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Biological Chemistry

Nanofibers Help Peptide Drugs Burst Through Blood-Brain Barrier

Drug Delivery: Peptides modified with a lipid group form tightly wrapped nanofibers that can slip into the brains of mice

by Katharine Sanderson
January 15, 2013

Crossing Over
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Credit: ACS Nano
Self-assembled peptide nanofibers can cross the blood-brain barrier in mice. This computer simulation of the fiber structure shows the fiber’s lipid core (cyan) and the backbones of the peptides that tightly wrap around the core (colored by amino acid in the peptide with D-alanine in blue, glycine in red, phenylalanine in purple, leucine in green, and arginine in orange).
Computer simulation of peptide nanofiber structure.
Credit: ACS Nano
Self-assembled peptide nanofibers can cross the blood-brain barrier in mice. This computer simulation of the fiber structure shows the fiber’s lipid core (cyan) and the backbones of the peptides that tightly wrap around the core (colored by amino acid in the peptide with D-alanine in blue, glycine in red, phenylalanine in purple, leucine in green, and arginine in orange).

With the addition of a greasy tail, a peptide drug wraps up into a nanofiber that can sneak through the blood-brain barrier in mice (ACS Nano, DOI: 10.1021/nn305193d). The scientists who developed the nanofibers think these structures could be an effective way to deliver peptide drugs to the brain.

Chemists have designed peptide drugs that hit targets in the brain in hopes of treating neuropathic pain or diseases such as Alzheimer’s and Parkinson’s diseases. But these peptides face a couple of hurdles: They are easily broken down by enzymes in the body, and they can’t cross the fiendishly hard-to-penetrate blood-brain barrier.

Ijeoma F. Uchegbu and Andreas G. Schätzlein at University College London and their colleagues tackled these problems by attaching a lipid group to a possible pain drug called dalargin. The blood-brain barrier tends to accept greasy molecules for passage, so the team thought the lipid tails would help the peptides slip into the brain. Other researchers have found that nanoparticles coated with surfactants can deliver peptide drugs to the brain (Pharm. Res., DOI: 10.1023/A:1022604120952).

The team discovered that their lipid-modified peptides assembled into nanofibers that are 20 nm in diameter and between 100 and 500 nm in length. The fibers have a greasy central shaft made from the lipid groups. The peptides fold tightly around the shaft. This arrangement is unlike other peptide nanosuctures, which look more like brushes, with peptides sticking out from the structure’s core, Uchegbu says.

To see if the nanofibers helped the drug reach the brain, the researchers injected one group of mice with the fibers and another with unmodified dalargin. After 30 minutes, they then used Raman scattering microscopy to look for the drug in tissues slices from the animals.

The scientists couldn’t find dalargin in the brain, liver, or blood of mice receiving the unmodified version. But they did detect their modified version of the drug in the livers and brains of mice injected with the nanofibers, and they saw a metabolite of dalargin in the animals’ blood.

To test whether the nanofibers blocked pain signals in the brain, Uchegbu’s team subjected both groups of mice to slight pain by placing their tails in hot water. The researchers then watched the animals’ reactions. The mice who received the unmodified drug flicked their tails away immediately, while the animals receiving the nanofibers held their tails in the water for eight seconds on average, suggesting the nanofiber mice experienced less pain.

Jörg Kreuter at Goethe University Frankfurt, in Germany, says the nanofiber delivery strategy is novel for peptide drugs. But he thinks the researchers should test it on other types of peptide drugs to ensure the method is generalizable. “Maybe these nanofibers are unique to dalargin,” he says.

Uchegbu believes the process can be made general and is now trying it on a class of drugs called enkephalins.

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