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Il glioblastoma multiforme (GBM) è un astrocitoma di IV grado ed è il tumore più comune e aggressivo del sistema nervoso centrale (SNC). Il GBM è caratterizzato da una natura infiltrante, un’alta eterogeneità, aggressività e recidiva. Attualmente non ci sono terapie risolutive e il trattamento standard è basato sul protocollo di Stupp, che prevede chirurgia, radioterapia e cicli di chemioterapia con temozolomide (TMZ). Tuttavia, la resistenza alla terapia e il cosiddetto ‘cancer immune escape’ sono delle sfide molto importanti per i medici e gli scienziati. La nanomedicina ha ricevuto molta attenzione grazie alla sua versatilità di applicazione, che include l’attraversamento della barriera emato-encefalica (BBB) e la veicolazione di farmaci al sito bersaglio. Inoltre, la nanomedicina è stata applicata con successo nel campo dell’immunoterapia tumorale, per esempio utilizzando nanoparticelle (NPs) per il trasporto di farmaci, anticorpi monoclonali o acidi nucleici. Il razionale dietro l’immunoterapia è la stimolazione del sistema immunitario affinché reagisca contro il cancro, anche in tumori con scarsa risposta immunitaria come il GBM. Nel campo della terapia delle malattie cerebrali, la nanomedicina si è rivelata uno strumento eccellente per la veicolazione di farmaci, specialmente considerando che le cellule tumorali di GBM possono sfruttare delle strutture cellulari come i Tunneling nanotubes (TnTs) per scambiare organelli, materiale cellulare, fattori solubili, farmaci e persino NPs. Data questa premessa, i TnTs potrebbero essere sfruttati per impedire questa comunicazione cellulare (inibendo la loro formazione) oppure per diffondere i farmaci chemioterapici tra cellule diverse. Infine, negli ultimi anni gli inibitori delle istone deacetilasi (HDAC, HDACis) sono stati studiati come farmaci antitumorali in diversi tumori, compreso il GBM. Gli HDACis sono suddivisi in pan-HDACis (che diminuiscono l’attività di tutte le HDAC zinco-dipendenti) e in HDACis selettivi (specifici per una o poche HDAC) ed è stata provata la loro efficacia nell’induzione dell’apoptosi, nella modificazione dell’espressione proteica e nel contrasto alla chemioresistenza. In questo lavoro abbiamo sintetizzato liposomi di 150 nm di diametro con all’interno il pan-HDACi Givinostat, sia non funzionalizzati che funzionalizzati con mApoE, un frammento peptidico già utilizzato per l’attraversamento della BBB e per il targeting tumorale. L’attività antitumorale di Givinostat, insieme all’espressione di recettori correlati all’internalizzazione cellulare di colesterolo, è stata analizzata in classici modelli 2D. Inoltre, la vitalità cellulare è stata analizzata utilizzando un costrutto stampato in 3D composto di chitosano e gelatina. La farmacocinetica e la penetrazione del farmaco nel cervello sono state studiate in topi sani confrontandole con il farmaco libero, mostrando un aumento significativo di entrambi i parametri. Questi risultati indicano che Givinostat potrebbe essere un buon candidato per il trattamento del GBM, anche somministrandolo insieme ad altre terapie già in uso. Ulteriori studi saranno indirizzati verso il miglioramento delle NPs utilizzando altre funzionalizzazioni e altri HDACis, come ad esempio l’HDACi selettivo per l’HDAC6 ITF3756, e prenderanno in considerazione lo sfruttamento dei TnT per il trasporto di farmaci e l’utilizzo degli HDACis come agenti immunoterapeutici. Glioblastoma multiforme (GBM) is a IV grade astrocytoma and it is the most common and aggressive tumor of the central nervous system (CNS). GBM is characterized by an infiltrative nature, high heterogeneity, aggressiveness, and recurrence. There are no curative treatments and the standard care is based on Stupp’s protocol, with surgery, radiotherapy and temozolomide (TMZ) chemotherapy. However, therapy resistance and cancer immune escape are important challenges for physicians and scientists. Nanomedicine gained a lot of attention given the versatility of its application, including the crossing of blood-brain barrier (BBB), specific targeted therapy and drug delivery. In addition, nanomedicine has been successfully applied in the field of cancer immunotherapy, for example using nanoparticles (NPs) for the delivery of drugs, monoclonal antibodies (mAbs) or nucleic acids. The rationale behind immunotherapy is to stimulate the immune system to react against cancer, even in tumors with scarce immune response like GBM. In the context of brain disease therapy, nanomedicine turned out to be an excellent tool also for drug delivery, especially considering that GBM cancer cells can exploit cellular structures like Tunneling nanotubes (TnTs) to exchange organelles, cellular material, soluble factors, drugs and even NPs. Given this information, TnTs could be exploited to prevent cellular communication (by inhibiting their formation) or to spread anticancer drugs among different cells. Finally, in the last years histone deacetylase (HDAC) inhibitors (HDACis) were investigated as anticancer drugs in many tumors, GBM included. HDACis are divided into pan-HDACi (that decrease the activity of all Zn-dependent HDACs) and selective-HDACis (specific for one or a few HDACs) and they were proven to be effective in inducing apoptosis, modifying protein expression and acting on therapy resistance. Here, we synthetized 150 nm-sized liposomes loaded with pan-HDACi Givinostat, both unfunctionalized and functionalized with mApoE that is a peptidic fragment already used for BBB crossing and tumor targeting. The anticancer activity of Givinostat, together with the expression of cholesterol uptake-related receptors, has been analyzed in classic 2D models. Moreover, cell viability was assessed using a 3D bioprinted construct made of chitosan and gelatin. In addition, pharmacokinetics and brain penetration have been investigated in healthy mice in comparison to the free drug, showing a significant increase in both parameters. These results indicate that Givinostat could be a good candidate for GBM treatment, also providing a co-treatment with already applied therapies. Further studies will be focused on the improvement of NPs using other functionalizations and other HDACis like the selective-HDAC6 ITF3756, on the exploitation of TnTs for drug delivery and on the investigation of HDACis as immunotherapeutic agents in GBM.

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.

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.

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.

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.

Simple Summary Communication between cells helps tumors acquire resistance to chemotherapy and makes the struggle against cancer more challenging. Tunneling nanotubes (TNTs) are long channels able to connect both nearby and distant cells, contributing to a more malignant phenotype. This finding might be useful in designing novel strategies of drug delivery exploiting these systems of connection. This would be particularly important to reach tumor niches, where glioblastoma stem cells proliferate and provoke immune escape, thereby increasing metastatic potential and tumor recurrence a few months after surgical resection of the primary mass. Along with the direct inhibition of TNT formation, TNT analysis, and targeting strategies might be useful in providing innovative tools for the treatment of this tumor. Abstract 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.

[This corrects the article DOI: 10.1016/j.isci.2023.107480.]., (© 2023 The Author(s).)