Gliomas are the most common primary central nervous system tumors with a dismal prognosis. Despite recent advances in surgery, radiotherapy, and chemotherapy, current treatment regimens have a modest survival benefit. A crucial challenge is to deliver drugs effectively to invasive glioma cells residing in a sanctuary within the central nervous system. New therapies are essential, and oligonucleotide-based approaches, including antisense, microRNAs, small interfering RNAs, and nucleic acid aptamers, may provide a viable strategy. Thanks to their unique characteristics (low size, good affinity for the target, no immunogenicity, chemical structures that can be easily modified to improve their in vivo applications), these molecules may represent a valid alternative to antibodies particularly to overcome challenges presented by the blood-brain barrier. Here we will discuss recent results on the use of oligonucleotides that will hopefully provide new effective treatment for gliomas. 1. Introduction Glioma is the most common primary brain tumor, generally characterized by highly infiltrative nature, high malignancy, and poor clinical outcome. Despite great advances in surgical techniques, radiotherapy, and chemotherapy, the prognosis of this tumor remains poor [1, 2]. Histologically gliomas are classified as astrocytomas, oligodendrogliomas, or ependymomas depending on cell morphology [3–7]. Genomic analysis of gliomas has revealed different subtypes that show distinct patterns of mutations, copy number alterations, and gene expression [8, 9]. On the basis of the grade of malignancy, as established by the World Health Organization [2], they can be further categorized as low grade (grade I and grade II) and high grade gliomas (grade III and grade IV). Grade I tumors are relatively benign and show the best prognosis. Grade II tumors contain some anaplastic cells and can progress to higher grade tumors. Grade III tumors show a high degree of anaplasia and mitotic activity and are often rapidly fatal. The most aggressive type of glioma is the grade IV astrocytoma or glioblastoma multiforme (GBM). This is a highly anaplastic and malignant tumor which is almost always fatal because of its resistance to radio—and chemotherapy. To date, antibody-based approaches have been developed for in vivo applications but, in most cases, adequate sensitivity has not yet been reached; they show toxicity in vivo and are not able to efficiently cross the blood-brain barrier (BBB). Promising alternative approach to antibodies is now represented by RNA and DNA oligonucleotides,
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