Friday, May 06, 2005

Nano-news

Drug molecules not only have to be effective at treating disease, they also have to be robust enough to get from the place where they enter the body to the place where they are designed to act. Given that bodies devote a lot of effort to hunting down and destroying things that are in the wrong place—whether those things be molecules, viruses, bacteria or even errant body cells—designing drugs that can do this is no mean feat.

That is doubly true when the drug in question actually acts by stimulating one of these “thing-in-the-wrong-place” mechanisms—which is precisely how drugs that provoke a phenomenon called RNA interference work. RNAi, as it is known for short, is an approach to pharmacology that might revolutionize the field if it could be made to work routinely. It uses a natural anti-virus mechanism to block the activity of disease-causing genes, so any illness caused by the activity (as opposed to the inactivity) of a particular gene might, in principle, be treated by it.

Getting RNAi drugs into the cells that need them is, though, proving harder than people expected. So news that Siwen Hu and Timothy Triche, of the Children's Hospital in Los Angeles, and Mark Davis, of the California Institute of Technology, think they have worked out how to do so in the case of one form of cancer could prove to be an important advance.

RNAi works by mugging one of the cell's molecular messengers. The information needed to make proteins—the molecules that do most of the work in a cell—is stored as genes in the double-stranded DNA of a cell's nucleus. When a particular protein is needed, this information is copied into a single-stranded molecule called RNA. The RNA then carries the message to the places where proteins are made, and the message is translated into protein.

Many viruses work by subverting this mechanism—injecting their own RNA into a cell in order to make that cell produce viral proteins instead. But viral RNA is often double-stranded when it enters a cell, so a nifty way for a cell to deal with viral invasions is to recognize and destroy double-stranded RNA. Which is exactly what happens. Double-stranded RNA of any variety is rapidly chopped up by most cells.

RNAi hijacks this process to stop the production of disease-causing proteins. Its drug molecules are also strands of RNA, but they are the chemical complements of the disease-causing messenger strands. That means they pair up with their targets to form double-stranded molecules, and those molecules then get chomped by the anti-virus mechanism. What has defeated researchers is getting the complement strands into diseased cells in large enough numbers. This is where Dr. Hu, Dr. Triche and Dr. Davis come in.

Their solution is to wrap the therapeutic RNA inside a “nanoparticle” made of two polymers called cyclodextrin and polyethylene glycol, and coated with a protein called transferrin. It is the transferrin that provides the magic. Its usual job is to carry iron atoms, which cannot penetrate cell membranes by themselves, into cells. It does this by grabbing hold of those atoms and then latching on to a cell-membrane protein called a transferrin receptor, which escorts it into the cell. The researchers reasoned that transferrin and its receptor might perform the same trick for their nanoparticles, and they knew that tumour cells have more transferrin receptors than healthy ones. So they reckoned this might be a way to get the nanoparticles to concentrate in tumours. Once inside, the acidic environment of the cell would dissolve the particle, releasing the RNA.

To test this idea out, they injected their nanoparticles into mice that had been engineered to suffer from Ewing's sarcoma, a rare childhood cancer. They chose this disease because it is caused by a novel gene not found in healthy individuals, and thus provides a clear and unambiguous target for the therapeutic RNA. The novel gene is created when two chromosomes, numbers 11 and 22, each break in two at particular weak spots, and part of chromosome 11 joins with part of chromosome 22. As bad luck would have it, the DNA at the junction forms a sequence that the cell's gene-reading machinery recognizes as a gene, and this gene spurs uncontrolled cell growth (in other words, cancer) in certain bone and muscle cells.

Mice injected with human Ewing's sarcoma cells develop secondary cancers similar to those seen in human patients. However, when the researchers injected their nanoparticles into the bloodstreams of animals with Ewing's tumours, the growth of those tumours slowed. Even better, if they injected the animals with nanoparticles shortly after injecting the cancer cells, they stopped the formation of secondary cancers in the first place.

Other scientists have shown that they can use RNAi to slow tumour growth in mice, but they have had to inject their RNA directly into the tumour, which is tricky. Dr. Hu, Dr. Triche and Dr. Davis are the first to demonstrate that they can inject it into an animal's bloodstream and then let it find its own way to the target. The three researchers are now working to perfect the system, so that it can be tested in people, and they are also making sure that it works in cancers other than Ewing's sarcoma. If they can do both of these things, they may have come up with the much-sought mechanism for propelling RNAi into the big time.

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