Precision delivery of RAS-inhibiting siRNA to KRAS driven cancer via peptide-based nanoparticles
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// 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: rcfields@wustl.edu 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.
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Nanoparticle-based platforms delivering KRAS-specific siRNAs have been shown to reach cancer cells, decrease KRAS levels and produce anticancer activity.
“This technology has been shown to be adequately delivered to cancer cells and to effectively decrease their KRAS levels, resulting in anticancer activity200–202 (Table 1).”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [201]
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Cites
Siegel, R. L., Miller, K. D., & Jemal, A. (2016) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.21332 · Cited by 16,003 · see citing works
FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer
Conroy, T., Desseigne, F., Ychou, M., Bouché, O., Guimbaud, R., Bécouarn, Y., Adenis, A., Raoul, J.-L., Gourgou-Bourgade, S., de la Fouchardière, C., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1011923 · Cited by 7,810 · see citing works
Whole genomes redefine the mutational landscape of pancreatic cancer
Initiative, A. P. C. G., Waddell, N., Pajic, M., Patch, A.-M., Chang, D. K., Kassahn, K. S., Bailey, P., Johns, A. L., Miller, D., Nones, K., et al. (2015) · Nature · doi:10.1038/nature14169 · Cited by 2,642 · see citing works
Hingorani, S. R., Wang, L., Multani, A. S., Combs, C., Deramaudt, T. B., Hruban, R. H., Rustgi, A. K., Chang, S., & Tuveson, D. A. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.04.023 · Cited by 2,609 · see citing works
The role of surface charge in cellular uptake and cytotoxicity of medical nanoparticles
Fröhlich, E. (2012) · International Journal of Nanomedicine · doi:10.2147/ijn.s36111 · Cited by 2,496 · see citing works
Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse
Hingorani, S. R., Petricoin, E. F., Maitra, A., Rajapakse, V., King, C., Jacobetz, M. A., Ross, S., Conrads, T. P., Veenstra, T. D., Hitt, B. A., et al. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00309-x · Cited by 2,471 · see citing works
A Comprehensive Survey of Ras Mutations in Cancer
Prior, I. A., Lewis, P. D., & Mattos, C. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-2612 · Cited by 2,063 · see citing works
Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism
Ying, H., Kimmelman, A. C., Lyssiotis, C. A., Hua, S., Chu, G. C., Fletcher-Sananikone, E., Locasale, J. W., Son, J., Zhang, H., Coloff, J. L., et al. (2012) · Cell · doi:10.1016/j.cell.2012.01.058 · Cited by 2,043 · see citing works
Drugging the undruggable RAS: Mission Possible?
Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J., & Der, C. J. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4389 · Cited by 1,997 · see citing works
Delivery materials for siRNA therapeutics
Kanasty, R., Dorkin, J. R., Vegas, A., & Anderson, D. (2013) · Nature Materials · doi:10.1038/nmat3765 · Cited by 1,800 · see citing works
Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy
Jiang, H., Hegde, S., Knolhoff, B. L., Zhu, Y., Herndon, J. M., Meyer, M. A., Nywening, T. M., Hawkins, W. G., Shapiro, I. M., Weaver, D. T., et al. (2016) · Nature Medicine · doi:10.1038/nm.4123 · Cited by 1,060 · see citing works
Self-citationEssential role for oncogenic Ras in tumour maintenance
Chin, L., Tam, A., Pomerantz, J. H., Wong, M., Holash, J., Bardeesy, N., Shen, Q., O'Hagan, R., Pantginis, J., Zhou, H., et al. (1999) · Nature · doi:10.1038/22788 · Cited by 928 · see citing works
siRNAs: applications in functional genomics and potential as therapeutics
Dorsett, Y., & Tuschl, T. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1345 · Cited by 909 · see citing works
Zhu, Y., Herndon, J. M., Sojka, D. K., Kim, K.-W., Knolhoff, B. L., Zuo, C., Cullinan, D. R., Luo, J. R., Bearden, A. R., Lavine, K. J., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.07.014 · Cited by 799 · see citing works
Self-citationDer, C. J., Krontiris, T. G., & Cooper, G. M. (1982) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.79.11.3637 · Cited by 785 · see citing works
Ras history: The saga continues
Cox, A. D., & Der, C. J. (2010) · Small GTPases · doi:10.4161/sgtp.1.1.12178 · Cited by 706 · see citing works
Tabernero, J. M., Shapiro, G. I., LoRusso, P. M., Cervantes, A. M. R., Schwartz, G. K., Weiss, G. J., Paz-Ares, L. G., Cho, D. C., Infante, J. R., Alsina, M., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0429 · Cited by 700 · see citing works
Investigating the optimal size of anticancer nanomedicine
Tang, L., Yang, X., Yin, Q., Cai, K., Wang, H., Chaudhury, I., Yao, C., Zhou, Q., Kwon, M., Hartman, J. A., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1411499111 · Cited by 658 · see citing works
Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer
Morton, J. P., Timpson, P., Karim, S. A., Ridgway, R. A., Athineos, D., Doyle, B., Jamieson, N. B., Oien, K. A., Lowy, A. M., Brunton, V. G., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908428107 · Cited by 657 · see citing works
Targeting protein prenylation for cancer therapy
Berndt, N., Hamilton, A. D., & Sebti, S. M. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3151 · Cited by 614 · see citing works
Estimation of rat mammary tumor volume using caliper and ultrasonography measurements
Faustino‐Rocha, A. I., Oliveira, P. A., Pinho, J. O., Teixeira-Guedes, C., Soares, R. M. M., da Costa, R. M. G., Colaço, B., Pires, M. J., Colaço, J., Ferreira, R. M., et al. (2013) · Lab Animal · doi:10.1038/laban.254 · Cited by 504 · see citing works
Oncogenic KRAS signalling in pancreatic cancer
Eser, S., Schnieke, A., Schneider, G., & Saur, D. (2014) · British Journal of Cancer · doi:10.1038/bjc.2014.215 · Cited by 504 · see citing works
The dark side of Ras: regulation of apoptosis
Cox, A. D., & Der, C. J. (2003) · Oncogene · doi:10.1038/sj.onc.1207111 · Cited by 438 · see citing works
Targeting Negative Surface Charges of Cancer Cells by Multifunctional Nanoprobes
Chen, B., Le, W., Wang, Y., Li, Z., Wang, D., Lin, L., Cui, S., Hu, J. J., Hu, Y., Yang, P., et al. (2016) · Theranostics · doi:10.7150/thno.16358 · Cited by 398 · see citing works
Feramisco, J. R., Gross, M. S., Kamata, T., Rosenberg, M. J., & Sweet, R. W. (1984) · Cell · doi:10.1016/0092-8674(84)90531-2 · Cited by 389 · see citing works
Pancreatic cancer: why is it so hard to treat?
Oberstein, P. E., & Olive, K. P. (2013) · Therapeutic Advances in Gastroenterology · doi:10.1177/1756283x13478680 · Cited by 334 · see citing works
Oncogenic Ras in tumour progression and metastasis
Giehl, K. (2005) · Biological Chemistry · doi:10.1515/bc.2005.025 · Cited by 287 · see citing works
Improving the efficiency of RNA interference in mammals
Mittal, V. (2004) · Nature Reviews Genetics · doi:10.1038/nrg1323 · Cited by 284 · see citing works
Oncogenic Ras and its role in tumor cell invasion and metastasis
Campbell, P. M., & Der, C. J. (2004) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2003.09.015 · Cited by 273 · see citing works
Strategies to improve tumor penetration of nanomedicines through nanoparticle design
Zhang, Y., Lin, R., Li, H., He, W., Du, J., & Wang, J. (2018) · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1519 · Cited by 269 · see citing works
Campbell, P. M., Groehler, A. L., Lee, K. M., Ouellette, M. M., Khazak, V., & Der, C. J. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-3752 · Cited by 215 · see citing works
RNAi-Based Treatment for Neovascular Age-Related Macular Degeneration by Sirna-027
Kaiser, P. K., Symons, R. C. A., Shah, S. M., Quinlan, E., Tabandeh, H., Diana, V., Reisen, G., Lockridge, J. A., Short, B. G., Guerciolini, R., et al. (2010) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2010.02.006 · Cited by 195 · see citing works
Pancreatic cancer: Stroma and its current and emerging targeted therapies
Kota, J., Hancock, J., Kwon, J. J., & Korc, M. (2017) · Cancer Letters · doi:10.1016/j.canlet.2016.12.035 · Cited by 171 · see citing works
Yan, H., Duan, X., Pan, H., Holguin, N., Rai, M. F., Akk, A. M., Springer, L. E., Wickline, S. A., Sandell, L. J., & Pham, C. T. N. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1608245113 · Cited by 154 · see citing works
Self-citationSoenen, S. J., Illyés, E., Vercauteren, D., Braeckmans, K., Májer, Z., Smedt, S. C. D., & Cuyper, M. D. (2009) · Biomaterials · doi:10.1016/j.biomaterials.2009.08.050 · Cited by 115 · see citing works
K-ras Codon-Specific Mutations Produce Distinctive Metabolic Phenotypes in Human Fibroblasts
Vizán, P., Boros, L. G., Figueras, A., Capellá, G., Mangues, R., Bassilian, S., Lim, S. K., Lee, W. P., & Cascante, M. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-0074 · Cited by 115 · see citing works
Ras inhibition via direct Ras binding—is there a path forward?
Wang, W., Fang, G., & Rudolph, J. (2012) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2012.07.082 · Cited by 104 · see citing works
Mahajan, U. M., Teller, S., Sendler, M., Palankar, R., van den Brandt, C., Schwaiger, T., Kühn, J., Ribback, S., Glöckl, G., Evert, M., et al. (2016) · Gut · doi:10.1136/gutjnl-2016-311393 · Cited by 97 · see citing works
Therapeutic Silencing of KRAS Using Systemically Delivered siRNAs
Pecot, C. V., Wu, S. Y., Bellister, S. A., Filant, J., Rupaimoole, R., Hisamatsu, T., Bhattacharya, R., Maharaj, A., Azam, S. H., Rodriguez‐Aguayo, C., et al. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0074 · Cited by 96 · see citing works
Hiraki, M., Nishimura, J., Takahashi, H., Wu, X., Takahashi, Y., Miyo, M., Nishida, N., Uemura, M., Hata, T., Takemasa, I., et al. (2015) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2015.5 · Cited by 95 · see citing works
Mechanisms of nanoparticle-mediated siRNA transfection by melittin-derived peptides
Hou, K. K., Pan, H., Ratner, L., Schlesinger, P. H., & Wickline, S. A. (2013) · ACS Nano · doi:10.1021/nn403311c · Cited by 95 · see citing works
Self-citationPeptide-siRNA nanocomplexes targeting NF-κB subunit p65 suppress nascent experimental arthritis
Zhou, H.-F., Yan, H., Pan, H., Hou, K. K., Akk, A. M., Springer, L. E., Hu, Y., Allen, J. S., Wickline, S. A., & Pham, C. T. N. (2014) · Journal of Clinical Investigation · doi:10.1172/jci75673 · Cited by 95 · see citing works
Self-citationMelittin derived peptides for nanoparticle based siRNA transfection
Hou, K. K., Pan, H., Lanza, G. M., & Wickline, S. A. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.01.037 · Cited by 91 · see citing works
Self-citationPei, Y., Liang, C., Huang, Y., Wang, J., Feng, J., Xu, M., Chen, Y., Song, Q., Jiang, G., Gu, X. Q., et al. (2019) · Small · doi:10.1002/smll.201900631 · Cited by 90 · see citing works
Targeted Therapies for Pancreatic Cancer and Hurdles Ahead
Aslan, M., Shahbazi, R., Ulubayram, K., & Özpolat, B. (2018) · Anticancer Research · doi:10.21873/anticanres.13026 · Cited by 88 · see citing works
Control of colorectal metastasis formation by K-Ras
Smakman, N., Rinkes, I. H. M. B., Voest, E. E., & Kranenburg, O. (2005) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2005.07.001 · Cited by 59 · see citing works
Zeng, L., Li, J., Wang, Y., Qian, C., Chen, Y., Zhang, Q., Wu, W., Zhong, L., Liang, J., Shuai, X., et al. (2013) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2013.08.007 · Cited by 48 · see citing works
Kafatos, G., Niepel, D., Lowe, K., Jenkins-Anderson, S., Westhead, H., Garawin, T., Traugottova, Z., Bilalis, A., Molnar, E., Tı́már, J., et al. (2017) · Biomarkers in Medicine · doi:10.2217/bmm-2016-0358 · Cited by 47 · see citing works
Pan, H., Palekar, R. U., Hou, K. K., Bacon, J., Yan, H., Springer, L. E., Akk, A. M., Yang, L., Miller, M. J., Pham, C. T. N., et al. (2018) · International Journal of Nanomedicine · doi:10.2147/ijn.s168556 · Cited by 32 · see citing works
Self-citationTaniuchi, K., Yawata, T., Tsuboi, M., Ueba, T., & Saibara, T. (2019) · Oncotarget · doi:10.18632/oncotarget.26880 · Cited by 32 · see citing works
Multiple Levels of MHC Class I Down‐Regulation by ras Oncogenes
Lohmann, S., Wollscheid, U., Huber, C., & Seliger, B. (1996) · Scandinavian Journal of Immunology · doi:10.1046/j.1365-3083.1996.d01-73.x · Cited by 30 · see citing works
Kabir, A. U., Lee, T. J., Pan, H., Berry, J. C., Krchma, K., Wu, J. H., Liu, F., Kang, H., Hinman, K., Yang, L., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.97349 · Cited by 23 · see citing works
Self-citationZeng, L., Li, J., Li, J., Zhang, Q., Qian, C., Wu, W., Zhong, L., Liang, J., Chen, Y., & Huang, K. (2014) · Pancreas · doi:10.1097/mpa.0000000000000241 · Cited by 19 · see citing works
The effect of H-ras expression on tumorigenicity and immunogenicity of Balb/c 3T3 fibroblasts
Ehrlich, T., Wishniak, O., Isakov, N., et al. (1993) · Immunology Letters · doi:10.1016/0165-2478(93)90156-v · Cited by 13 · see citing works
Reduced stimulation of helper T cells by Ki-ras transformed cells.
Maudsley, D. J., Bateman, W. J., & Morris, A. G. (1991) · PubMed · Cited by 10 · see citing works
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Punekar, S. R., Velcheti, V., Neel, B. G., & Wong, K.-K. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00671-9 · Cited by 549 · see citing works
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Janssen, K., Claes, F., Van de Velde, D., Wehbi, V. L., Houben, B., Lampi, Y., Nys, M., Khodaparast, L., Khodaparast, L., Louros, N., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2214921120 · Cited by 10 · see citing works
- Authors
- Strand, M. S., Krasnick, B. A., Pan, H., Zhang, X., Bi, Y., Brooks, C., Wetzel, C., Sankpal, N., Fleming, T., Goedegebuure, S. P., DeNardo, D. G., Gillanders, W. E., Hawkins, W. G., Wickline, S. A., & Fields, R. C.
- Affiliations
- Washington University in St. Louis (US)
- University of South Florida (US)
- St. Joseph's Hospital and Medical Center (US)
- Corresponding author
- Strand, Matthew S.
- Krasnick, Bradley A.
- ORCID
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2019-07-30
- Volume
- 10
- Issue
- 46
- Pages
- 4761-4775
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC6677667
- OpenAlex
- W2981491884
- Cited by
- 74
- References
- 55
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 17 · 2023: 11 · 2022: 12 · 2021: 11 · 2020: 8
- FWCI
- 2.56
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
- Digital Commons - University of South Florida (University of South Florida) (submittedVersion, cc-by)
- Funders
- Washington University in St. Louis
- Foundation for Barnes-Jewish Hospital
- Sidney Kimmel Foundation
- National Cancer Institute (P50CA196510, T32CA009621)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- siRNA delivery, KRAS, RAS inhibition, peptide-based nanoparticles, pancreatic ductal adenocarcinoma, gastrointestinal cancer, desmoplasia, tumor microenvironment, siRNA stability, tumor growth inhibition
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