A combined microRNA-based targeted therapeutic approach to eradicate glioblastoma stem-like cells

• Published in: Journal of controlled release Vol. 238; pp. 43 - 57
• Main Authors: Esposito, Carla L., Nuzzo, Silvia, Kumar, Swati A., Rienzo, Anna, Lawrence, Clare L., Pallini, Roberto, Shaw, Lisa, Alder, Jane E., Ricci-Vitiani, Lucia, Catuogno, Silvia, de Franciscis, Vittorio
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 28.09.2016
• Subjects: Antagomirs - genetics; Antagomirs - therapeutic use; Aptamer; Aptamers, Nucleotide - metabolism; Aptamers, Nucleotide - therapeutic use; Axl Receptor Tyrosine Kinase; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - therapy; Cancer stem cells; Cell Line, Tumor; Gene Transfer Techniques; Genetic Therapy - methods; Glioblastoma; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Glioma - therapy; Humans; microRNA; MicroRNAs - antagonists & inhibitors; MicroRNAs - genetics; MicroRNAs - therapeutic use; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, Platelet-Derived Growth Factor beta - antagonists & inhibitors; Receptor, Platelet-Derived Growth Factor beta - metabolism; Targeted delivery; microRNA; Aptamer; Cancer stem cells; Targeted delivery; Glioblastoma
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2016.07.032

A minor population of glioblastoma stem-like cells (GSCs) has been implicated in the relapse and resistance of glioblastoma to therapeutic treatments. Based on knowledge of the involvement of multiple microRNAs in GSC propagation, we designed a combinational approach to target the GSC population with multiple miRNA-based therapeutics. As carriers for the targeted delivery we took advantage of two aptamers that bind to, and inhibit, the receptor tyrosine kinases, Axl and PDGFRβ. We showed that the aptamer conjugates are transported through an in vitro blood-brain barrier (BBB) model. Furthermore, combining miR-137 and antimiR-10b synergizes with the receptor inhibitory function of aptamer carriers and prevents GSC expansion. Results highlighted the potential of combining multifunctional RNA-based therapeutics for selective targeting of GSCs and offer a proof of principle strategy to potentially fulfill the still unmet need for effective and safe treatment of glioma. [Display omitted]