Providing Proof of RNA Interference in Humans

Photo: Schemantic of a targeted nanoparticle

Moreover, the team provided the first demonstration that this new type of therapy, infused into the bloodstream, can make its way to human tumors in a dose-dependent fashion – i.e., a higher number of nanoparticles sent into the body leads to a higher number of nanoparticles in the tumor cells.

These results demonstrate the feasibility of using both nanoparticles and RNAi-based therapeutics in patients, and open the door for future "game-changing" therapeutics that attack cancer and other diseases at the genetic level, says Mark Davis, the Warren and Katharine Schlinger Professor of Chemical Engineering at Caltech, and the research team's leader.

Still, there have been numerous potential roadblocks to the application of RNAi technology as therapy in humans. One of the most problematic has been finding a way to ferry the therapeutics, which are made up of fragile siRNAs, into tumor cells after direct injection into the bloodstream. Davis, however, had a solution. He and his team eventually created a four-component system that can self-assemble into a targeted, siRNA-containing nanoparticle.

"These nanoparticles are able to take the siRNAs to the targeted site within the body," says Davis. Once they reach their target – in this case, the cancer cells within tumors – the nanoparticles enter the cells and release the siRNAs.

Davis and his colleagues were able to show that the higher the nanoparticle dose administered to the patient, the higher the number of particles found inside the tumor cells—the first example of this kind of dose-dependent response using targeted nanoparticles.

Davis says, the evidence showed the siRNAs had done their job. In the tumor cells analyzed by the researchers, the mRNA encoding the cell-growth protein ribonucleotide reductase had been degraded. This degradation, in turn, led to a loss of the protein.

"There are many cancer targets that can be efficiently blocked in the laboratory using siRNA, but blocking them in the clinic has been elusive," says Antoni Ribas, associate professor of medicine and surgery at UCLA's Jonsson Comprehensive Cancer Center. "This is because many of these targets are not amenable to be blocked by traditionally designed anti-cancer drugs."; Source: California Institute of Technology