1. In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight.
- Author
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Dahlman JE, Barnes C, Khan O, Thiriot A, Jhunjunwala S, Shaw TE, Xing Y, Sager HB, Sahay G, Speciner L, Bader A, Bogorad RL, Yin H, Racie T, Dong Y, Jiang S, Seedorf D, Dave A, Sandu KS, Webber MJ, Novobrantseva T, Ruda VM, Lytton-Jean AKR, Levins CG, Kalish B, Mudge DK, Perez M, Abezgauz L, Dutta P, Smith L, Charisse K, Kieran MW, Fitzgerald K, Nahrendorf M, Danino D, Tuder RM, von Andrian UH, Akinc A, Schroeder A, Panigrahy D, Kotelianski V, Langer R, and Anderson DG
- Subjects
- Animals, Cell Line, Humans, Mice, Nanoparticles ultrastructure, Neoplasms genetics, Neoplasms therapy, RNA, Small Interfering genetics, RNA, Small Interfering therapeutic use, Endothelial Cells metabolism, Nanoparticles chemistry, Polymers chemistry, RNA Interference, RNA, Small Interfering administration & dosage
- Abstract
Dysfunctional endothelium contributes to more diseases than any other tissue in the body. Small interfering RNAs (siRNAs) can help in the study and treatment of endothelial cells in vivo by durably silencing multiple genes simultaneously, but efficient siRNA delivery has so far remained challenging. Here, we show that polymeric nanoparticles made of low-molecular-weight polyamines and lipids can deliver siRNA to endothelial cells with high efficiency, thereby facilitating the simultaneous silencing of multiple endothelial genes in vivo. Unlike lipid or lipid-like nanoparticles, this formulation does not significantly reduce gene expression in hepatocytes or immune cells even at the dosage necessary for endothelial gene silencing. These nanoparticles mediate the most durable non-liver silencing reported so far and facilitate the delivery of siRNAs that modify endothelial function in mouse models of vascular permeability, emphysema, primary tumour growth and metastasis.
- Published
- 2014
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