BioEd Online

Small man-made peptides help sneak drug-bearing nanobeads past the body’s ever-vigilant immune system.

To work effectively drugs and imaging agents need to get to the place they’re needed most, diseased cells or tumours, and nanoparticles are being developed to help carry them there. But all therapeutic molecules face a deadly foe – the immune system with its macrophages designed to spot any intruding molecules in the blood and destroy them in a process called phagocytosis.

Researchers at the University of Pennsylvania, Philadelphia, US, have found a way to stop macrophages eating approaching drug-bearing nanoparticles. They have designed and made a small segment of a crucial membrane protein – CD47, which is recognised as safe by macrophages. Molecules that contain CD47 can get past macrophages and into blood cells.

Dennis Discher, who led the work, says he was inspired when he saw another groups’ work describing the structure of CD47. “I saw a minimal part of CD47 we could take out and make,” he says. This was the part of CD47 that attaches to a macrophage receptor protein, allowing the macrophage to let the protein, and its cargo, into the cell the macrophage is guarding. The work is published today in Science [1].

With the help of computer simulations, to make sure it was folded correctly and was stable, the group designed and made a 20 amino-acid peptide based on that CD47 fragment. They then stuck the peptide to commercially-available polystyrene nanobeads. The beads also carried a dye which showed up with fluorescence spectroscopy.

Those beads were injected into mice along with the same amount of other beads tagged with a different colour fluorophore but not the peptide. After half an hour, the mouse blood had four times as many beads with the peptide fragment than the other bead, showing that many more of these beads had got past the macrophage defence.

The team then looked at mice with tumours and saw that the peptide-tagged nanobeads accumulated in the tumours, making them show up clearly thanks to their fluorescent markers. Nanoparticles tend to accumulate in tumours because of the tumour’s haphazard structure and leaky blood vessels. The nanoparticles spill through these blood vessels and get stuck in the tumour.

Buoyed by their evidence that the peptide-carrying nanobeads were circulating happily in the blood, Discher’s team also tagged the peptide-carrying nanobeads with anticancer drug paclitaxel. They saw that their system shrank tumours as well as the current drug carrier, cremophore, which has toxic side effects.

Neil Barclay, from the University of Oxford was part of the team that worked out the structure of CD47, that inspired Disher’s work. “It’s neat,” he says of Discher’s work. “It’s a new way of trying to get the immune system to prevent phagocytosis of drugs or particles.”

Discher hopes that with custom-made nanobeads, rather than the off-the-shelf ones he used here, the system can be improved. “We want to make this accessible and reproducible,” he says.