Description

Abstract

Glioblastoma remains the deadliest primary brain tumor, largely due to insufficient drug penetration across the blood–brain barrier (BBB), pronounced intratumoral heterogeneity, and rapid recurrence driven by invasive and treatment-resistant subpopulations. Amaryllidaceae alkaloids (AAs) display potent multimodal anticancer activity, including  inhibition of translation, STAT3 signaling, and actin-dependent migration, but their clinical development has been hindered by poor solubility, unfavorable pharmacokinetics, and toxicity. This project aims to overcome these limitations by developing a dual-action therapeutic system based on a new bioactive and BBB-permeable glycolipid that provides intrinsic anti-glioblastoma activity and efficient drug loading. This new nanotherapy aims to improve brain delivery, enhance tumor selectivity, enable sustained tumor-targeted release of AAs and importantly leads to synergistic effects. Through systematic formulation development, PK/safety assessment, orthotopic efficacy studies, and tumor-microenvironment profiling, the project seeks to generate a first-in-class therapeutic platform capable of addressing the fundamental drivers of GBM progression and resistance, with strong potential for clinical translation.