Human trials – that’s news. Nanoparticles that target cancer have been in the laboratories (and floating around rodent blood) for many years, but a team of researchers and doctors from the California Institute of Technology (Caltech, USA) has moved the tests (Phase I) to human subjects – into people with cancer. That’s a big step. They now have the first proof that a targeted nanoparticle can find a tumor and deliver an anti-cancer material. Therein is the big news: The anti-cancer material delivered by the nanoparticle is a form of RNA (siRNA) that blocks the cancer cells from producing proteins – thus killing them. This is the first time that this potentially important method of treating cancer has been proven to have an effect in humans.
The approach begins with the work of the 2006 Nobelists in Medicine, Andrew Fire and Craig Mello, demonstrating a new method to prevent a cell from producing a specific protein. They accomplished this by attaching a double stranded small interfering RNA (siRNA) to the RNA of cells. This turned off a specific gene through what they called RNA interference (RNAi).
The importance of this approach for cancer research was that it showed how to attack a cancerous cell not through its (abnormal) proteins, which are difficult to access with a treatment, and instead attack the messenger – the RNA. RNA in several forms has a primary task within cells of transferring the instructions from DNA in the nucleus to the protein manufacturing components outside of the nucleus (the ribosomes). By attaching the right siRNA to the RNA of a cancerous cell, it turns off the production of certain proteins.
This approach, in theory, was very promising, but there were difficulties, the most important being that siRNA didn’t survive delivery into a cell. Here is where nanotechnology provided the solution. Nanoparticles – by nature very small (1/100,000th of the width of a hair) – could easily penetrate the cell wall (membrane). By attaching siRNA molecules to nanoparticles, the molecules survived crossing the cell membrane and then could deliver the siRNA to the targeted mRNA. The composition of the siRNA and its nanoparticle transportation is a proprietary process (now commercially licensed), but involves a self-assembling polymer (jargon for molecular chains that will automatically bond into a predesigned form).
Phase I clinical trials, which in the pharmacological trade means testing for dosage levels in human applications, commenced in 2008 and is now being reported in the journal Nature. The trials demonstrated that the nanoparticles could find the targeted cells (in tumors), penetrate the cell membranes, and release their cargo of siRNA. They were also able to show that higher levels of nanoparticles (higher dosage) resulted in more nanoparticles in tumor cells. More importantly, analysis of the cells indicated that the siRNA had done its job – broken up the cell’s RNA at the targeted location. For the first time in homo vivo it could be shown that production of a specific protein could be blocked by the introduction of a protein specific siRNA. The RNA interference effect worked.
“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. This research provides the first evidence that what works in the lab could help patients in the future by the specific delivery of siRNA using targeted nanoparticles. We can start thinking about targeting the untargetable.”
These were Phase I trials with one target protein. This is a long way from finding a spectrum of protein targets, or passing other phases of clinical trials. It will be years before this anti-cancer approach will be approved for general use – but – this is promising by almost any standard.