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Peer reviewed: True, Novel therapeutic and diagnostic methods are sorely needed for gliomas, which contribute yearly to hundreds of thousands of cancer deaths worldwide. Despite the outpouring of research efforts and funding aimed at improving clinical outcomes for patients with glioma, the prognosis for high-grade glioma, and especially glioblastoma, remains dire. One of the greatest obstacles to improving treatment efficacy and destroying cancer cells is the safe delivery of chemotherapeutic drugs and biologics to the tumor site at a high enough dose to be effective. Over the past few decades, a burst of research has leveraged nanotechnology to overcome this obstacle. There has been a renewed interest in adapting previously understudied dendrimer nanocarriers for this task. Dendrimers are small, highly modifiable, branched structures featuring binding sites for a variety of drugs and ligands. Recent studies have demonstrated the potential for dendrimers and dendrimer conjugates to effectively shuttle therapeutic cargo to the correct tumor location, permeate the tumor, and promote apoptosis of tumor cells while minimizing systemic toxicity and damage to surrounding healthy brain tissue. This review provides a primer on the properties of dendrimers; outlines the mechanisms by which they can target delivery of substances to the site of brain pathology; and delves into current trends in the application of dendrimers to drug and gene delivery, and diagnostic imaging, in glioma. Finally, future directions for translating these in vitro and in vivo findings to the clinic are discussed.

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.

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.

Translation of novel therapies for brain cancer into clinical practice is of the utmost importance as primary brain tumors are responsible for more than 200,000 deaths worldwide each year. While many research efforts have been aimed at improving survival rates over the years, prognosis for patients with glioblastoma and other primary brain tumors remains poor. Safely delivering chemotherapeutic drugs and other anti-cancer compounds across the blood–brain barrier and directly to tumor cells is perhaps the greatest challenge in treating brain cancer. Polymeric nanoparticles (NPs) are powerful, highly tunable carrier systems that may be able to overcome those obstacles. Several studies have shown appropriately-constructed polymeric NPs cross the blood–brain barrier, increase drug bioavailability, reduce systemic toxicity, and selectively target central nervous system cancer cells. While no studies relating to their use in treating brain cancer are in clinical trials, there is mounting preclinical evidence that polymeric NPs could be beneficial for brain tumor therapy. This review includes a variety of polymeric NPs and how their associated composition, surface modifications, and method of delivery impact their capacity to improve brain tumor therapy.