Versatile cationic lipids for siRNA delivery
| Autor: | Casey Pence, Majed Matar, David Ulkoski, Leslie Wilkinson, Jason G. Fewell, Elaine Brunhoeber, Kirby Wallace, Diane McClure, Gregory Slobodkin, Jennifer Rice, Richard Congo, Angela Rea-Ramsey, Kevin Polach, Jeff Sparks, Khursheed Anwer |
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| Rok vydání: | 2012 |
| Předmět: |
Gene knockdown
L-Lactate Dehydrogenase Cell Survival Chemistry Caveolin 1 Gene Transfer Techniques Pharmaceutical Science Lipids In vitro Polyethylene Glycols RNAi Therapeutics Cell biology Mice Biochemistry In vivo RNA interference Cell Line Tumor Toxicity Polyamines Systemic administration PEGylation Animals Nanoparticles RNA Small Interfering |
| Zdroj: | Journal of Controlled Release. 158:269-276 |
| ISSN: | 0168-3659 |
| Popis: | Exploitation of the RNA interference (RNAi) pathway offers the promise of new and effective therapies for a wide variety of diseases. Clinical development of new drugs based on this platform technology is still limited, however, by a lack of safe and efficient delivery systems. Here we report the development of a class of structurally versatile cationic lipopolyamines designed specifically for delivery of siRNA which show high levels of target transcript knockdown in a range of cell types in vitro. A primary benefit of these lipids is the ease with which they may be covalently modified by the addition of functional molecules. For in vivo applications one of the core lipids (Staramine) was modified with methoxypolyethylene glycols (mPEGs) of varying lengths. Upon systemic administration, PEGylated Staramine nanoparticles containing siRNA targeting the caveolin-1 (Cav-1) transcript caused a reduction of the Cav-1 transcript of up to 60%, depending on the mPEG length, specifically in lung tissue after 48h compared to treatment with non-silencing siRNA. In addition, modification with mPEG reduced toxicity associated with intravenous administration. The ability to produce a high level of target gene knockdown in the lung with minimal toxicity demonstrates the potential of these lipopolyamines for use in developing RNAi therapeutics for pulmonary disease. |
| Databáze: | OpenAIRE |
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