Minicells, the spiky gold balls, emerge from the leaky blood vessel within the tumour mass. They proceed to disable the tumour cells with a one-two punch as shown in the enlarged tumour cell below. Following the arrows clockwise, the minicells first deliver siRNA to disable the MDR pump (small purple dumbbells). Then they deliver the cancer drugs (small red spheres).
Credit: Russell Kightley
MELBOURNE: Specially designed 'minicells' successfully target and kill cancer cells – the new technology has the "potential to deliver drugs that were considered undeliverable," scientists say.
In mice seeded with human tumours, then treated with this new technique, the recovery rate was 100%. In the next few months, EnGeneIc will recruit 20 long-term cancer patients for a phase one safety trial at three Melbourne hospitals.
The study, by Jennifer MacDiarmid and Himanshu Brahmbhatt of EnGeneIC, a privately held Australian bioscience company founded in 2001, is the cover story of the July issue of Nature Biotechnology.
Fighting drug-resistant cancer
One of the major problems in cancer treatment today is that the cancer often returns in a form that is resistant to treatment. But many drugs that are developed to fight cancer can not be used because they are too toxic or they are unstable in the blood stream.
Cancers evolve, just like organisms, and develop new genetic mutations that fight off the drugs used against them. In recent years the discovery of small interfering RNA (siRNA) has provided the means to beat cancer at its own game.
Small interfering RNA can neutralise whatever new genetic mutations the cancer develops. "The beauty of siRNA is that we can tailor the therapy to the tumour", says MacDiarmid.
The problem is that siRNA is unstable – it normally works within cells, and doesn't travel well via the bloodstream. Until now, doctors and scientists had no way of using siRNA to fight cancer in patients.
'Trojan horse' enters cancer cells
"Delivery, delivery, delivery has been the major problem", says MacDiarmid. EnGeneIC's solution was to develop a 'Trojan horse' that would seek and enter cancer cells and then disarm them using siRNA.
Their Trojan horse is made from the bacterium Salmonella typhimurium. MacDiarmid and Brahmbhatt genetically engineered bacteria so that they not only split in two they also budded off fragments at their ends.
These fragments, dubbed 'minicells', are ideally equipped to act as Trojan horses. For one thing their robust bacterial cell wall makes them capable of surviving the rough and tumble of a trip through the bloodstream.
They can also be fitted with a guidance system: molecules called lipopolysaccharides form part of their cell membranes, and these serve as attachment points for antibodies that target receptors on tumour cells.
Other carrier systems for siRNA have been proposed and tested, such as fat bubbles known as liposomes, but these are more flimsy and difficult to fit with an antibody-based guidance system.
Opens door for new drugs
Another plus is that the targeted minicell does not trigger much of an immune response so the minicells can be injected over and over again, the scientists say. Their size makes the minicells more lethal to tumours than to healthy tissue. At 400nm in diameter, they tend to fall out of the slipshod new blood vessels that supply tumours. Blood vessels that supply healthy tissue are leak-proof.
The ability of minicells to deliver their cargo directly to tumours has Bruce Stillman, the President of the Cold Spring Harbour Laboratory in Long Island, New York excited, "This has the potential to deliver drugs that were [previously] considered undeliverable", he says.
Drug companies have developed innumerate cancer-targeting drugs that never made it into the market place because of toxicity or, in the case of siRNA, because they were too unstable in the bloodstream. "Most of the expense of drug development lies in the process of making things bio-available or low toxicity. This technique bypasses all of that."
In every case the tumours shrank
So far, pet dogs with terminal cancer have been the first patients to benefit from the power of minicells. In a study reported in Cancer Cell in 2007, the dogs were injected with minicells that delivered cancer drugs, such as doxorubicin.
Because very little of the drug was released into the bloodstream, the dogs suffered few side effects yet whopping doses were delivered to the tumours. In every case the dog's tumours shrank. "Many dogs are in remission; the owners are delighted", says MacDiarmid.
In the study released today, the minicells were used against drug-resistant tumours in a one, two punch strategy. This time the patients were mice that had been seeded with human tumours.
The tumours were drug-resistant because they ramped up their output of a gene called MDR1, which codes for a protein that pumps drugs out of the tumour cells.
In the first punch, minicells delivered siRNA to disable the MDR1 pump. Five days later, minicells delivered the coup de grace – drugs that the tumours could no longer resist. 100% of the mice recovered. MacDiarmid says they have seen similar as yet unpublished results in pet dogs with drug-resistant tumours.
In the next few months, the company will recruit 20 long-term cancer patients for a phase one safety trial at three Melbourne hospitals. Stillmann, though cautious about the road ahead, says the dog studies augur well: "Dogs are as close as you can get to human cancer." Adds Bryan Williams, the Director of the Monash Institute of Medical Research in Melbourne: "It's an exciting new technology but the big issue is safety."
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