Glabrescione B delivery by self-assembling micelles efficiently inhibits tumor growth in preclinical models of Hedgehog-dependent medulloblastoma

Aberrant activation of the Hedgehog (Hh) pathway leads to development several tumors, including medulloblastoma (MB), most common pediatric brain malignancy. Hh inhibitors acting on GLI1, final effector signaling, offer a valuable opportunity overcome pitfalls existing therapies treat Hh-driven cancers. In this study, toxicity, delivery, biodistribution, and anticancer efficacy Glabrescione B (GlaB), selective GLI1 inhibitor, were investigated in preclinical models Hh-dependent MB. To its poor water solubility, GlaB was formulated with self-assembling amphiphilic polymer forming micelles, called mPEG5kDa-cholane. mPEG5kDa-cholane/GlaB showed high drug loading stability, low cytotoxicity, long permanence bloodstream. We found that mPEG5kDa-cholane efficiently enhanced solubility GlaB, thus avoiding use organic solvents. possesses favorable pharmacokinetics negligible toxicity. Remarkably, encapsulated micelles delivered through blood-brain barrier drastically inhibited tumor growth both allograft orthotopic Our findings reveal is good candidate for treatment tumors provide relevant implications translation into clinical practice.