Givinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and Pharmacokinetics

SIMPLE SUMMARY: Glioblastoma is the most common malignant brain tumor with a high grade of recurrence, invasiveness, and aggressiveness. Currently, there are no curative treatments; therefore, the discovery of novel molecules with anti-tumor activity or suitable drug delivery systems are important research topics. The aim of the present study was to investigate the anti-tumor activity of Givinostat, a pan-HDAC inhibitor, and to design an appropriate liposomal formulation to improve its pharmacokinetics profile and brain delivery. The present work demonstrates that the incorporation of Givinostat in liposomes composed of cholesterol and sphingomyelin improves its in vivo half-life and increases the amount of drug reaching the brain in a mouse model. Furthermore, this formulation preserves the anti-tumor activity of glioblastoma in 2D and 3D in vitro models. These features make liposome-Givinostat formulations potential candidates for glioblastoma therapy. ABSTRACT: 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.