By Heather Rock Woods

By mixing two common cell ingredients, scientists have assembled tiny hollow tubes whose ends can be open or closed, giving them great potential to serve as drug capsules thousands of times thinner than a human hair, but still 10 times wider than a gene.

With an open-close switch, these ‘lipid-protein nanotubes’ may prove to be an excellent way to encapsulate a therapeutic drug or gene and then release it in the appropriate location.

The research team from UC Santa Barbara (UCSB) investigated the structures of their nanotubes by using a sophisticated analysis of x-ray scattering data gathered at SSRL, combined with high-resolution transmission electron microscopy.

Gene therapy currently relies on incorporating therapeutic genes within engineered viruses, which then ‘infect’ the cells where the genes are needed. Scientists have been seeking a non-viral way to deliver genes and have increasingly turned to positively charged lipids.

The biological tubes are made from lipids and microtubules. Lipid membranes, made of fatty acids, form the protective lining around cells and also make smaller packets containing everything from crucial sustenance to cell garbage. They typically have a negative charge.

This study used a synthetic lipid with a positive charge to coat a negatively charged hollow cylinder made of microtubules. Microtubules are the skeletons and train tracks of cells, and play a key role in cell division. In this case, the microtubules were the scaffolding for the lipid.

“It’s literally like a drug capsule, just tiny,” said Cyrus Safinya, professor of materials and physics at UCSB.

When the charge per unit area of the lipid membrane gets high enough, the lipid coats the microtubules, forming the nanotubes. The coating either seals the ends of the tube or leaves them open, depending mainly on the overall electrical charge of the nanotubes.

“It’s a combination of the actual charge of the complex plus the relative area of the membrane to the microtubule,” said Safinya.

In the lab, researchers can adjust the charge and add either more lipid or more microtubule components to flip the switch between open and closed. But that is difficult in the body, so the team is now studying ways to trigger the tubes to open or close based on pH, which naturally varies in the human body.

“The pH is expected to change the charge of certain lipids. It’s an easier way of tuning the nanotubes to load them up with the molecule you want —a gene silencer, a gene that encodes for a protein, a drug—and then release the molecule where and when you want,” Safinya said.

In making the nanotubes, the researchers varied certain chemical properties, resulting in different nanotube structures. For example, the scattering and microscopy data showed that when the lipid membrane was thick, it beaded up on the surface of the microtubules, like water on a duck’s back, rather than fully coating the tubes.

The research was published in the Proceedings of the National Academy of Sciences in late July. The first author is Uri Raviv, a postdoctoral researcher in Safinya’s lab and a fellow of the International Human Frontier Science Program Organization. Researchers included members of Safinya’s laboratory and members of the laboratory of Leslie Wilson, UCSB professor of biochemistry. The National Science Foundation and the National Institutes of Health supported this research.