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

Paola Infante, Alessio Malfanti, Deborah Quaglio, Silvia Balducci, Sara De Martin, Francesca Bufalieri, Francesca Mastrotto, Irene Basili, Mariangela Garofalo, Ludovica Lospinoso Severini, Mattia Mori, Isabella Manni, Marta Moretti, Carmine Nicoletti, Giulia Piaggio, Paolo Caliceti, Bruno Botta, Francesca Ghirga, Stefano Salmaso, Lucia Di Marcotullio

Research output: Contribution to journalArticlepeer-review

Abstract

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 mPEG5kDa-cholane. mPEG5kDa-cholane/GlaB showed high drug loading and stability, low cytotoxicity, and long permanence in the bloodstream. We found that mPEG5kDa-cholane efficiently enhanced the solubility of GlaB, thus avoiding the use of organic solvents. mPEG5kDa-cholane/GlaB possesses favorable pharmacokinetics and negligible toxicity. Remarkably, GlaB encapsulated in mPEG5kDa-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 mPEG5kDa-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.

Original languageEnglish
Pages (from-to)220-231
Number of pages12
JournalCancer Letters
Volume499
DOIs
Publication statusPublished - 2020

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