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DNA to direct and switch off chemo

28 July 2009

Researchers in the US have developed a new approach to cancer chemotherapy using short DNA strands to help target delivery of the drug directly to cancer cells, and 'call it off' should problems arise.

Chemotherapy has notoriously unpleasant side effects as it hits healthy cells as well as cancerous tumour cells. A key challenge has been to find ways of delivering the toxic drugs exclusively to the target cells without affecting the healthy cells around them. Yi Lu and co-workers at the University of Illinois at Urbana-Champaign, US, combined an established way of packaging drugs with a way of recognising cancer cells to create a novel, highly targeted drug delivery system, and for the first time demonstrated a way to 'turn off' drug delivery by disrupting the targeting ability of the molecules.

The researchers used cisplatin, a widely used, highly potent anti-cancer drug that has substantial side effects. They packaged the drug in liposomes, small pockets (around 200 nm diameter) made of lipids similar to those found in cell membranes. 

In order to help the liposomes find the cancer cells, the researchers equipped them with short DNA strands (known as aptamers) known to bind to nucleolin, a cell surface protein that is present in high numbers on the outside of fast proliferating cells such as cancer cells. 

Using a fluorescent dye to track the molecules, the researchers used cultivated breast cancer cells as a target and demonstrated that the aptamer-liposome conjugate could deliver the drug into the cancer cells with high efficiency. As first author Zehui Cao explains: 'Only when the aptamer's target, nucleolin, is present on the cell surface, [would] the aptamer-functionalised liposomes be captured on the cell membrane,' at which point the liposome's cargo is swallowed up by the cell and the drug delivered directly to the target site. 

Using a DNA-based aptamer as part of the drug delivery mechanism has the additional advantage that it can be 'switched off' by injection of a complementary strand of DNA. The complementary DNA (cDNA) acts as an antidote to the drug delivery system as the complementary base pairing between the aptamer and the cDNA disrupts the aptamer's target-binding structure, meaning it can no longer find and bind to the cancer cells and deliver the drug. In theory, this could enable doctors to turn off a chemotherapy drug after injection if they observe unexpected side effects.  

'Targeting chemotherapy drugs directly at cancer cells is an important research area as it could reduce the unpleasant side-effects of cancer treatment,' says Jessica Harris, information officer at Cancer Research UK. 'Although this research presents an exciting way to deliver chemotherapy drugs, it's at an early stage, so whether it will translate into improved treatments for cancer patients remains to be seen.'

Michael Gross


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Z Cao et al, Angew. Chem. Int. Ed., 2009, DOI 10.1002/anie.200901452

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