Abnormal activation of Hedgehog (Hh) signaling is responsible for several tumors such as medulloblastoma (MB) [1]. Hh inhibitors acting on GLI1, the final effector of Hh signaling, represent a valuable opportunity to overcome the pitfalls of the existing therapies to treat Hh-driven cancers [2]. In a previous study we identified Glabrescione B (GlaB), a natural isoflavone that proved to inhibit Gli1/DNA interaction. [3] The physical availability of GlaB by isolation from plant is unfeasible due to important limitations, so the total synthesis of GlaB is proposed. [4] To overcome its poor water solubility, several formulation strategies will be investigated to encapsulate GlaB in polymeric micelles, to promote the delivery of the drug.[5] The most promising one, GlaB formulated with a self-assembling amphiphilic polymer forming micelles, called mPEG5kDa-cholane, enhanced the solubility of the isoflavone. GlaB encapsulated in mPEG5kDa-cholane micelles was tested both in vitro and in vivo Hh-dependent MB models, and the biodistribution in brain and cerebellum will be assessed by the High-Performance Liquid Chromatography (HPLC) combined with Mass Spectrometry (MS). Our findings reveal mPEG5kDa-cholane/GlaB is a good candidate for preclinical practice in the treatment of Hh-dependent tumors.
mPEG5kDa-cholane/Glabrescione B delivery system as promising tool for the treatment of Hh-dependent tumors / Vergine, V., Infante, P., Malfanti, A., Quaglio, D., Balducci, S., De Martin, S., Bufalieri, F., Mastrotto, F., Basili, I., Garofalo, M., LOSPINOSO SEVERINI, L., Mori, M., Manni, I., Moretti, M., Nicoletti, C., Piaggio, G., Caliceti, P., Botta, B., Ghirga, F., Salmaso, S., et al.. - (2020). (Stratagem cost WG2 on Synthesis and nanodelivery strategies for new therapeutic tools against Multidrug Resistant Tumours online ).
mPEG5kDa-cholane/Glabrescione B delivery system as promising tool for the treatment of Hh-dependent tumors
Valeria Vergine
;Paola Infante;Deborah Quaglio;Silvia Balducci;Francesca Bufalieri;Irene Basili;Ludovica Lospinoso Severini;Marta Moretti;Carmine Nicoletti;Bruno Botta;Francesca Ghirga;Lucia Di Marcotullio
2020
Abstract
Abnormal activation of Hedgehog (Hh) signaling is responsible for several tumors such as medulloblastoma (MB) [1]. Hh inhibitors acting on GLI1, the final effector of Hh signaling, represent a valuable opportunity to overcome the pitfalls of the existing therapies to treat Hh-driven cancers [2]. In a previous study we identified Glabrescione B (GlaB), a natural isoflavone that proved to inhibit Gli1/DNA interaction. [3] The physical availability of GlaB by isolation from plant is unfeasible due to important limitations, so the total synthesis of GlaB is proposed. [4] To overcome its poor water solubility, several formulation strategies will be investigated to encapsulate GlaB in polymeric micelles, to promote the delivery of the drug.[5] The most promising one, GlaB formulated with a self-assembling amphiphilic polymer forming micelles, called mPEG5kDa-cholane, enhanced the solubility of the isoflavone. GlaB encapsulated in mPEG5kDa-cholane micelles was tested both in vitro and in vivo Hh-dependent MB models, and the biodistribution in brain and cerebellum will be assessed by the High-Performance Liquid Chromatography (HPLC) combined with Mass Spectrometry (MS). Our findings reveal mPEG5kDa-cholane/GlaB is a good candidate for preclinical practice in the treatment of Hh-dependent tumors.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
