Nanomedicines for Systemic Delivery of RNAi Therapeutics - RNA Interference from Biology to Therapeutics - page 127

that has shown very promising outcomes is suitable for mucosal diseases or subcu-
taneous tissues.
For intravenous systemic administration, the delivery approaches need to protect
the RNAi molecules from degradation by serum nucleases, avoid clearance from
the circulatory system by renal filtration, transport the siRNA molecules across the
vascular endothelial barrier, facilitate effective biodistribution and accumulation at
the appropriate tissue, and promote efficient uptake and endosomal escape into the
cytoplasm of the target cells where they can associated with RISC and guide the
cleavage of target mRNA. The reader is referred to an excellent review on the ana-
tomical barriers [ 35 ] .
Systemic delivery of naked siRNAs has been demonstrated by the hydrodynamic
method. This method, whose precise mechanism of action is unknown but may
involve pressure-mediated cellular penetration, involves rapid injection of a large
volume of siRNA in physiologic solutions (about 10% of the body weight adminis-
tered within 5-10 s) [ 36, 37 ]. Hepatocyte cells in the liver are the main target of this
approach. Different studies have been performed with this method, demonstrating
functional knock-down of speci fi c genes in the liver of animals [ 36- 39 ] . Nevertheless,
due to volume overload sideeffects, the hydrodynamic method is not relevant for
human therapeutic use.
Naked siRNAs could also be utilised for targeting the kidney. When systemati-
cally administrated, large amount of naked siRNAs are excreted by the glomerulus
(<40 kDa Mw) and reabsorbed in the proximal tubule. The accumulation of free
siRNA in the kidney is 40 times higher than in any other organ, an ideal propriety
for selective gene therapy. Studies in rat models for renal injury indicated functional
silencing of p53, a major pro-apoptotic gene, and renal protection, both in single
and multiple injection administration [ 40 ]. A product based on these studies, QPI-
1002, is being developed by Quark Pharmaceuticals for systemic delivery of p53-
siRNA in acute renal injury and delayed graft function.
Accumulation in the kidney of systemic naked siRNA is due to physiological
consequence. Otherwise, strategies for systemic delivery of siRNA to alternative
sites must rely on transport within nanocarriers or as nano-conjugates such as
siRNA-cholestrol conjugates or fusion proteins carrying siRNAs. These carriers
should be composed of fully degradable materials (to avoid undesired and probably
toxic accumulation of the delivery system components in the body) and should act
on specific cells or tissues while avoid damaging others.
Systemic siRNA delivery strategies are divided into two major categories: pas-
sive and active cellular delivery. Passive delivery exploits the inherited tendency of
nanoparticles to accumulate in organs of the reticuloendothelial system (RES) also
known as the mononuclear phagocytic system (MPS). The MPS, part of the immune
system, consists of phagocytic cells located in reticular connective tissue, primarily
monocytes, dendritic cells and macrophages. These cells accumulate in lymph
nodes, the spleen, and liver that phagocytose foreign particles such as viruses, bac-
teria and parasites recognised by size, shape and charge. Passive targeting siRNAs
to the liver can be achieved due to the highly perfused nature of the liver and phago-
cytic capture by resident phagocytic Kupffer cells located in the liver lining the