(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.
“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
(Nanowerk News) Conventional treatments for diseases such as cancer can carry harmful side effects—and the primary reason is that such treatments are not targeted specifically to the cells of the body where they’re needed. What if drugs for cancer, cardiovascular disease, and other diseases can be targeted specifically and only to cells that need the medicine, and leave normal tissues untouched?
“While nanoparticle shape has been shown to impact cellular uptake, the latest study shows that specific tissues can be targeted by controlling the shape of nanoparticles. Keeping the material, volume, and the targeting antibody the same, a simple change in the shape of the nanoparticle enhances its ability to target specific tissues,” said Mitragotri.
“The elongated particles are more effective,” added Ruoslahti. “Presumably the reason is that if you have a spherical particle and it has binding sites on it, the curvature of the sphere allows only so many of those binding sites to interact with membrane receptors on the surface of a cell.”
In contrast, the elongated nanorods have a larger surface area that is in contact with the surface of the endothelial cells. More of the antibodies that coat the nanorod can therefore bind receptors on the surface of endothelial cells, and that leads to more effective cell adhesion and more effective drug delivery.
Testing targeted nanoparticles
Mitragotri’s lab tested the efficacy of rod-shaped nanoparticles in synthesized networks of channels called “synthetic microvascular networks,” or SMNs, that mimic conditions inside blood vessels. The nanoparticles were also tested in vivo in animal models, and separately in mathematical models.
The researchers also found that nanorods targeted to lung tissue in mice accumulated at a rate that was two-fold over nanospheres engineered with the same targeting antibody. Also, enhanced targeting of nanorods was seen in endothelial cells in the brain, which has historically been a challenging organ to target with drugs.
Nanoparticles have been studied as vessels to carry drugs through the body. Once they are engineered with antibodies that bind to specific receptors on the surface of targeted cells, these nanoparticles also can, in principle, become highly specific to the disease they are designed to treat.
Ruoslahti, a pioneer in the field of cell adhesion—how cells bind to their surroundings—has developed small chain molecules called peptides that can be used to target drugs to tumors and atherosclerotic plaques.
“Greater specific attachment exhibited by rod-shaped particles offers several advantages in the field of drug delivery, particularly in the delivery of drugs such as chemotherapeutics, which are highly toxic and necessitate the use of targeted approaches,” the authors wrote in their paper.
The studies demonstrate that nanorods with a high aspect ratio attach more effectively to targeted cells compared with spherical nanoparticles. The findings hold promise for the development of novel targeted therapies with fewer harmful side effects.