MADISON, Wisc.—With their potential as both research tools and therapeutic molecules, siRNAs have gained wider interest of late, but targeting the molecules to specific cell or tissue types in vivo remains a challenge. Recently, however, researchers at Mirus Bio and the University of Wisconsin devised a nanoparticle system that allows them to precisely target and release siRNA molecules.
As they described in PNAS, the delivery system is based on the conjugation of siRNA molecules to an endosomolytic agent, PBAVE, which is comprised of poly(butyl and amino vinyl ethers). This construct is also decorated with the shielding agent PEG and a tissue-specific targeting agent. In the present work, the researchers used N-acetylgalactosamine (NAG) to target the particles—which they’ve dubbed siRNA Dynamic PolyConjugates—to hepatocytes.
The researchers tested the system in vitro with mouse primary hepatocytes and noted that siRNA conjugates targeting the mouse apolipoprotein B gene (apoB) knocked down apoB mRNA by about 80%. They then repeated the experiment in vivo by injecting the tails of mice with the nanoparticles and noted similar results at both the apoB mRNA and protein levels. Similar experiments using siRNA against the gene for peroxisome proliferator-activated receptor alpha offered similar results.
The researchers saw few signs of toxicity, and gene expression reduction appeared to be dose-dependent and of significant duration. Furthermore, by changing NAG to mannose, they could effectively change the targeting of the constructs from hepatocytes to other liver cells, which carry mannose receptors.