Glabrescione B delivery by self-assembling micelles efficiently inhibits tumor growth in preclinical models of Hedgehog-dependent medulloblastoma
Glabrescione B delivery by self-assembling micelles efficiently inhibits tumor growth in preclinical models of Hedgehog-dependent medulloblastoma
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DOI：
10.1016/j.canlet.2020.11.028
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发表时间：
2021-02-28
期刊：
影响因子：
9.7
通讯作者：
Di Marcotullio, Lucia
中科院分区：
文献类型：
--
作者：
Infante, Paola;Malfanti, Alessio;Di Marcotullio, Lucia
Hedgehog(HH)通路的异常激活导致了几种肿瘤的发展，包括髓母细胞瘤(MB)，这是儿童最常见的脑部恶性肿瘤。HH抑制剂作用于HH信号的最终效应者GLI1，为克服现有治疗HH驱动的癌症的陷阱提供了宝贵的机会。在这项研究中，研究了选择性GLI1抑制剂GLabrescione B(GLab)在HH依赖MB的临床前模型中的毒性、释放、生物分布和抗癌效果。为了克服其较差的水溶性，GLab被配制成一种自组装的两亲性聚合物形成胶束，称为mpeg(5 KDa)-胆烷。MEg(5 KDa)-胆烷/GLab具有高载药量和高稳定性、低细胞毒性和较长的血液持久性。我们发现，mPEG(5 KDa)-胆烷能有效地提高GLaB的溶解度，从而避免了有机溶剂的使用。MEg(5 KDa)-胆烷/GLab具有良好的药代动力学，毒性可忽略不计。值得注意的是，包裹在mpeg(5 KDa)-胆烷胶束中的Gab可以通过血脑屏障传递，并在Hh依赖MB的同种异体和原位模型中显著抑制肿瘤生长。我们的研究结果表明，mPG(5 KDa)-胆烷/GLab是一种很好的治疗HH驱动的肿瘤的候选药物，并为GLab转化为临床实践提供了相关的启示。
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 Hhdependent MB. Our findings reveal that mPEG(5kDa)-cholane/GlaB is a good candidate for the treatment of Hh-driven tumors and provide relevant implications for the translation of GlaB into clinical practice.