TY - JOUR
T1 - Precision delivery of RAS-inhibiting siRNA to KRAS driven cancer via peptide-based nanoparticles
AU - Strand, Matthew S.
AU - Krasnick, Bradley A.
AU - Pan, Hua
AU - Zhang, Xiuli
AU - Bi, Ye
AU - Brooks, Candace
AU - Wetzel, Christopher
AU - Sankpal, Narendra
AU - Fleming, Timothy
AU - Peter Goedegebuure, S.
AU - DeNardo, David G.
AU - Gillanders, William E.
AU - Hawkins, William G.
AU - Wickline, Samuel A.
AU - Fields, Ryan C.
N1 - Funding Information:
MSS and BAK credit support from the Washington University School of Medicine Surgical Oncology Basic Science and Translational Research Training Program grant T32CA009621, from the National Cancer Institute (NCI). In addition, research reported in this publication was supported by the Washington University SPORE in Pancreatic Cancer grant P50CA196510 from the National Cancer Institute (NCI) of the National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. In addition, we acknowledge support from American Cancer Society Institutional Review Grant (ACS-IRG), the American Surgical Association Foundation Fellowship, the Alvin J. Siteman Cancer Center and Barnes-Jewish Hospital Foundation Cancer Frontier Fund, the Society of Surgical Oncology James Ewing Foundation, the Sidney Kimmel Foundation, and the David Riebel Cancer Fund at Washington University in St. Louis.
Publisher Copyright:
© Strand et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Gastrointestinal cancer
KW - Nanoparticle agents
KW - Oncoprotein
KW - Pancreatic cancer
UR - http://www.scopus.com/inward/record.url?scp=85070830341&partnerID=8YFLogxK
M3 - Article
C2 - 31413817
AN - SCOPUS:85070830341
SN - 1949-2553
VL - 10
SP - 4761
EP - 4775
JO - Oncotarget
JF - Oncotarget
IS - 46
ER -