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Influence; particle size on the in vivo potency; lipid nanoparticle formulations; siRNA
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DOI：10.1016/j.jconrel.2016.05.059.png)
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Abstract
En 中文
Lipid nanoparticles (LNP) can provide a clinically effective method for delivering small interfering RNA (siRNA) to silence pathological genes in hepatocytes. The gene silencing potency;
these LNP-siRNA systems has been shown to depend on a variety;
factors including association with serum factors such as ApoE and the pK(a);
component ionizable lipids. Here we investigate the influence;
LNP size, an important parameter affecting tissue penetration;
LNP systems, on the pharmacokinetics, biodistribution, and hepatic gene silencing potency;
LNP-siRNA systems following intravenous administration. For LNP systems stabilized by a polyethylene glycol (PEG)-lipid that can dissociate from the LNP following injection, it is shown that small (diameter <= 30 nm) systems are considerably less potent than their larger counterparts. This is attributed in part to the ability;
other lipid components, particularly the ionizable amino-lipid, to dissociate from the LNP following dissociation;
the PEG-lipid. Small LNP stabilized by PEG-lipids with slow dissociation rates exhibited much reduced aminolipid dissociation rates, however such systems are relatively impotent due to the continued presence;
the PEG coating. These results demonstrate the delicate balance between the in vivo potency;
LNP-siRNA systems and the residence times;
component lipids in the LNP particle itself and suggest new directions to optimize the in vivo gene silencing potency;
small LNP-siRNA systems. (C) 2016 Published by Elsevier B. V.
Keywords:
Lipid nanoparticles
Liposomes
siRNA
Nanomedicine
Drug delivery
Lipid exchange
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