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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Why the Shape of Nanoparticles Matters


QDOTS imagesCAKXSY1K 8(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?  
A new study involving Sanford-Burnham’s Erkki Ruoslahti, M.D.,  Ph.D., contributing to work by Samir Mitragotri, Ph.D., at the University of  California, Santa Barbara, found that the shape of nanoparticles can enhance  drug targeting. The study, published in Proceedings of the National Academy  of Sciences (“Using shape effects to target antibody-coated  nanoparticles to lung and brain endothelium”), found that rod-shaped  nanoparticles—or nanorods—as opposed to spherical nanoparticles, appear to  adhere more effectively to the surface of endothelial cells that line the inside  of blood vessels.
“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 already used in some cancer 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.
Promising results
“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.
Source: Sanford-Burnham Medical Research Institute 

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