Givinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and Pharmacokinetics
Glioblastoma is the most common and aggressive brain tumor, associated with poor prognosis and survival, representing a challenging medical issue for neurooncologists. Dysregulation of histone-modifying enzymes (HDACs) is commonly identified in many tumors and has been linked to cancer proliferation...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/12/2978 |
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| author | Lorenzo Taiarol Chiara Bigogno Silvia Sesana Marcelo Kravicz Francesca Viale Eleonora Pozzi Laura Monza Valentina Alda Carozzi Cristina Meregalli Silvia Valtorta Rosa Maria Moresco Marcus Koch Federica Barbugian Laura Russo Giulio Dondio Christian Steinkühler Francesca Re |
| author_facet | Lorenzo Taiarol Chiara Bigogno Silvia Sesana Marcelo Kravicz Francesca Viale Eleonora Pozzi Laura Monza Valentina Alda Carozzi Cristina Meregalli Silvia Valtorta Rosa Maria Moresco Marcus Koch Federica Barbugian Laura Russo Giulio Dondio Christian Steinkühler Francesca Re |
| author_sort | Lorenzo Taiarol |
| collection | DOAJ |
| description | Glioblastoma is the most common and aggressive brain tumor, associated with poor prognosis and survival, representing a challenging medical issue for neurooncologists. Dysregulation of histone-modifying enzymes (HDACs) is commonly identified in many tumors and has been linked to cancer proliferation, changes in metabolism, and drug resistance. These findings led to the development of HDAC inhibitors, which are limited by their narrow therapeutic index. In this work, we provide the proof of concept for a delivery system that can improve the in vivo half-life and increase the brain delivery of Givinostat, a pan-HDAC inhibitor. Here, 150-nm-sized liposomes composed of cholesterol and sphingomyelin with or without surface decoration with mApoE peptide, inhibited human glioblastoma cell growth in 2D and 3D models by inducing a time- and dose-dependent reduction in cell viability, reduction in the receptors involved in cholesterol metabolism (from −25% to −75% of protein levels), and reduction in HDAC activity (−25% within 30 min). In addition, liposome-Givinostat formulations showed a 2.5-fold increase in the drug half-life in the bloodstream and a 6-fold increase in the amount of drug entering the brain in healthy mice, without any signs of overt toxicity. These features make liposomes loaded with Givinostat valuable as potential candidates for glioblastoma therapy. |
| first_indexed | 2024-03-10T00:11:50Z |
| format | Article |
| id | doaj.art-271284399d1849779bf2c9a4ae04e24c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T00:11:50Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-271284399d1849779bf2c9a4ae04e24c2023-11-23T15:57:23ZengMDPI AGCancers2072-66942022-06-011412297810.3390/cancers14122978Givinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and PharmacokineticsLorenzo Taiarol0Chiara Bigogno1Silvia Sesana2Marcelo Kravicz3Francesca Viale4Eleonora Pozzi5Laura Monza6Valentina Alda Carozzi7Cristina Meregalli8Silvia Valtorta9Rosa Maria Moresco10Marcus Koch11Federica Barbugian12Laura Russo13Giulio Dondio14Christian Steinkühler15Francesca Re16School of Medicine and Surgery, University of Milano-Bicocca, 20854 Monza, ItalyAPHAD srl, 20090 Buccinasco, ItalySchool of Medicine and Surgery, University of Milano-Bicocca, 20854 Monza, ItalySchool of Medicine and Surgery, University of Milano-Bicocca, 20854 Monza, ItalySchool of Medicine and Surgery, University of Milano-Bicocca, 20854 Monza, ItalyExperimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, ItalyExperimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, ItalyExperimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, ItalyExperimental Neurology Unit, School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, ItalyInstitute of Bioimaging and Molecular Physiology (IBFM), National Research Council (CNR), 20054 Segrate, ItalySchool of Medicine and Surgery, University of Milano-Bicocca, 20854 Monza, ItalyINM—Leibniz Institute for New Materials, Campus D2 2, 66123 Saarbrücken, GermanyDepartment of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, ItalyDepartment of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, ItalyAPHAD srl, 20090 Buccinasco, ItalyItalfarmaco SpA, 20092 Cinisello Balsamo, ItalySchool of Medicine and Surgery, University of Milano-Bicocca, 20854 Monza, ItalyGlioblastoma is the most common and aggressive brain tumor, associated with poor prognosis and survival, representing a challenging medical issue for neurooncologists. Dysregulation of histone-modifying enzymes (HDACs) is commonly identified in many tumors and has been linked to cancer proliferation, changes in metabolism, and drug resistance. These findings led to the development of HDAC inhibitors, which are limited by their narrow therapeutic index. In this work, we provide the proof of concept for a delivery system that can improve the in vivo half-life and increase the brain delivery of Givinostat, a pan-HDAC inhibitor. Here, 150-nm-sized liposomes composed of cholesterol and sphingomyelin with or without surface decoration with mApoE peptide, inhibited human glioblastoma cell growth in 2D and 3D models by inducing a time- and dose-dependent reduction in cell viability, reduction in the receptors involved in cholesterol metabolism (from −25% to −75% of protein levels), and reduction in HDAC activity (−25% within 30 min). In addition, liposome-Givinostat formulations showed a 2.5-fold increase in the drug half-life in the bloodstream and a 6-fold increase in the amount of drug entering the brain in healthy mice, without any signs of overt toxicity. These features make liposomes loaded with Givinostat valuable as potential candidates for glioblastoma therapy.https://www.mdpi.com/2072-6694/14/12/2978glioblastomaliposomesHDAC inhibitorbraincancer |
| spellingShingle | Lorenzo Taiarol Chiara Bigogno Silvia Sesana Marcelo Kravicz Francesca Viale Eleonora Pozzi Laura Monza Valentina Alda Carozzi Cristina Meregalli Silvia Valtorta Rosa Maria Moresco Marcus Koch Federica Barbugian Laura Russo Giulio Dondio Christian Steinkühler Francesca Re Givinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and Pharmacokinetics Cancers glioblastoma liposomes HDAC inhibitor brain cancer |
| title | Givinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and Pharmacokinetics |
| title_full | Givinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and Pharmacokinetics |
| title_fullStr | Givinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and Pharmacokinetics |
| title_full_unstemmed | Givinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and Pharmacokinetics |
| title_short | Givinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and Pharmacokinetics |
| title_sort | givinostat liposomes anti tumor effect on 2d and 3d glioblastoma models and pharmacokinetics |
| topic | glioblastoma liposomes HDAC inhibitor brain cancer |
| url | https://www.mdpi.com/2072-6694/14/12/2978 |
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