug exposure to healthy brain. These findings demonstrate a potent strategy and novel mechanism for targeted intracranial pharmacodelivery that overcomes the restrictive endothelial barrier to achieve enhanced tumor-selective penetration and has therapeutic implications for other diseases within the central nervous system. Citation Format: Daniel A. Heller, Daniel Tylawsky, G. Praveen Raju. P-selectin-targeted delivery of intracranial therapeutics across an intact BBB in Sonic Hedgehog medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1992. |
