Nanostructured lipid carrier formulation for delivering poorly water-soluble ITF3756 HDAC inhibitor Marcelo Kravicz, Lorenzo Taiarol, Juliana S.R. Viegas, Giulia Sierri, Michele Mauri, Marcus Koch, Christian Steinkühler, Francesca Re Journal of Drug Delivery Science and Technology, 2024 Histone deacetylases (HDACs) are enzymes that play crucial roles in cellular processes by hydrolyzing acetyl-L-lysine side chains in core histones, thereby regulating gene expression and maintaining homeostasis. Histone deacetylase inhibitors (HDACi) have emerged as promising agents, particularly in cancer treatment, due to their ability to induce cytotoxic and pro-apoptotic effects. Selective HDAC6 inhibitors, such as ITF3756, have shown low off-target toxicity and promising pharmacological activities, but their poor water solubility limits their application in nanoparticulate drug delivery systems. Here, we optimized a nanostructured lipid carrier (NLC) formulation for delivering ITF3756 using the design of experiments (DOE) and response surface methodology (RSM). An interaction between the factor surfactant and formulation volume was observed, thus demonstrating that the surfactant concentration impacts the NLC size. It can be speculated that the higher the amount of the drug in the formulation, the lower the polydispersion index (PDI), thus resulting in more stable nanostructures. The optimized ITF3756-NLC demonstrated a size of 51.1 ± 0.3 nm, 8.85 ± 4.71 mV charge, and high entrapment efficiency (EE%), maintaining stability for 60 days. Moreover, ITF3756-NLC enhanced α-tubulin acetylation in melanoma, lung, and brain cancer cell lines, indicating retained or improved bioactivity. The ITF3756-NLC formulation offers a viable approach for enhancing the bioavailability and therapeutic efficacy of HDAC6 inhibitors, demonstrating potential for clinical applications in cancer immunotherapy. • An interaction was observed between the factors “surfactant” and “formulation volume”. • A small amount of ITF3756 incorporated in the nanostructured lipid carriers stabilised the NLC formulation. • Adding a small amount of the drug enhances the nanoparticle stability, providing reliable results for up to 60 days. • An increase in the acetylation levels of α-tubulin in tumor cell lines treated with ITF3756-NLC is observed.
Erratum: A tetracationic porphyrin with dual anti-prion activity (iScience (2023) 26(9), (S2589004223015572), (10.1016/j.isci.2023.107480)) Antonio Masone, Chiara Zucchelli, Enrico Caruso, Giada Lavigna, Hasier Eraña, Gabriele Giachin, Laura Tapella, Liliana Comerio, Elena Restelli, Ilaria Raimondi, Saioa R. Elezgarai, Federica De Leo, Giacomo Quilici, Lorenzo Taiarol, Marvin Oldrati, Nuria L. Lorenzo, Sandra García-Martínez, Alfredo Cagnotto, Jacopo Lucchetti, Marco Gobbi, Ilaria Vanni, Romolo Nonno, Michele A. Di Bari, Mark D. Tully, Valentina Cecatiello, Giuseppe Ciossani, Sebastiano Pasqualato, Eelco Van Anken, Mario Salmona, Joaquín Castilla, Jesús R. Requena, Stefano Banfi, Giovanna Musco, Roberto Chiesa Iscience, 2023 (iScience 26, 107480; September 15, 2023) In the originally published version of this article, an error occurred during figure preparation, where the authors duplicated the lower middle panel in Figure 1G. This error has been corrected online with the insertion of the correct image in the lower right panel. The authors apologize for this error and any confusion it may have caused.Figure 1. Zn(II)-BnPyP down-regulates PrPC (corrected)View Large Image Figure ViewerDownload Hi-res image Download (PPT) A tetracationic porphyrin with dual anti-prion activityMasone et al.iScienceJuly 27, 2023In BriefPharmacology; Molecular neuroscience; Cell biology Full-Text PDF Open Access
A tetracationic porphyrin with dual anti-prion activity Antonio Masone, Chiara Zucchelli, Enrico Caruso, Giada Lavigna, Hasier Eraña, Gabriele Giachin, Laura Tapella, Liliana Comerio, Elena Restelli, Ilaria Raimondi, Saioa R. Elezgarai, Federica De Leo, Giacomo Quilici, Lorenzo Taiarol, Marvin Oldrati, Nuria L. Lorenzo, Sandra García-Martínez, Alfredo Cagnotto, Jacopo Lucchetti, Marco Gobbi, Ilaria Vanni, Romolo Nonno, Michele A. Di Bari, Mark D. Tully, Valentina Cecatiello, Giuseppe Ciossani, Sebastiano Pasqualato, Eelco Van Anken, Mario Salmona, Joaquín Castilla, Jesús R. Requena, Stefano Banfi, Giovanna Musco, Roberto Chiesa Iscience, 2023 Prions are deadly infectious agents made of PrP Sc , a misfolded variant of the cellular prion protein (PrP C ) which self-propagates by inducing misfolding of native PrP C . PrP Sc can adopt different pathogenic conformations (prion strains), which can be resistant to potential drugs, or acquire drug resistance, hampering the development of effective therapies. We identified Zn(II)-BnPyP, a tetracationic porphyrin that binds to distinct domains of native PrP C , eliciting a dual anti-prion effect. Zn(II)-BnPyP binding to a C-terminal pocket destabilizes the native PrP C fold, hindering conversion to PrP Sc ; Zn(II)-BnPyP binding to the flexible N-terminal tail disrupts N- to C-terminal interactions, triggering PrP C endocytosis and lysosomal degradation, thus reducing the substrate for PrP Sc generation. Zn(II)-BnPyP inhibits propagation of different prion strains in vitro , in neuronal cells and organotypic brain cultures. These results identify a PrP C -targeting compound with an unprecedented dual mechanism of action which might be exploited to achieve anti-prion effects without engendering drug resistance.
Givinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and Pharmacokinetics 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 Cancers, 2022 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.
Reduced levels of ABCA1 transporter are responsible for the cholesterol efflux impairment in β‐amyloid‐induced reactive astrocytes: Potential rescue from biomimetic HDLs Giulia Sierri, Roberta Dal Magro, Barbara Vergani, Biagio Eugenio Leone, Beatrice Formicola, Lorenzo Taiarol, Stefano Fagioli, Marcelo Kravicz, Lucio Tremolizzo, Laura Calabresi, Francesca Re International Journal of Molecular Sciences, 2022 The cerebral synthesis of cholesterol is mainly handled by astrocytes, which are also responsible for apoproteins’ synthesis and lipoproteins’ assembly required for the cholesterol transport in the brain parenchyma. In Alzheimer disease (AD), these processes are impaired, likely because of the astrogliosis, a process characterized by morphological and functional changes in astrocytes. Several ATP-binding cassette transporters expressed by brain cells are involved in the formation of nascent discoidal lipoproteins, but the effect of beta-amyloid (Aβ) assemblies on this process is not fully understood. In this study, we investigated how of Aβ1-42-induced astrogliosis affects the metabolism of cholesterol in vitro. We detected an impairment in the cholesterol efflux of reactive astrocytes attributable to reduced levels of ABCA1 transporters that could explain the decreased lipoproteins’ levels detected in AD patients. To approach this issue, we designed biomimetic HDLs and evaluated their performance as cholesterol acceptors. The results demonstrated the ability of apoA-I nanodiscs to cross the blood–brain barrier in vitro and to promote the cholesterol efflux from astrocytes, making them suitable as a potential supportive treatment for AD to compensate the depletion of cerebral HDLs.
The 3.0 cell communication: New insights in the usefulness of tunneling nanotubes for glioblastoma treatment Lorenzo Taiarol, Beatrice Formicola, Stefano Fagioli, Giulia Sierri, Alessia D’Aloia, Marcelo Kravicz, Antonio Renda, Francesca Viale, Roberta Dal Magro, Michela Ceriani, Francesca Re Cancers, 2021 Glioblastoma (GBM) is a particularly challenging brain tumor characterized by a heterogeneous, complex, and multicellular microenvironment, which represents a strategic network for treatment escape. Furthermore, the presence of GBM stem cells (GSCs) seems to contribute to GBM recurrence after surgery, and chemo- and/or radiotherapy. In this context, intercellular communication modalities play key roles in driving GBM therapy resistance. The presence of tunneling nanotubes (TNTs), long membranous open-ended channels connecting distant cells, has been observed in several types of cancer, where they emerge to steer a more malignant phenotype. Here, we discuss the current knowledge about the formation of TNTs between different cellular types in the GBM microenvironment and their potential role in tumor progression and recurrence. Particularly, we highlight two prospective strategies targeting TNTs as possible therapeutics: (i) the inhibition of TNT formation and (ii) a boost in drug delivery between cells through these channels. The latter may require future studies to design drug delivery systems that are exchangeable through TNTs, thus allowing for access to distant tumor niches that are involved in tumor immune escape, maintenance of GSC plasticity, and increases in metastatic potential.
Oxidative stress boosts the uptake of cerium oxide nanoparticles by changing brain endothelium microvilli pattern Roberta Dal Magro, Agostina Vitali, Stefano Fagioli, Alberto Casu, Andrea Falqui, Beatrice Formicola, Lorenzo Taiarol, Valeria Cassina, Claudia Adriana Marrano, Francesco Mantegazza, Umberto Anselmi-Tamburini, Patrizia Sommi, Francesca Re Antioxidants, 2021 Vascular oxidative stress is considered a worsening factor in the progression of Alzheimer’s disease (AD). Increased reactive oxygen species (ROS) levels promote the accumulation of amyloid-β peptide (Aβ), one of the main hallmarks of AD. In turn, Aβ is a potent inducer of oxidative stress. In early stages of AD, the concomitant action of oxidative stress and Aβ on brain capillary endothelial cells was observed to compromise the blood–brain barrier functionality. In this context, antioxidant compounds might provide therapeutic benefits. To this aim, we investigated the antioxidant activity of cerium oxide nanoparticles (CNP) in human cerebral microvascular endothelial cells (hCMEC/D3) exposed to Aβ oligomers. Treatment with CNP (13.9 ± 0.7 nm in diameter) restored basal ROS levels in hCMEC/D3 cells, both after acute or prolonged exposure to Aβ. Moreover, we found that the extent of CNP uptake by hCMEC/D3 was +43% higher in the presence of Aβ. Scanning electron microscopy and western blot analysis suggested that changes in microvilli structures on the cell surface, under pro-oxidant stimuli (Aβ or H2O2), might be involved in the enhancement of CNP uptake. This finding opens the possibility to exploit the modulation of endothelial microvilli pattern to improve the uptake of anti-oxidant particles designed to counteract ROS-mediated cerebrovascular dysfunctions.
An update of nanoparticle-based approaches for glioblastoma multiforme immunotherapy Lorenzo Taiarol, Beatrice Formicola, Roberta Dal Magro, Silvia Sesana, Francesca Re Nanomedicine, 2020 Glioblastoma multiforme is a serious medical issue in the brain oncology field due to its aggressiveness and recurrence. Immunotherapy has emerged as a valid approach to counteract the growth and metastasization of glioblastoma multiforme. Among the different innovative approaches investigated, nanoparticles gain attention because of their versatility which is key in allowing precise targeting of brain tumors and increasing targeted drug delivery to the brain, thus minimizing adverse effects. This article reviews the progress made in this field over the past 2 years, focusing on nonspherical and biomimetic particles and on vectors for the delivery of nucleic acids. However, challenges still need to be addressed, considering the improvement of the particles passage across the blood–meningeal barrier and/or the blood–brain barrier, promoting the clinical translatability of these approaches.
