Affinito Alessandra, Quintavalle Cristina, Esposito Carla Lucia, Roscigno Giuseppina, Vilardo Claudia, Nuzzo Silvia, Ricci-Vitiani Lucia, De Luca Gabriele, Pallini Roberto, Kichkailo Anna S, Lapin Ivan N, de Franciscis Vittorio, Condorelli Gerolama
Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Via Pansini 5, 80131 Naples, Italy; Percuros B.V., Enschede, the Netherlands.
Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Via Pansini 5, 80131 Naples, Italy; Percuros B.V., Enschede, the Netherlands.
Mol Ther Nucleic Acids. 2019 Dec 6;18:99-109. doi: 10.1016/j.omtn.2019.08.015. Epub 2019 Aug 22.
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. Despite progress in surgical and medical neuro-oncology, prognosis for GBM patients remains dismal, with a median survival of only 14-15 months. The modest benefit of conventional therapies is due to the presence of GBM stem cells (GSCs) that cause tumor relapse and chemoresistance and, therefore, that play a key role in GBM aggressiveness and recurrence. So far, strategies to identify and target GSCs have been unsuccessful. Thus, the development of an approach for GSC detection and targeting would be fundamental for improving the survival of GBM patients. Here, using the cell-systematic evolution of ligand by exponential (SELEX) methodology on human primary GSCs, we generated and characterized RNA aptamers that selectively bind GSCs versus undifferentiated GBM cells. We found that the shortened version of the aptamer 40L, which we have called A40s, costained with CD133-labeled cells in human GBM tissue, suggestive of an ability to specifically recognize GSCs in fixed human tissues. Of note, both 40L and A40s were rapidly internalized by cells, allowing for the delivery of the microRNA miR-34c and the anti-microRNA anti-miR-10b, demonstrating that these aptamers can serve as selective vehicles for therapeutics. In conclusion, the aptamers 40L and A40s can selectively target GSCs. Given the crucial role of GSCs in GBM recurrence and therapy resistance, these aptamers represent innovative drug delivery candidates with a great potential in the treatment of GBM.
胶质母细胞瘤（GBM）是成人中最具侵袭性的原发性脑肿瘤。尽管手术和医学神经肿瘤学取得了进展，但GBM患者的预后仍然很差，中位生存期仅为14 - 15个月。传统疗法的益处有限，这是由于GBM干细胞（GSCs）的存在，这些干细胞会导致肿瘤复发和化疗耐药，因此在GBM的侵袭性和复发中起关键作用。到目前为止，识别和靶向GSCs的策略一直没有成功。因此，开发一种检测和靶向GSCs的方法对于提高GBM患者的生存率至关重要。在这里，我们使用指数富集的配体系统进化（SELEX）方法对人原发性GSCs进行研究，生成并表征了与未分化的GBM细胞相比能选择性结合GSCs的RNA适配体。我们发现适配体40L的缩短版本，我们称之为A40s，在人GBM组织中与CD133标记的细胞共染色，这表明它有能力在固定的人体组织中特异性识别GSCs。值得注意的是，40L和A40s都能被细胞快速内化，从而实现微小RNA miR - 34c和抗微小RNA抗miR - 10b的递送，这表明这些适配体可以作为治疗药物的选择性载体。总之，适配体40L和A40s可以选择性地靶向GSCs。鉴于GSCs在GBM复发和治疗耐药中的关键作用，这些适配体代表了具有创新意义的药物递送候选物，在GBM治疗中具有巨大潜力。
