Nano Science and Technology Institute
Nanotech 2008 Vol. 2
Nanotech 2008 Vol. 2
Nanotechnology 2008: Life Sciences, Medicine & Bio Materials - Technical Proceedings of the 2008 NSTI Nanotechnology Conference and Trade Show, Volume 2
 
Chapter 4: Drug & Gene Delivery Systems
 

Oral Delivery of Map4K4 siRNA to Macrophages Inhibits TNF alpha Production and Protects against a LPS-Galactosamine Challenge in Mice

Authors:M. Aouadi, G. Tesz, E. Soto, M. Wang, S. Nicoloro, G. Ostroff, M. Czech
Affilation:University of Massachusetts Medical School, US
Pages:332 - 335
Keywords:oral siRNA delivery, Map4K4, inflammation
Abstract:RNA interference (RNAi) is a new, promising approach to selectively regulate gene expression through modulating mRNA stability and translation. However, the efficient delivery of 21 mer dsRNA molecules (siRNA) to affect RNAi remains a challenge. Here we report on the development of a new delivery technology based on the in situ layer by layer synthesis of siRNA containing nanoplexes encapsulated within hollow yeast cell wall particles (YCWP). YCWP provide for receptor-mediated oral bioavailability and macrophage targeting of nanoplexed cargos, such as siRNA. We have identified a mitogen-activated protein kinase (Map4K4) that controls adipocyte signaling (PNAS 14; 103(7): 2087–2092 2006). In addition, Map4K4 controls TNFalpha expression in macrophages in response to an LPS challenge. siRNA targeting Map4k4 formulated in YCWP and administered to C57BL/6J mice (10 ug siRNA/Kg) by intraperitoneal or oral routes for 8 days effectively knocked down Map4K4 and TNF mRNA levels (>50%) in murine peritoneal exudate cells, and in splenic and liver macrophages compared to a YCWP delivered scrambled siRNA control. Mice orally pretreated with YCWP encapsulated Map4K4 siRNA (10 ug siRNA/Kg) for 8 days were significantly protected against an LD90 challenge of LPS-Galactosamine. These results demonstrate the efficient in vivo YCWP-mediated delivery of siRNA by both systemic and oral routes and the utility of targeting Map4K4 to modulate inflammatory processes.
Oral Delivery of Map4K4 siRNA to Macrophages Inhibits TNF alpha Production and Protects against a LPS-Galactosamine Challenge in MiceView PDF of paper
ISBN:978-1-4200-8504-4
Pages:808
Hardcopy:$159.95
 
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