Strategies to better treat glioblastoma: antiangiogenic agents and endothelial cell targeting agents.

Glioblastoma multiforme (GBM) is the most prevalent and aggressive form of glioma, with poor prognosis and high mortality rates. As GBM is a highly vascularized cancer, antiangiogenic therapies to halt or minimize the rate of tumor growth are critical to improving treatment. In this review, antiangiogenic therapies, including small-molecule drugs, nucleic acids and proteins and peptides, are discussed. The authors further explore biomaterials that have been utilized to increase the bioavailability and bioactivity of antiangiogenic factors for better antitumor responses in GBM. Finally, the authors summarize the current status of biomaterial-based targeting moieties that target endothelial cells in GBM to more efficiently deliver therapeutics to these cells and avoid off-target cell or organ side effects.

The Role of Angiogenesis-Inducing microRNAs in Vascular Tissue Engineering.

Angiogenesis is an important process in tissue repair and regeneration as blood vessels are integral to supply nutrients to a functioning tissue. In this review, the application of microRNAs (miRNAs) or anti-miRNAs that can induce angiogenesis to aid in blood vessel formation for vascular tissue engineering in ischemic diseases such as peripheral arterial disease and stroke, cardiac diseases, and skin and bone tissue engineering is discussed. Endothelial cells (ECs) form the endothelium of the blood vessel and are recognized as the primary cell type that drives angiogenesis and studied in the applications that were reviewed. Besides ECs, mesenchymal stem cells can also play a pivotal role in these applications, specifically, by secreting growth factors or cytokines for paracrine signaling and/or as constituent cells in the new blood vessel formed. In addition to delivering miRNAs or cells transfected/transduced with miRNAs for angiogenesis and vascular tissue engineering, the utilization of extracellular vesicles (EVs), such as exosomes, microvesicles, and EVs collectively, has been more recently explored. Proangiogenic miRNAs and anti-miRNAs contribute to angiogenesis by targeting the 3'-untranslated region of targets to upregulate proangiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and hypoxia-inducible factor-1 and increase the transduction of VEGF signaling through the PI3K/AKT and Ras/Raf/MEK/ERK signaling pathways such as phosphatase and tensin homolog or regulating the signaling of other pathways important for angiogenesis such as the Notch signaling pathway and the pathway to produce nitric oxide. In conclusion, angiogenesis-inducing miRNAs and anti-miRNAs are promising tools for vascular tissue engineering for several applications; however, future work should emphasize optimizing the delivery and usage of these therapies as miRNAs can also be associated with the negative implications of cancer.

The Application of microRNAs in Biomaterial Scaffold-Based Therapies for Bone Tissue Engineering.

In recent years, the application of microRNAs (miRNAs) or anti-microRNAs (anti-miRNAs) that can induce expression of the runt-related transcription factor 2 (RUNX2), a master regulator of osteogenesis, has been investigated as a promising alternative bone tissue engineering strategy. In this review, biomaterial scaffold-based applications that have been used to deliver cells expressing miRNAs or anti-miRNAs that induce expression of RUNX2 for bone tissue engineering are discussed. An overview of the components of the scaffold-based therapies including the miRNAs/anti-miRNAs, cell types, gene delivery vectors, and scaffolds that have been applied are provided. To date, there have been nine miRNAs/anti-miRNAs (i.e., miRNA-26a, anti-miRNA-31, anti-miRNA-34a, miRNA-135, anti-miRNA-138, anti-miRNA-146a, miRNA-148b, anti-miRNA-221, and anti-miRNA-335) that have been incorporated into scaffold-based bone tissue engineering applications and investigated in an in vivo bone critical-sized defect model. For all of the biomaterial scaffold-based miRNA therapies that have been developed thus far, cells that are transfected or transduced with the miRNA/anti-miRNA are loaded into the scaffolds and implanted at the site of interest instead of locally delivering the miRNA/anti-miRNAs directly from the scaffolds. Thus, future work may focus on developing biomaterial scaffolds to deliver miRNAs or anti-miRNAs into cells in vivo.