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Bolaamphiphiles as carriers for siRNA delivery: From chemical syntheses to practical applications

Gupta, Kshitij and Afonin, Kirill A and Viard, Mathias and Herrero, Virginia and Kasprzak, Wojciech and Kagiampakis, Ioannis and Kim, Taejin and Koyfman, Alexey Y and Puri, Anu and Stepler, Marissa and Sappe, Alison and KewalRamani, Vineet N and Grinberg, Sarina and Linder, Charles and Heldman, Eliahu and Blumenthal, Robert and Shapiro, Bruce A (2015) Bolaamphiphiles as carriers for siRNA delivery: From chemical syntheses to practical applications. In: JOURNAL OF CONTROLLED RELEASE, 213 . pp. 142-151.

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Official URL: http://dx.doi.org/10.1016/j.jconrel.2015.06.041


In this study we have investigated a new class of cationic lipids - ``bolaamphiphiles'' or ``bolas'' - for their ability to efficiently deliver small interfering RNAs (siRNAs) to cancer cells. The bolas of this study consist of a hydrophobic chain with one or more positively charged head groups at each end. Recently, we reported that micelles of the bolas GLH-19 and GLH-20 (derived from vernonia oil) efficiently deliver siRNAs, while having relatively low toxicities in vitro and in vivo. Our previous studies validated that; bolaamphiphiles can be designed to vary the magnitude of siRNA shielding, its delivery, and its subsequent release. To further understand the structural features of bolas critical for siRNAs delivery, new structurally related bolas (GLH-58 and GLH-60) were designed and synthesized from jojoba oil. Both bolas have similar hydrophobic domains and contain either one, in GLH-58, or two, in GLH-60 positively charged head groups at each end of the hydrophobic core. We have computationally predicted and experimentally validated that GLH-58 formed more stable nano sized micelles than GLH-60 and performed significantly better in comparison to GLH-60 for siRNA delivery. GLH-58/siRNA complexes demonstrated better efficiency in silencing the expression of the GFP gene in human breast cancer cells at concentrations of 5 mu g/mL, well below the toxic dose. Moreover, delivery of multiple different siRNAs targeting the HIV genome demonstrated further inhibition of virus production. Published by Elsevier B.V.

Item Type: Journal Article
Additional Information: Copy right for this article belongs to the ELSEVIER SCIENCE BV, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
Keywords: Bolaamphiphiles; Molecular dynamics simulations; Cryo-EM; FRET; siRNA drug delivery; RNAi induced gene silencing
Department/Centre: Division of Chemical Sciences > Inorganic & Physical Chemistry
Date Deposited: 24 Sep 2015 04:36
Last Modified: 24 Sep 2015 04:36
URI: http://eprints.iisc.ac.in/id/eprint/52384

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