Glioblastoma multiforme is the most lethal intrinsic brain tumor. Even with the existing treatment regimen of surgery, radiation, and chemotherapy, the median survival time is only 15–23 months. The invasive nature of this tumor makes its complete removal very difficult, leading to a high recurrence rate of over 90%. Drug delivery to glioblastoma is challenging because of the molecular and cellular heterogeneity of the tumor, its infiltrative nature, and the blood–brain barrier. Understanding the critical characteristics that restrict drug delivery to the tumor is necessary to develop platforms for the enhanced delivery of effective treatments. In this review, we address the impact of tumor invasion, the molecular and cellular heterogeneity of the tumor, and the blood–brain barrier on the delivery and distribution of drugs using potential therapeutic delivery options such as convection-enhanced delivery, controlled release systems, nanomaterial systems, peptide-based systems, and focused ultrasound.

Glioblastoma is a malignant brain tumor characterized by rapid growth, diffuse invasion and therapeutic resistance. We recently used microRNA expression profiles to subclassify glioblastoma into five genetically and clinically distinct subclasses, and showed that microRNAs both define and contribute to the phenotypes of these subclasses. Here we show that miR-29a activates a multi-faceted growth and invasion program that promotes glioblastoma aggressiveness. microRNA expression profiles from 197 glioblastomas were analyzed to identify the candidate miRNAs that are correlated to glioblastoma aggressiveness. The candidate miRNA, miR-29a, was further studied in vitro and in vivo. Members of the miR-29 subfamily display increased expression in the two glioblastoma subclasses with the worst prognoses (astrocytic and neural). We observed that miR-29a is among the microRNAs that are most positively-correlated with PTEN copy number in glioblastoma, and that miR-29a promotes glioblastoma growth and invasion in part by targeting PTEN. In PTEN-deficient glioblastoma cells, however, miR-29a nevertheless activates AKT by downregulating the metastasis suppressor, EphB3. In addition, miR-29a robustly promotes invasion in PTEN-deficient glioblastoma cells by repressing translation of the Sox4 transcription factor, and this upregulates the invasion-promoting protein, HIC5. Indeed, we identified Sox4 as the most anti-correlated predicted target of miR-29a in glioblastoma. Importantly, inhibition of endogenous miR-29a decreases glioblastoma growth and invasion in vitro and in vivo, and increased miR-29a expression in glioblastoma specimens correlates with decreased patient survival. Taken together, these data identify miR-29a as a master regulator of glioblastoma growth and invasion.