@article{9b52d1b4ae9945e1a77c2edc662139e9,
title = "In silico, in vitro, and in vivo studies indicate the potential use of bolaamphiphiles for therapeutic siRNAs delivery",
abstract = "Specific small interfering RNAs (siRNAs) designed to silence different oncogenic pathways can be used for cancer therapy. However, non-modified naked siRNAs have short half-lives in blood serum and encounter difficulties in crossing biologicalmembranes due to their negative charge. These obstacles can be overcome by using siRNAs complexed with bolaamphiphiles, consisting of two positively charged head groups that flank an internal hydrophobic chain. Bolaamphiphiles have relatively low toxicities, long persistence in the blood stream, and most importantly, in aqueous conditions can form poly-cationic micelles thus, becoming amenable to association with siRNAs. Herein, two different bolaamphiphiles with acetylcholinehead groups attached to an alkyl chain in two distinct configurations are compared for their abilities to complex with siRNAsand deliver them into cells inducing gene silencing. Our explicit solvent molecular dynamics (MD) simulations showed that bolaamphiphiles associate with siRNAs due to electrostatic, hydrogen bonding, and hydrophobic interactions. These in silicostudies are supported by various in vitro and in cell culture experimental techniques as well as by some in vivo studies. Results demonstrate that depending on the application, the extent of siRNA chemical protection, delivery efficiency, and further intracellular release can be varied by simply changing the type of bolaamphiphile used.",
keywords = "Bolaamphiphiles, Cryo-EM, FRET, Molecular dynamics simulations, Poly-cationic micelles, RNA-based therapeutics, SiRNA delivery, Specific gene silencing",
author = "Taejin Kim and Afonin, {Kirill A.} and Mathias Viard and Koyfman, {Alexey Y.} and Selene Sparks and Eliahu Heldman and Sarina Grinberg and Charles Linder and Blumenthal, {Robert P.} and Shapiro, {Bruce A.}",
note = "Funding Information: This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD and the National Cancer Institute's Advanced Biomedical Computing Center (ABCC) of the Frederick National Laboratory for Cancer Research, Frederick, MD. The authors thank Nimit Patel, Lisa Riffle, and Joseph Kalen in the Small Animal Imaging Program at the Frederick National Laboratory for Cancer Research for their guidance and support in animal imaging. They also thank Matthew Dougherty for help in preparing the movies and EckartBindewald for technical assistance. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute. This work has been funded in whole or in part with Federal funds from the Frederick National Laboratory for Cancer Research, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported in part by the National Institutes of Health P41GM103832 and RC2GM092599 and the Postdoctoral Training Fellowship from the Keck Center Computational Cancer Biology Training Program of the Gulf Coast Consortia to A.Y.K. (CPRIT grant no. RP101489).",
year = "2013",
month = jan,
day = "1",
doi = "10.1038/mtna.2013.5",
language = "English",
volume = "2",
pages = "e80",
journal = "Molecular Therapy Nucleic Acids",
issn = "2162-2531",
publisher = "Cell Press",
}
