Aberrant activation of the Hedgehog (Hh) pathway leads to the development of several tumors, including medulloblastoma (MB), the most common pediatric brain malignancy. Hh inhibitors acting on GLI1, the final effector of Hh signaling, offer a valuable opportunity to overcome the pitfalls of the existing therapies to treat Hh-driven cancers. In this study, the toxicity, delivery, biodistribution, and anticancer efficacy of Glabrescione B (GlaB), a selective GLI1 inhibitor, were investigated in preclinical models of Hh-dependent MB. To overcome its poor water solubility, GlaB was formulated with a self-assembling amphiphilic polymer forming micelles, called mPEG_5kDa-cholane. mPEG_5kDa-cholane/GlaB showed high drug loading and stability, low cytotoxicity, and long permanence in the bloodstream. We found that mPEG_5kDa-cholane efficiently enhanced the solubility of GlaB, thus avoiding the use of organic solvents. mPEG_5kDa-cholane/GlaB possesses favorable pharmacokinetics and negligible toxicity. Remarkably, GlaB encapsulated in mPEG_5kDa-cholane micelles was delivered through the blood-brain barrier and drastically inhibited tumor growth in both allograft and orthotopic models of Hh-dependent MB. Our findings reveal that mPEG_5kDa-cholane/GlaB is a good candidate for the treatment of Hh-dependent tumors and provide relevant implications for the translation of GlaB into clinical practice.

Hedgehog（Hh）通路的异常激活导致几种肿瘤的发展，包括髓母细胞瘤（MB），这是最常见的小儿脑恶性肿瘤。作用于HLI信号的最终效应器GLI1的Hh抑制剂为克服现有疗法治疗Hh致癌的陷阱提供了宝贵的机会。在这项研究中，在Hh依赖性MB的临床前模型中研究了选择性GLI1抑制剂Glabrescione B（GlaB）的毒性，递送，生物分布和抗癌功效。为了克服其不良的水溶性，GlaB是用一种自组装的两亲聚合物形成的胶束（称为mPEG _5kDa-胆_烷）配制的。_聚乙二醇_5kDa-cholane / GlaB表现出高的药物负载量和稳定性，低的细胞毒性以及在血液中的持久性。我们发现，mPEG _5kDa-胆烷可有效提高GlaB的溶解度，从而避免使用有机溶剂。mPEG _5kDa-胆烷/ GlaB具有良好的药代动力学和可忽略的毒性。值得注意的是，封装在mPEG _5kDa胆_甾醇胶束中的GlaB通过血脑屏障传递，并在Hh依赖性MB的同种异体移植和原位移植模型中均显着抑制了肿瘤的生长。我们的发现表明，mPEG _5kDa-胆_甾醇/ GlaB是治疗Hh依赖性肿瘤的良好候选者，并为GlaB转化为临床实践提供了相关的含义。