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

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

doi:10.1016/j.canlet.2020.11.028

Cited by 24 publications

(19 citation statements)

References 46 publications

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“…Recently, GlaB has been successfully encapsulated in a colloidal formulation of mPEG 5kDa -cholane-based micelles, in order to ameliorate its solubility, biodistribution, ability to cross the BBB, and consequently its effectiveness in inhibiting SHH-MB growth (Table 1; Figure 1) (Infante et al, 2021). mPEG 5kDa -cholane is an amphiphilic polymer demonstrated to remarkably enhance the biopharmaceutical properties of either small or macromolecular drugs (Ambrosio et al, 2016).…”

Section: Drug Delivery Systems For Gli Inhibitorsmentioning

confidence: 99%

“…Recently, GlaB has been successfully encapsulated in a colloidal formulation of mPEG 5kDa -cholane–based micelles, in order to ameliorate its solubility, biodistribution, ability to cross the BBB, and consequently its effectiveness in inhibiting SHH-MB growth ( Table 1 ; Figure 1 ) ( Infante et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Compared to other amphiphilic polymers tested, mPEG 5kDa -cholane yielded the highest GlaB solubility: 1.18 mM GlaB concentration was obtained with 0.4 mM of mPEG5 kDa -cholane, corresponding to 26,000 fold GlaB concentration in water. GlaB-loaded micelles obtained with mPEG 5kDa -cholane had a typical spherical micelle shape with a size of 16.9 ± 0.7 nm and a loading capacity of 27% w/w ( Infante et al, 2021 ). Thanks to these properties, GlaB formulated in mPEG 5kDa -cholane (mPEG 5kDa -cholane/GlaB) affected the in vitro proliferation of primary SHH-MB cell cultures derived from Math1-cre/Ptc C/C mice and significantly impaired GLI1 transcriptional activity compared to free GlaB ( Infante et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…GlaB-loaded micelles obtained with mPEG 5kDa -cholane had a typical spherical micelle shape with a size of 16.9 ± 0.7 nm and a loading capacity of 27% w/w ( Infante et al, 2021 ). Thanks to these properties, GlaB formulated in mPEG 5kDa -cholane (mPEG 5kDa -cholane/GlaB) affected the in vitro proliferation of primary SHH-MB cell cultures derived from Math1-cre/Ptc C/C mice and significantly impaired GLI1 transcriptional activity compared to free GlaB ( Infante et al, 2021 ). Promising data have also been reported in vivo : mPEG 5kDa -cholane/GlaB administered with the dose of 9 mg/kg to nude mice grafted with primary HH-dependent MB cells strongly reduced the tumor growth rate and tumor volume more than GlaB dissolved at the same concentration in 2-HP-βCD/ethanol (3:1) or with cremophor/DMSO containing mixtures.…”

Section: Introductionmentioning

confidence: 99%

“…In agreement with these results, i.v. administration of mPEG 5kDa -cholane/GlaB drastically reduced tumor growth also in an orthotopic model of HH-dependent MB ( Infante et al, 2021 ). These findings highlight that mPEG 5kDa -cholane/GlaB is a promising candidate for clinical studies for the treatment of HH-dependent cancers and nowadays is the most encouraging drug delivery formulation for GLI inhibitors efficient in counteracting SHH-MB growth in preclinical investigation.…”

Section: Introductionmentioning

confidence: 99%

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Drug Delivery Systems for Hedgehog Inhibitors in the Treatment of SHH-Medulloblastoma

et al. 2021

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Medulloblastoma (MB) is a highly aggressive pediatric tumor of the cerebellum. Hyperactivation of the Hedgehog (HH) pathway is observed in about 30% of all MB diagnoses, thereby bringing out its pharmacological blockade as a promising therapeutic strategy for the clinical management of this malignancy. Two main classes of HH inhibitors have been developed: upstream antagonists of Smoothened (SMO) receptor and downstream inhibitors of GLI transcription factors. Unfortunately, the poor pharmacological properties of many of these molecules have limited their investigation in clinical trials for MB. In this minireview, we focus on the drug delivery systems engineered for SMO and GLI inhibitors as a valuable approach to improve their bioavailability and efficiency to cross the blood–brain barrier (BBB), one of the main challenges in the treatment of MB.

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Section: Drug Delivery Systems For Gli Inhibitorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Drug Delivery Systems for Hedgehog Inhibitors in the Treatment of SHH-Medulloblastoma

et al. 2021

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Design and Synthesis of New Withaferin A Inspired Hedgehog Pathway Inhibitors

Bonandi

Mori

Infante

et al. 2021

Chemistry A European J

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Withanolides constitute a well‐known family of plant‐based alkaloids characterised by widespread biological properties, including the ability of interfering with Hedgehog (Hh) signalling pathway. Following our interest in natural products and in anticancer compounds, we report here the synthesis of a new class of Hh signalling pathway inhibitors, inspired by withaferin A, the first isolated member of withanolides. The decoration of our scaffolds was rationally supported by in silico studies, while functional evaluation revealed promising candidates, confirming once again the importance of natural products as inspiration source for the discovery of novel bioactive compounds. A stereoselective approach, based on Brown chemistry, allowed the obtainment and the functional evaluation of the enantiopure hit compounds.

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