The Trojan horse is a legend often trotted out to describe new cancer therapies. Natalie Artzi and colleagues at Harvard and the Massachusetts Institute of Technology have developed a Trojan horse with a twist. Their therapeutic agent doesn’t slip inside a cancer cell to throw open the doors to a wave of attacking drug molecules; it slips a lethal dose of anticancer drug into the cell then slams the doors shut, sealing the cancer cell’s fate.
Artzi’s reverse-Trojan horse approach, a newly patented technology that uses gold nanoparticles to ferry the anticancer drug into cancer cells, has been published in Proceedings of the National Academy of Sciences.
“The way they’ve put together existing techniques to create an innovative system is very clever,” says Suzanne Cutts, molecular biologist at the La Trobe Institute for Molecular Science in Melbourne.
Using a nanoscale delivery system to chaperone anticancer drugs into cancer cells potentially overcomes some of the problems associated with cancer therapies. These include their toxic effect on healthy cells and their instability when floating free in the body (which means much of the drug disintegrates before it reaches the cancer). And then, once the drug is inside the cancerous tissue, many cancers fight back, turning on drug resistance genes to make protein machines that push the drug back out of the cell.
Artzi’s gold nanoparticles tackle all three problems at once.
For a cancer cell to produce the proteins needed to pump a drug out of the cell, the relevant stretch of DNA in its nucleus must first be read and copied into strands of “messenger RNA”, which carry the information to the cell’s protein-production machinery.
Researchers in the 1980s found it was possible to disable messenger RNA by introducing matching short strands of DNA or RNA into the cell – they stop the messenger by sticking to it. But naked DNA or RNA strands are unstable and have proved difficult to get into cancer cells; a gold nanoparticle may be the Trojan horse they need.
Gold is stable, can have other molecules attached to it, is easy to handle even at nanometre sizes, is readily pulled into cells, and has been found safe in humans.
So Artzi’s team made small gold nanoparticles around 13 nanometres wide (600 times smaller than the width of a red blood cell) and decorated the outside with short chains of DNA “hairpins” – stretches of DNA that fold back on themselves and knit together like teeth on a zipper. These hairpins only unzip when they encounter a perfectly matched piece of messenger RNA – the messenger RNA responsible for a drug-resistance protein called ABCC1.
And between the teeth of the hairpin zipper nanoparticles, the team nestled an anticancer drug called 5FU, which is known to be a target of ABCC1.
After only two weeks, she found tumours were reduced by more than 90%
The researchers packaged the drug-loaded nanoparticles into a hydrogel glue which slowly released the particles into the cells around it. They hoped the nanoparticles would enter into the cancer cells much like a Trojan horse. Once inside and in contact with the messenger RNA, the hairpin of DNA would flip out of its zipped configuration and latch on to the RNA, blocking its action. At the same time, infantry molecules of 5FU placed in the zipper would be released and free to kill the cell from within.
Artzi implanted the glue next to aggressive drug-resistant tumours in mice. After only two weeks, she found the tumours were reduced by more than 90% – and that 80% of the drug resistance gene was silenced. “We were excited to see this and were encouraged by how well the treatment worked with just one application,” she says.
This is the first particle designed to deliver a drug to a tumour while simultaneously switching off its drug resistance gene. But whereas nanoparticles implanted in a hydrogel glue can fight the tumour sitting next to it, aggressive cancers can spread around the body and finding them can be tricky.
Artzi’s nanoparticles may also one day hold an answer to this problem. Her team has engineered the gold nanoparticles to carry a fluorophore – a molecular flare – inside each DNA hairpin, which is released as soon as the hairpin opens and the drug is released. This could be tracked using techniques such as whole-body fluorescence imaging, pinpointing exactly where tumours are located.
Artzi and her team are looking to test this idea on tumours that have spread to the stomach, by simply injecting the nanoparticles into the bloodstream to see if these nanoparticles will light up the cancer tissue – a possibility Cutts calls “amazing”.
Perhaps most importantly, Artzi says, the Trojan horse nanoparticle is not restricted to targeting just the ABCC1 gene. Alternative DNA strands could be zippered on to the nanoparticle that block different drug resistance genes and carry different drugs. “It’s our hope that this will make it to the clinic,” Artzi says.
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