RNAi Nanoparticles Show Promise in Brain Cancer
By Anette Breindl
Researchers have developed a nanoparticle, made up of siRNAs around a gold core, that could cross the blood-brain barrier and, in animals, silence a gene that is overexpressed most cases of glioblastoma multiforme.
“We report for the first time, to our knowledge, that we can systemically deliver RNAi for delivery to the brain,” co-corresponding author Alexander Stegh told BioWorld Today.
That ability represents an advance in delivering drugs to the brain – and in delivering RNAi anywhere.
“With RNAi, the biggest issue is finding ways to deliver them,” Stegh said.
Stegh and his colleagues called the nanoparticles they have developed spherical nucleic acids or SNAs. As the name might suggest, they consist of siRNAs forming a sphere around a gold core. And in that sphere, co-corresponding author Chad Mirkin said, “they exhibit dramatically different properties than their linear cousins.”
Specifically, such SNAs enter cells easily, do not cause an immune response, and have a longer half-life than regular siRNAs. The reasons are not entirely clear, but the team contended that it lies in the nanoparticles’ 3D architecture. The way the RNA is configured on the gold core leads to a negative charge, and extremely high salt concentration on the surface. That, in turn, fends off the enzymes that normally rapidly degrade siRNAs.
Those more stable nanoparticles get into cells because they are taken up by so-called scavenger receptors.
Getting siRNAs into cells has been one of the problems in harnessing RNAi’s potential. But the SNAs, Mirkin said, “go into almost any cell line we’ve studied to date, with the exception of mature red blood cells.”
SNAs cannot be targeted to specific cell types – the targeting is purely at the levels of the gene that is silenced. In fact, SNAs are so good at getting into cells that the team originally thought local delivery would be critical, and focused their initial experiments on melanoma.
But at some point, Mirkin said, it occurred to the scientists that “if these things go to cells so well, maybe they’ll cross the blood-brain barrier . . . and lo and behold, they do.”
In their new studies, which appeared in the Oct. 31 , 2013, issue of Science Translational Medicine, Stegh and Mirkin, who are both at Northwestern University, and their colleagues showed that SNA constructs crossed the blood-brain barrier and accumulated in tumors.
Because SNAs cannot be targeted to specific cells, the targeting needs to occur at the genetic level, with target genes being highly overexpressed in diseases cells. For their glioblastoma work, they targeted the gene Bcl2like12, which is overexpressed in more than 90 percent of glioblastomas, and higher levels correlate with worse survival.
In mouse studies, the drug crossed the blood-brain barrier and accumulated specifically in tumor cells – a phenomenon that was most likely due to the leakiness of the blood-brain barrier in the vicinity of tumors, given that the SNAs are not specifically targeted to tumor cells.
Bcl2Like12 knockdown increased tumor cell apoptosis, and treatment lowered tumor weights and increased the survival time.
Glioblastoma is genetically an extremely complex cancer, and so despite the encouraging data, Stegh was unequivocal about the Bcl2like12-targeting SNA’s ability to succeed as a monotherapy: “A clear no,” he said. “A combination therapeutic is the only way to go.”
The team is working to identify genes that could be targeted synergistically with Bcl2like12. Initial clinical trials will likely add the SNA to radiation and Temodar (temozolomide, Merck & Co. Inc.), which are the current standard of care.
The drug, if it crosses the human blood-brain barrier as well as the mouse one, could find applications not just in tumors – although glioblastoma patients, with its average survival from diagnosis of just over 14 months, could certainly use more weapons in their arsenal.
But they are not the only ones. Mirkin said that “this is one of the few, in fact maybe the only construct known involving gene regulation types approaches . . . where you can get significant accumulation in the sites that matter. . . . It could be equally important or even more important in the area of neurodegenerative diseases.”
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