STAT3 Gene Silencing by Aptamer-siRNA Chimera as Selective Therapeutic for Glioblastoma

Carla Lucia Esposito; Silvia Nuzzo; Silvia Catuogno; Simona Romano; Filomena de Nigris; Vittorio de Franciscis

doi:10.1016/j.omtn.2017.12.021

STAT3 Gene Silencing by Aptamer-siRNA Chimera as Selective Therapeutic for Glioblastoma

Mol Ther Nucleic Acids. 2018 Mar 2:10:398-411. doi: 10.1016/j.omtn.2017.12.021. Epub 2017 Dec 30.

Authors

Carla Lucia Esposito¹, Silvia Nuzzo², Silvia Catuogno³, Simona Romano⁴, Filomena de Nigris⁵, Vittorio de Franciscis³

Affiliations

¹ IEOS, CNR, Naples, Italy. Electronic address: c.esposito@ieos.cnr.it.
² IEOS, CNR, Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.
³ IEOS, CNR, Naples, Italy.
⁴ Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Naples, Italy.
⁵ Department of Biochemistry, Biophysics and General Pathology, University of Campania "Luigi Vanvitelli," Naples, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA.

Abstract

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.

Keywords: STAT3; aptamer; glioblastoma; siRNA; targeted delivery.