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Researchers Use New RNA Approach To Deliver siRNAs into Cancer Cells


Researchers at Purdue University and their collaborators have developed a new RNA-based technology to ferry siRNA and other therapeutic molecules into cancer cells.Their approach, published this month in two articles in Human Gene Therapy and Nano Letters, uses so-called packaging RNA, or pRNA, from bacteriophage phi29 as the delivery vehicle.

Normally, pRNA forms hexamers that are part of the DNA-packaging motor of the bacteriophage. The researchers, led by Peixuan Guo, a professor of molecular virology and director of the Laboratory of Gene Therapy at Purdue University, engineered pRNA to form either dimers or trimers that range in size from 20 to 40 nanometers. Each of the pRNA subunits is fused to either a ligand — for example folic acid or aptamers — that specifically recognizes cancer cells, or to a therapeutic molecule, such as siRNAs or ribozymes. Once such a nanoparticle, containing both the ligand and the therapeutic, docks to a cancer cell, it is taken up into the cell by endocytosis, where the drug gets released.

According to the two articles, the particles were able to enter cultured cancer cells and silence genes that prevent apoptosis. In addition, they suppressed the ability of these cancer cells, when injected into mice, to form tumors.

Replacing part of the pRNA with siRNA did not interfere with the folding of either molecule, they found, nor did it impact the formation of the dimers or trimers. Also, the chimeric pRNA complex was processed into functional double-stranded specific siRNA by Dicer inside the cell.

The researchers used siRNA targeting pro- or anti-apoptotic factors and found that both silenced their target genes specifically and efficiently.

According to Guo, his RNA-based nanoparticles have two main advantages: Since they do not contain any protein, the body will not mount an immune response to them, so they could potentially be used in repeated treatment cycles for chronic diseases like cancer or viral infections with HIV or hepatitis B virus. "RNA will not induce [an] antibody, except in a complex with a protein, but this is protein-free," he told RNAi News this week.

Secondly, due to their size, the particles have a longer retention time in the body than molecules smaller than 10 nanometers that are quickly eliminated by the bloodstream and kidney. However, they are small enough — less than 100 nanometers — to be taken up via endocytosis.

The researchers are still working on making the system more stable in the body by chemically modifying the pRNA. "It's quite stable, but the stability in the blood stream still needs to be improved," Guo said. In addition, they have been working on reducing non-specific toxicity of the particles, again by chemically modifying them. "We already have excellent results," which are yet to be published, he added.

Guo has filed four patent applications on the technology but asked Purdue not to offer them for licensing until the two articles were published. The technology is "now ready for licensing," he noted.

At the moment, the application of pRNA for cancer therapy is not the main focus of Guo's lab, he added — most of his research funding is for studying the pRNA that is driving the DNA-packaging motor. He is currently not collaborating with any specific group on developing the technology further for cancer treatment, but has sent his nanoparticles out to approximately 60 labs to test them.

— Julia Karow ([email protected])

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