The blood-brain barrier (BBB) constitutes a microvascular network responsible for excluding most drugs from the brain. Treatment of brain tumors is limited by the impermeability of the BBB and, consequently, survival outcomes for malignant brain tumors remain poor. Nanoparticles (NPs) represent a potential solution to improve drug transport to brain tumors, given their small size and capacity to target tumor cells. Here, we review the unique physical and chemical properties of NPs that aid in BBB transport and discuss mechanisms of NP transport across the BBB, including paracellular transport, carrier-mediated transport, and adsorptive- and receptor-mediated transcytosis. The major types of NPs investigated for treatment of brain tumors are detailed, including polymeric NPs, liposomes, solid lipid NPs, dendrimers, metals, quantum dots, and nanogels. In addition to their role in drug delivery, NPs can be used as imaging contrast agents and can be conjugated with imaging probes to assist in visualizing tumors, demarcating lesion boundaries and margins, and monitoring drug delivery and treatment response. Multifunctional NPs can be designed that are capable of targeting tumors for both imaging and therapeutic purposes. Finally, limitations of NPs for brain tumor treatment are discussed.

Glioblastoma (GBM) is an aggressive primary astrocytoma associated with short overall survival. Treatment for GBM primarily consists of maximal safe surgical resection, radiation therapy, and chemotherapy using temozolomide. Nonetheless, recurrence and tumor progression is the norm, driven by tumor stem cell activity and a high mutational burden. Focused ultrasound (FUS) has shown promising results in preclinical and clinical trials for treatment of GBM and has received regulatory approval for the treatment of other neoplasms. Here, we review the range of applications for FUS in the treatment of GBM, which depend on parameters, including frequency, power, pulse duration, and duty cycle. Low-intensity FUS can be used to transiently open the blood–brain barrier (BBB), which restricts diffusion of most macromolecules and therapeutic agents into the brain. Under guidance from magnetic resonance imaging, the BBB can be targeted in a precise location to permit diffusion of molecules only at the vicinity of the tumor, preventing side effects to healthy tissue. BBB opening can also be used to improve detection of cell-free tumor DNA with liquid biopsies, allowing non-invasive diagnosis and identification of molecular mutations. High-intensity FUS can cause tumor ablation via a hyperthermic effect. Additionally, FUS can stimulate immunological attack of tumor cells, can activate sonosensitizers to exert cytotoxic effects on tumor tissue, and can sensitize tumors to radiation therapy. Finally, another mechanism under investigation, known as histotripsy, produces tumor ablation via acoustic cavitation rather than thermal effects.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with an extremely poor prognosis. There is a dire need to develop effective therapeutics to overcome the intrinsic and acquired resistance of GBM to current therapies. The process of developing novel anti-neoplastic drugs from bench to bedside can incur significant time and cost implications. Drug repurposing may help overcome that obstacle. A wide range of drugs that are already approved for clinical use for the treatment of other diseases have been found to target GBM-associated signaling pathways and are being repurposed for the treatment of GBM. While many of these drugs are undergoing pre-clinical testing, others are in the clinical trial phase. Since GBM stem cells (GSCs) have been found to be a main source of tumor recurrence after surgery, recent studies have also investigated whether repurposed drugs that target these pathways can be used to counteract tumor recurrence. While several repurposed drugs have shown significant efficacy against GBM cell lines, the blood–brain barrier (BBB) can limit the ability of many of these drugs to reach intratumoral therapeutic concentrations. Localized intracranial delivery may help to achieve therapeutic drug concentration at the site of tumor resection while simultaneously minimizing toxicity and side effects. These strategies can be considered while repurposing drugs for GBM.

The deregulation of energetic and cellular metabolism is a signature of cancer cells. Thus, drugs targeting cancer cell metabolism may have promising therapeutic potential. Previous reports demonstrate that the widely used normoglycemic agent, metformin, can decrease the risk of cancer in type 2 diabetics and inhibit cell growth in various cancers, including pancreatic, colon, prostate, ovarian, and breast cancer. While metformin is a known adenosine monophosphate-activated protein kinase (AMPK) agonist and an inhibitor of the electron transport chain complex I, its mechanism of action in cancer cells as well as its effect on cancer metabolism is not clearly established. In this review, we will give an update on the role of metformin as an antitumoral agent and detail relevant evidence on the potential use and mechanisms of action of metformin in cancer. Analyzing antitumoral, signaling, and metabolic impacts of metformin on cancer cells may provide promising new therapeutic strategies in oncology.

Glioblastoma is the most common malignant primary central nervous system tumor and one of the most debilitating cancers. The prognosis of patients with glioblastoma remains poor, and the management of this tumor, both in its primary and recurrent forms, remains suboptimal. Despite the tremendous efforts that are being put forward by the research community to discover novel efficacious therapeutic agents and modalities, no major paradigm shifts have been established in the field in the last decade. However, this does not mirror the abundance of relevant findings and discoveries made in preclinical glioblastoma research. Hence, developing and utilizing appropriate preclinical models that faithfully recapitulate the characteristics and behavior of human glioblastoma is of utmost importance. Herein, we offer a holistic picture of the evolution of preclinical models of glioblastoma. We further elaborate on the commonly used in vitro and vivo models, delving into their development, favorable characteristics, shortcomings, and areas of potential improvement, which aids researchers in designing future experiments and utilizing the most suitable models. Additionally, this review explores progress in the fields of humanized and immunotolerant mouse models, genetically engineered animal models, 3D in vitro models, and microfluidics and highlights promising avenues for the future of preclinical glioblastoma research.

Glioblastoma (GBM) is an aggressive tumor of the central nervous system categorized by the World Health Organization as a Grade 4 astrocytoma. Despite treatment with surgical resection, adjuvant chemotherapy, and radiation therapy, outcomes remain poor, with a median survival of only 14-16 months. Although tumor regression is often observed initially after treatment, long-term recurrence or progression invariably occurs. Tumor growth, invasion, and recurrence is mediated by a unique population of glioblastoma stem cells (GSCs). Their high mutation rate and dysregulated transcriptional landscape augment their resistance to conventional chemotherapy and radiation therapy, explaining the poor outcomes observed in patients. Consequently, GSCs have emerged as targets of interest in new treatment paradigms. Here, we review the unique properties of GSCs, including their interactions with the hypoxic microenvironment that drives their proliferation. We discuss vital signaling pathways in GSCs that mediate stemness, self-renewal, proliferation, and invasion, including the Notch, epidermal growth factor receptor, phosphatidylinositol 3-kinase/Akt, sonic hedgehog, transforming growth factor beta, Wnt, signal transducer and activator of transcription 3, and inhibitors of differentiation pathways. We also review epigenomic changes in GSCs that influence their transcriptional state, including DNA methylation, histone methylation and acetylation, and miRNA expression. The constituent molecular components of the signaling pathways and epigenomic regulators represent potential sites for targeted therapy, and representative examples of inhibitory molecules and pharmaceuticals are discussed. Continued investigation into the molecular pathways of GSCs and candidate therapeutics is needed to discover new effective treatments for GBM and improve survival.