Novel nanoparticle to deliver powerful RNA interference drugs

201306047919620(Nanowerk News) Silencing genes that have malfunctioned  is an important approach for treating diseases such as cancer and heart disease.  One effective approach is to deliver drugs made from small molecules of  ribonucleic acid, or RNA, which are used to inhibit gene expression. The drugs,  in essence, mimic a natural process called RNA interference.
In a new paper appearing today online in the journal, ACS  Medicinal Chemistry Letters (“In Vivo Delivery of RNAi by Reducible Interfering  Nanoparticles (iNOPs)”), researchers at Sanford-Burnham Medical Research  Institute have developed nanoparticles that appear to solve a big challenge in  delivering the RNA molecules, called small interfering RNA, or siRNA, to the  cells where they are needed. By synthesizing a nanoparticle that releases its  siRNA cargo only after it enters targeted cells, Dr. Tariq M. Rana and  colleagues showed in mice that they could deliver drugs that silenced the genes  they wanted.
“Our study describes a strategy to reduce toxic effects of  nanoparticles, and deliver a cargo to its target,” said Dr. Rana, whose paper,  “In Vivo Delivery of RNAi by Reducible Interfering Nanoparticles (iNOPs),” also  included contributions from researchers at the University of Massachusetts  Medical School and the University of California at San Diego. “We’ve found a way  to release the siRNA compounds, so it can be more effective where it’s needed,”  Dr. Rana said.
In their experiment, the team synthesized what they call  interfering nanoparticles, or iNOPs, made from repetitively branched molecules  of a small natural polymer called poly-L-lysine. The iNOPs were specially  designed with positively charged residues connected by disulfide bonds and these  iNOPS assemble into a complex with negatively charged siRNA molecules. It’s the  bonds that ensure that the siRNA molecules remain with the nanoparticle, named  iNOP-7DS. However, once inside targeted cells, a naturally occurring and  abundant antioxidant called glutathione breaks the bond, releasing the siRNA  molecules. In their experiment, Dr. Rana and colleagues showed in the lab that  iNOP-7DS is reducible – that is, the disulfide bonds holding the siRNA molecules  can be broken.
They next showed that iNOP-7DS can be delivered effectively  inside cultured murine liver cells, where the siRNA molecules silenced a gene  called ApoB. This gene has been notoriously difficult to regulate in liver cells  with small molecule drugs; high levels of the protein that ApoB encodes can lead  to plaques that cause vascular disease.
Dr. Rana’s lab further showed in tests that their nanoparticle  remained stable in serum, suggesting that it is not degraded in the bloodstream.  Finally, the researchers showed in tests with mice that their nanoparticle  iNOP-7DS can be delivered effectively to the liver, spleen, and lung; and it  suppressed the level of messenger RNA involved in the expression of the ApoB  gene. In their in vivo experiment, they found that extremely small doses of  siRNA were effective.
The next step, Dr. Rana said, is to increase the efficacy of  iNOP-7DS in other in vivo experiments. “We would like to target not only ApoB,  but cancer causing genes as well and in other tissues. That is the next goal.”  By marshaling the naturally occurring phenomenon of RNA interference, scientists  are developing new ways to silence errant gene expression involved in illnesses.  The nanoparticles developed by Dr. Rana and colleagues offer a potential new  strategy for delivering this powerful therapeutic approach.
Source: Sanford-Burnham Medical Research Institute 

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