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New Scientist Magazine, May 9, 2007

A delivery system that directs cancer drugs to tumours virtually anywhere in the body could dramatically reduce the side effects of chemotherapy. The technique, which uses fragments of bacteria to target a tumour, avoids the need to flood the patient’s system with toxic drugs.

Himanshu Brahmbhatt and Jennifer MacDiarmid of the company Engeneic in Sydney, Australia, have found that they can make bacteria such as Salmonella enterica and E. coli divide at their ends, instead of at their centres, to produce small buds of cytoplasm which they call “Engeneic delivery vehicles” (EDVs). The EDVs are washed repeatedly to remove any toxins. “They look like bacteria but have no chromosomes and are non-living,” MacDiarmid says.

These mini-bacteria are easy to make and can be loaded with chemicals. “We haven’t yet found a drug that you couldn’t load,” MacDiarmid says. “Because they have a rigid membrane they won’t break down when injected, so they carry their payload happily to the target site,” she adds.

The next step was to make the EDVs target specific tissues. They did this using two monoclonal antibodies connected via a linker molecule. One of the antibodies attaches to the EDV’s surface, while its partner is specific to a protein on the target tumour. The Her2 receptor on breast cancer cells, which is targeted by the drug Herceptin, is such a target.

Targeting is also aided by the fact that blood vessels supplying cancer cells are often slightly porous, and the 400-nanometre-wide EDVs are the perfect size to fall through these holes into the tumour tissue. After binding to the receptor, ERVs enter the cell, where they are broken down and release their payload. “Within 2 hours of intravenous administration more than 30 per cent of the dose ends up in the tumour micro-environment,” says Brahmbhatt, who presented the findings at the RNAi 2007 conference in Boston last week.

To test the technique, MacDiarmid and Brahmbhatt packaged the cancer drug doxorubicin into EDVs targeted at human breast cancer tissue, leukaemia and ovarian tumours, and injected them into mice with these types of tumours ( Cancer Cell, vol 11, p 431). The treatment significantly slowed the growth of tumours compared with those in untreated mice. What’s more, far less of the drug was needed when delivered by EDVs compared with when it was injected directly.

Also, dogs with advanced non-Hodgkin’s lymphoma showed a significant reduction in tumour size when treated with EDVs carrying doxorubicin.

Safety tests in pigs and monkeys have so far shown no sign of toxicity or significant immune reaction against the EDVs, Engeneic says. The company hopes to begin human trials this year.

Engeneic says that EDVs may allow tumours to be zapped by more drugs than is normally possible, thus increasing the odds that the therapy will work. Oncologists tend to be reluctant to prescribe multiple drugs because of the risk of side effects – and when they do, they usually reduce the dosage to limit toxicity.

Preliminary tests in mice suggest that EDVs could also be used to deliver therapies such as RNA interference (RNAi), in which one of the major hurdles has been getting the active strands of RNA to the target. The team tested this using a form of RNAi designed to prevent the production of a protein that causes multi-drug resistance in cancer cells. Sure enough, the treatment reversed resistance to doxorubicin in mice with human uterine cancer tumours.

Johannes Fruehauf, who studies cancer and RNAi at Beth Israel Deaconess Medical Centre in Boston, is impressed by Engeneic’s approach. “Previous efforts to develop targeted nanoparticles have focused on synthetic methods, which are very expensive,” he says. “Here they are using bacteria like little biorobots.”

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