Systemic delivery of hk raf-1 sirna polyplexes inhibits mda-mb-435 xenografts
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ABSTRACT Our past research has focused on identifying an effective carrier composed of histidine and lysine for delivery of nucleic acid into cells. For this purpose, we developed
histidine-lysine-rich (HK) polymers with specific sequences and branching. We have found that branched HK polymers in complex with Raf-1 siRNA markedly decreased Raf-1 mRNA and induced
apoptosis in cell lines _in vitro_. The primary focus of the present study was to determine an effective carrier to deliver siRNA systemically to tumor xenografts. After comparing HK:Raf-1
polyplexes for their _in-vivo_ efficacy, we investigated in greater detail whether one of these polymers, H3K(+H)4b, in complex with Raf-1 siRNA, inhibited the growth of MDA-MB-435
xenografts. H3K(+H)4b is a four-branched HK peptide whose predominant repeating sequence within the terminal arm is -HHHK-. After the first tail-vein injection in a mouse model, there was a
statistically significant reduction in tumor size between the H3K(+H)4b:Raf-1 siRNA-treated and the control groups (_P_<0.01). By the third injection, there was nearly a 50% reduction in
the Raf-1 siRNA-treated group compared to the control siRNA-treated or -untreated group. Consistent with a significant effect of the HK:Raf-1 polyplex on the tumor, there were marked
histological changes, increased apoptosis and fewer vessels in the Raf-1 siRNA-treated group. Raf-1 protein within the tumor was significantly decreased after treatment with the HK:Raf-1
siRNA polyplex compared to the control treatment groups. Despite the striking effect on the tumor by the HK Raf-1 siRNA, there was little evidence of toxicity in normal tissues with this
therapy. By harnessing the ability to modify the amino-acid sequence and branching of HK polymers, we expect continued development of HK polymers as _in-vivo_ carriers of siRNA. Access
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SIMILAR CONTENT BEING VIEWED BY OTHERS A PLATFORM TECHNOLOGY FOR ULTRA-LONG ACTING INTRATUMORAL THERAPY Article Open access 18 June 2024 INVESTIGATION OF THE ENHANCED ANTITUMOUR POTENCY OF
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Download references ACKNOWLEDGEMENTS We are grateful to Dr Pamela Talalay for her careful reading and useful comments concerning the article. We thank Dr Nicholas Ambulos and Dr Pat
Campbell of the Maryland Biopolymer laboratory for synthesizing the peptides in this study. This study was supported by the National Cancer Institute CA70394. AUTHOR INFORMATION Author notes
* P Scaria & M C Woodle Present address: 4Current Address: Aparna Biosciences, Rockville, MD 20852, USA., AUTHORS AND AFFILIATIONS * Department of Pathology, University of Maryland,
Baltimore, MD, USA Q Leng & A J Mixson * Intradigm Corporation, Palo Alto, CA, USA P Scaria & M C Woodle * Sirnaomics Inc., Gaithersburg, MD, USA P Lu Authors * Q Leng View author
publications You can also search for this author inPubMed Google Scholar * P Scaria View author publications You can also search for this author inPubMed Google Scholar * P Lu View author
publications You can also search for this author inPubMed Google Scholar * M C Woodle View author publications You can also search for this author inPubMed Google Scholar * A J Mixson View
author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to A J Mixson. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS
ARTICLE CITE THIS ARTICLE Leng, Q., Scaria, P., Lu, P. _et al._ Systemic delivery of HK Raf-1 siRNA polyplexes inhibits MDA-MB-435 xenografts. _Cancer Gene Ther_ 15, 485–495 (2008).
https://doi.org/10.1038/cgt.2008.29 Download citation * Received: 14 November 2007 * Revised: 03 February 2008 * Accepted: 08 March 2008 * Published: 16 May 2008 * Issue Date: August 2008 *
DOI: https://doi.org/10.1038/cgt.2008.29 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not
currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * Histidine * lysine * peptides * Raf-1 * tumor xenograft