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

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.

Dual Functionalized Liposomes for Selective Delivery of Poorly Soluble Drugs to Inflamed Brain Regions

“…We built dual-functional liposomes to deliver poorly bioavailable drugs across the BBB, and to release them in response to up-regulated MMPs in neuroinflammatory microenvironments. Such profile is due to (i) the co-assembly of lipids with MMP-responsive peptide-fatty acid chimeras (MSLP molecules), yielding nano-sized liposomes able to release their payload in response to increased MMP2 and MMP9 levels; and to (ii) the surface functionalization of such liposomes with a modified peptide derived from apolipoprotein E (mApoE), capable, in vitro and in vivo, to mediate brain drug delivery [29,30,[49][50][51].…”

Nanoparticle’s Shape Is the Game-Changer for a Customized Delivery through Tunneling Nanotubes among Glioblastoma Cells

“…For this purpose, spherical, discoidal and deformable nanoparticles were synthetized in order to evaluate if the nanoparticles shape could influence their ability to be transferred via TNTs. These nanoparticles were evaluated in 2D and 3D in vitro models composed of human GBM cells, carrying the EGFRvIII mutation and resistant to temozolomide [3].…”

Roadmap on nanomedicine for the central nervous system

“…The NPs, suitably functionalized and with a long blood-residency time, can cross the BBB and release active molecules at target sites in the brain, minimizing side effects. It has been demonstrated that the concentration of drug that reaches the brain is higher if it is formulated in NPs, rather than when administered alone [98]. For example, it was shown that the concentration of rivastigmine that reaches the brain is about four times higher when embedded in NPs than when it is free [99].…”