Brain-Targeted Delivery of Phenformin Using Phospholipid and Non-Phospholipid Vesicles for SHH Medulloblastoma.

Medulloblastoma (MB) is the most frequent brain malignancy in children, frequently driven by deregulated Sonic Hedgehog (SHH) signaling. We previously identified the antidiabetic drug phenformin (Phen) as a potent Gli1 inhibitor that suppresses SHH-subtype MB growth. Despite its efficacy, systemic administration of Phen is limited by its potential to induce lactic acidosis, primarily through the suppression of hepatic gluconeogenesis. Here, we provide proof-of-concept that phospholipid (liposomes) and non-phospholipid (niosomes) vesicles (<200 nm) can be used to deliver phenformin selectively. Our results show that these vesicle-based delivery systems efficiently entrap Phen (around 50%) and release it into SHH MB cells, reducing proliferation and activating energy stress responses at higher doses. Furthermore, treated cells exhibit marked downregulation of SHH target genes Gli1 and Ptch1. In vivo, phenformin-loaded nanocarriers selectively increased drug accumulation in cerebellar tumors while minimizing systemic and hepatic exposure. Notably, niosomes demonstrated superior brain tumor targeting compared to free drug or liposome administration, as reflected by higher intratumoral concentrations of Phen compared to free drug or liposome administration. Consistent with this targeted delivery, we observed a substantial decline in intratumoral Gli1 and Ptch1 expression, confirming effective SHH pathway modulation. Together, these findings propose a promising nanotechnology-based method to improve phenformin therapeutic index in SHH MB by enhancing tumor specificity and reducing systemic toxicity.