With delivery remaining a key hurdle facing the development of RNAi drugs, last week two groups — one from academia and one from industry — were awarded government-sponsored grants to support their efforts to address the delivery challenge for siRNA-based treatments for cancer.
The first award, a two-year grant worth roughly $178,000 in its first year, was made by the National Cancer Institute to Konstantin Sokolov, an adjunct associate professor of biomedical engineering at the University of Texas MD Anderson Cancer Center, for his lab’s efforts to develop nanomaterial that has both therapeutic and imaging properties.
“One of the major challenges of modern medicine is the development of novel approaches for the efficient delivery of therapeutics and molecular-specific treatment of pathology that can be carried out under imaging guidance and monitoring,” Sokolov said in his grant’s abstract. “Recent advances in nanotechnology, biochemistry, and molecular biology give an opportunity to combine all these capabilities in a single entity … [and] we will use [these] achievements … to engineer a nanomaterial with both therapeutic and MRI contrast-enhancing capabilities.”
Specifically, Sokolov and his colleagues aim to create a material that consists of a gold-coated iron oxide nanoparticle carrier with “attached oligonucleotide handles that interact with fluorinated aptamer-siRNA chimera molecules through complementary nucleotides,” the abstract states.
The aptamer portion of the molecule will be specific for a cancer biomarker, while the siRNA will be designed to inhibit the expression of genes determined to be essential for cancer cell survival. The oligo handles, meanwhile, will “interact with and reversibly de-activate the aptamer portion of the chimera … [to] ensure that the particles do not spontaneously bind to their target, especially in normal tissue.”
“Successful completion of this project will make an important advance toward realization of one of the ultimate goals of cancer medicine: a material that can be used to simultaneously detect and treat cancer.”
Sokolov plans to deliver the nanomaterial into cancer tissue and evaluate their accumulation and biodistribution through magnetic resonance imaging, according to the grant’s abstract. Near-infrared radiation will then be delivered to the treatment site, heating the gold layer of the molecule and melting the double-stranded helix binding the oligo handles to the aptamers. Such a reaction is expected to result in the release of the chimeras into the cancerous tissue.
“We hypothesize that release and diffusion of chimera molecules can be imaged by … MRI,” Sokolov noted in the abstract. “The aptamer portion will refold and regain molecular specificity, delivering the therapeutic siRNA inside cancer cells, thereby inducing cell death.”
Initial testing will be done in cell culture and mouse xenograft models.
“Successful completion of this project will make an important advance toward realization of one of the ultimate goals of cancer medicine: a material that can be used to simultaneously detect and treat cancer,” Sokolov added.
The second grant, which runs for six months and is worth about $100,000, was awarded by the National Science Foundation to Lisa Kemp, the CSO of private biomaterials firm Ablitech, to develop siRNAs with reversible modifications for the treatment of pancreatic cancer.
“The difficulty with current siRNA delivery is that the enzymes in the body degrade the siRNA before it can reach its target,” Kemp wrote in the NSF grant’s abstract. “Most current siRNA technologies on the market are based on permanent modifications to the RNA itself to enable delivery … [but] these modifications typically involve changes to the internal linkages of the siRNA, which often decreases the [agent’s] gene-silencing ability.”
According to the grant’s abstract, Ablitech is developing siRNAs with reversible modifications that are designed only to attach the RNAi molecule to a polymer network; the backbone of the oligo is left unchanged.
“This will allow for the delivery of the most effective siRNA units rather than sacrificing efficacy for enzymatic stability,” the abstract states.
Although Ablitech expects this so-called Poly-RNA technology to be applicable to a variety of indications, the company is aiming at cancer, with an initial focus on pancreatic cancer.
“Large pharmaceutical companies such as Merck, Bristol-Myers Squibb, Pfizer, and others that possess large marketing and distribution channels dominate this market and in recent years have commercialized technologies licensed from small, innovative companies,” the NSF grant’s abstract notes. “Ablitech seeks to follow this model for the commercialization of Poly-RNA.”