Switching Off Cancer Using Nanoparticles
Scientists at Cal Tech in Pasadena have used targeted nanoparticles to alter the gene expression of cancer cells in human cancer patients. Their phase 1 clinical trial established the efficacy of their targeting approach and was published in the 21 March advanced online Nature.
Lead author Dr Mark E Davis, the Warren and Katharine Schlinger Professor of Chemical Engineering at Caltech, told the press that in principle:
"Every protein now is druggable because its inhibition is accomplished by destroying the mRNA."
"And we can go after mRNAs in a very designed way, given all the genomic data that are and will become available," he added.
However, as is often the case, what looks straightforward in theory is fraught with obstacles when you try and apply it in practice. One such difficulty, when trying to apply RNAi technology to humans is, how do you deliver such tiny, fragile molecules, the small interfering RNAs (siRNAs), to the tumors?
Senior author Dr Antoni Ribas, an associate professor of medicine and surgery and a researcher at UCLA's Jonsson Comprehensive Cancer Center, said:
"There are many cancer targets that can be efficiently blocked in the laboratory using siRNA, but blocking them in the clinic has been elusive."
Davis and colleagues had a solution: they had already been working on ways to deliver nucleic acids into cells before RNAi was discovered. They eventually came up with a method featuring four components, one of which is a unique polymer that can assemble itself into a targeted nanoparticle that carries siRNA.
Davis explained that their nanoparticles can take the siRNAs into the targeted site within the body, and when they reach their target, the cancer cells inside the tumor, the nanoparticles enter the cells and release the siRNAs.
The researchers used a new method developed at Caltech to find and image the nanoparticles inside cells biopsied from the tumors of several patients taking part in the trial.
They also found that the more nanoparticles a patient was given, the more were present in the tumor cells: thus establishing there was a dose-dependent response.
But what was even better, said Davis, was they found evidence the siRNAs had done their job: in the cells they analyzed, which had been targeted to prevent production of the cell-growth protein ribonucleotide reductase, they found the corresponding mRNA had been degraded. Thus effectively the siRNAs had silenced the gene that was fuelling cancer growth.
Davis explained that this was the first time that anyone has found an RNA fragment from patient cells showing that the RNAi mechanism had severed the mRNA at exactly the correct base:
"It proves that the RNA interference mechanism can happen using siRNA in a human," said Davis.
"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," he added. _MedicalNews
As the authors say, this is just the beginning. Silencing gene expression by targeting the mRNA is only a temporary approach. If such treatment kills all of the cancer cells -- and leaves normal cells alone -- then being only temporary will not be an impediment.
But in many types of cancer -- and other disease -- it will not be enough merely to block the offensive mRNA. You will want to alter the DNA itself to put a permanent stop to the flow of a particular unwanted mRNA. That will require a different approach altogether.
The challenge is vast and seemingly unending. But it is worthwhile.