Chemotherapy timing is key to success

Nanoparticles that stagger delivery of two drugs knock out aggressive tumours in mice

Researchers at Massachusetts Institute of Technology (MIT) in the US have devised a novel cancer treatment that destroys tumour cells by first disarming their defences, then hitting them with a lethal dose of DNA damage

In studies with mice, the team showed that this one-two punch, which relies on a nanoparticle that carries two drugs and releases them at different times, dramatically shrinks lung and breast tumours.

The MIT team, led by Michael Yaffe, the David H. Koch Professor in Science, and Paula Hammond, the David H. Koch Professor in Engineering, described their findings in the 8 May online edition of Science Signaling.

'I think it’s a harbinger of what nanomedicine can do for us in the future,' says Hammond, who is a member of MIT’s Koch Institute for Integrative Cancer Research. 'We’re moving from the simplest model of the nanoparticle – just getting the drug in there and targeting it – to having smart nanoparticles that deliver drug combinations in the way that you need to really attack the tumour.'

Doctors routinely give cancer patients two or more different chemotherapy drugs in the hope that a multi-pronged attack will be more successful than a single drug. While many studies have identified drugs that work well together, a 2012 paper from Yaffe’s lab was the first to show that the timing of drug administration can dramatically influence the outcome.

It’s a harbinger of what nanomedicine can do for us in the future

In that study, Yaffe and former MIT postdoc Michael Lee found they could weaken cancer cells by administering the drug erlotinib, which shuts down one of the pathways that promote uncontrolled tumour growth. These pretreated tumour cells were much more susceptible to treatment with a DNA-damaging drug called doxorubicin than cells given the two drugs simultaneously.

Erlotinib, which targets a protein called the epidermal growth factor (EGF) receptor, found on tumour cell surfaces, has been approved by the US FDA to treat pancreatic cancer and some types of lung cancer. Doxorubicin is used to treat many cancers, including leukaemia, lymphoma, and bladder, breast, lung, and ovarian tumours.

Staggering these drugs proved particularly powerful against a 'triple-negative' breast cancer cell, which does not have overactive oestrogen, progesterone, or HER2 receptors. Triple-negative tumours, which account for about 16% of breast cancer cases, are much more aggressive than other types and tend to strike younger women.

To approach this problem, Yaffe teamed up with Hammond, who with her graduate student, Stephen Morton, devised dozens of candidate particles. The most effective were liposomes, which are spherical droplets surrounded by a fatty outer shell.

Once the particles reach a tumour and are taken up by cells, the particles start to break down

The MIT team designed their liposomes to carry doxorubicin inside the particle’s core, with erlotinib embedded in the outer layer. The particles are coated with a polymer called PEG, which protects them from being broken down in the body or filtered out by the liver and kidneys. Another tag, folate, helps direct the particles to tumour cells, which express high quantities of folate receptors.

Once the particles reach a tumour and are taken up by cells, the particles start to break down. Erlotinib, carried in the outer shell, is released first, but doxorubicin release is delayed and takes more time to seep into cells, giving erlotinib time to weaken the cells’ defences. Yaffe says there is a lag of between four and 24 hours between when erlotinib peaks in its effectiveness and the doxorubicin is at its most effective.

The researchers tested the particles in mice implanted with two types of human tumours: triple-negative breast tumours and non-small-cell lung tumours. Both types shrank significantly. Furthermore, packaging the two drugs in liposome nanoparticles made them much more effective than the traditional forms of the drugs.

The team is now testing the particles in mice that are genetically programmed to develop tumours on their own, instead of having human tumour cells implanted in them.

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