期刊
MOLECULAR THERAPY-NUCLEIC ACIDS
卷 2, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mtna.2013.5
关键词
bolaamphiphiles; cryo-EM; molecular dynamics simulations; FRET; poly-cationic micelles; RNA-based therapeutics; siRNA delivery; specific gene silencing
资金
- Intramural Research Program of the NIH, National Cancer Institute
- Frederick National Laboratory for Cancer Research, National Institutes of Health [HHSN261200800001E]
- National Institutes of Health [P41GM103832, RC2GM092599]
- Keck Center Computational Cancer Biology Training Program of the Gulf Coast Consortia (CPRIT) [RP101489]
However, non-modified naked siRNAs have short half-lives in blood serum and encounter difficulties in crossing biological membranes 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 acetylcholine head groups attached to an alkyl chain in two distinct configurations are compared for their abilities to complex with siRNAs and 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 silico studies 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.
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