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[This corrects the article DOI: 10.1016/j.omtn.2018.01.001.].
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Glioblastoma multiforme (GBM) is the most prevalent and lethal malignant intracranial tumor in the brain, with very poor prognosis and survival. The epidermal growth factor receptor variant III (EGFRvIII) contributes to increased oncogenicity that does not occur through binding EGFR ligands and instead occurs through constitutive activation, which enhances glioma tumorigenicity and resistance to targeted therapy. Aptamers are nucleic acids with high affinity and specificity to targets selected by systematic evolution of ligands by exponential enrichment (SELEX), and are usually developed as antagonists of disease-associated factors. Herein, we generated a DNA aptamer U2, targeting U87-EGFRvIII cells, and demonstrated that U2 alters the U87-EGFRvIII cell growth, radiosensitivity, and radiotherapy of glioblastoma cells. We detected U2 and U87-EGFRvIII cells by flow cytometry and confocal microscopy to explore the binding ability of U2 to U87-EGFRvIII cells. Then, we found that aptamer U2 inhibits the proliferation, migration, invasion, and downstream signaling of U87-EGFRvIII cells. Moreover, the U2 aptamer can increase the radiosensitivity of U87-EGFRvIII in vitro and has a better antitumor effect on 188Re-U2 in vivo. Therefore, the results revealed the promising potential of the U2 aptamer to be a new type of drug candidate and aptamer-targeted drug delivery system for glioblastoma therapy.
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An initial step in amyloid-ß (Aß) production includes amyloid precursor protein (APP) cleavage via ß-Site amyloid precursor protein cleaving enzyme 1 (BACE1). Increased levels of brain Aß have been implicated in the pathogenesis of Alzheimer's disease (AD). Thus, ß-secretase represents a primary target for inhibitor drug development in AD. In this study, aptamers were obtained from combinatorial oligonucleotide libraries using a technology referred to as systematic evolution of ligands by exponential enrichment (SELEX). A purified human BACE1 extracellular domain was used as a target to conduct an in vitro selection process using SELEX. Two DNA aptamers were capable of binding to BACE1 with high affinity and good specificity, with Kd values in the nanomolar range. We subsequently confirmed that one aptamer, A1, exhibited a distinct inhibitory effect on BACE1 activity in an AD cell model. We detected the effects of M17-APPsw cells that stably expressed Swedish mutant APP after aptamer A1 treatment. Aß40 and Aß42 concentrations secreted by M17-APPsw cells decreased intracellularly and in culture media. Furthermore, Western blot analysis indicated that sAPPß expression significantly decreased in the A1 treated versus control groups. These findings support the preliminary feasibility of an aptamer evolved from a SELEX strategy to function as a potential BACE1 inhibitor. To our knowledge, this is the first study to acquire a DNA aptamer that exhibited binding specificity to BACE1 and inhibited its activity.