Precision delivery of RAS-inhibiting siRNA to KRAS driven cancer via peptide-based nanoparticles

Abstract

// Matthew S. Strand 1 , * , Bradley A. Krasnick 1 , * , Hua Pan 2 , Xiuli Zhang 1 , Ye Bi 1 , Candace Brooks 1 , Christopher Wetzel 1 , Narendra Sankpal 1 , Timothy Fleming 3 , S. Peter Goedegebuure 1 , David G. DeNardo 4 , William E. Gillanders 1 , William G. Hawkins 1 , Samuel A. Wickline 2 and Ryan C. Fields 1 1 Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA 2 University of South Florida Health, Division of Cardiovascular Sciences, Tampa, FL, USA 3 Norton Thoracic Institute, St. Joseph Hospital, Phoenix, AZ, USA 4 Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA * These authors contributed equally to this work Correspondence to: Ryan C. Fields, email: [e-mail] Keywords: nanoparticle agents; pancreatic cancer; gastrointestinal cancer; oncoprotein Received: March 12, 2019     Accepted: June 29, 2019     Published: July 30, 2019 ABSTRACT Over 95% of pancreatic adenocarcinomas (PDACs), as well as a large fraction of other tumor types, such as colorectal adenocarcinoma, are driven by KRAS activation. However, no direct RAS inhibitors exist for cancer therapy. Furthermore, the delivery of therapeutic agents of any kind to PDAC in particular has been hindered by the extensive desmoplasia and resultant drug delivery challenges that accompanies these tumors. Small interfering RNA (siRNA) is a promising modality for anti-neoplastic therapy due to its precision and wide range of potential therapeutic targets. Unfortunately, siRNA therapy is limited by low serum half-life, vulnerability to intracellular digestion, and transient therapeutic effect. We assessed the ability of a peptide based, oligonucleotide condensing, endosomolytic nanoparticle (NP) system to deliver siRNA to KRAS-driven cancers. We show that this peptide-based NP is avidly taken up by cancer cells in vitro , can deliver KRAS-specific siRNA, inhibit KRAS expression, and reduce cell viability. We further demonstrate that this system can deliver siRNA to the tumor microenvironment, reduce KRAS expression, and inhibit pancreatic cancer growth in vivo . In a spontaneous KPPC model of PDAC, this system effectively delivers siRNA to stroma-rich tumors. This model has the potential for translational relevance for patients with KRAS driven solid tumors.