Esposito Carla Lucia, Nuzzo Silvia, Catuogno Silvia, Romano Simona, de Nigris Filomena, de Franciscis Vittorio
IEOS, CNR, Naples, Italy.
IEOS, CNR, Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.
Mol Ther Nucleic Acids. 2018 Mar 2;10:398-411. doi: 10.1016/j.omtn.2017.12.021. Epub 2017 Dec 30.
Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor in adults, and despite advances in neuro-oncology, the prognosis for patients remains dismal. The signal transducer and activator of transcription-3 (STAT3) has been reported as a key regulator of the highly aggressive mesenchymal GBM subtype, and its direct silencing (by RNAi oligonucleotides) has revealed a great potential as an anti-cancer therapy. However, clinical use of oligonucleotide-based therapies is dependent on safer ways for tissue-specific targeting and increased membrane penetration. The objective of this study is to explore the use of nucleic acid aptamers as carriers to specifically drive a STAT3 siRNA to GBM cells in a receptor-dependent manner. Using an aptamer that binds to and antagonizes the oncogenic receptor tyrosine kinase PDGFRβ (Gint4.T), here we describe the design of a novel aptamer-siRNA chimera (Gint4.T-STAT3) to target STAT3. We demonstrate the efficient delivery and silencing of STAT3 in PDGFRβ GBM cells. Importantly, the conjugate reduces cell viability and migration in vitro and inhibits tumor growth and angiogenesis in vivo in a subcutaneous xenograft mouse model. Our data reveals Gint4.T-STAT3 conjugate as a novel molecule with great translational potential for GBM therapy.
胶质母细胞瘤（GBM）是成人中最常见且侵袭性最强的原发性脑肿瘤，尽管神经肿瘤学取得了进展，但患者的预后仍然很差。信号转导和转录激活因子3（STAT3）已被报道为高度侵袭性间充质GBM亚型的关键调节因子，其直接沉默（通过RNAi寡核苷酸）已显示出作为抗癌疗法的巨大潜力。然而，基于寡核苷酸的疗法的临床应用依赖于更安全的组织特异性靶向和增加膜穿透的方法。本研究的目的是探索使用核酸适配体作为载体，以受体依赖性方式将STAT3小干扰RNA特异性地驱动至GBM细胞。使用一种与致癌受体酪氨酸激酶PDGFRβ结合并拮抗的适配体（Gint4.T），在此我们描述了一种新型的靶向STAT3的适配体-小干扰RNA嵌合体（Gint4.T-STAT3）的设计。我们证明了STAT3在PDGFRβ GBM细胞中的有效递送和沉默。重要的是，该缀合物在体外降低细胞活力和迁移，并在皮下异种移植小鼠模型中体内抑制肿瘤生长和血管生成。我们的数据表明Gint4.T-STAT3缀合物是一种具有巨大GBM治疗转化潜力的新型分子。
