NANOREACTION Credit: Nano Lett.

Packaging drugs inside synthetic cells that can sense and respond to their environment, like real biological cells do, could open up new possibilities in targeted drug delivery. Now, for the first time, researchers have engineered a synthetic cell with a protein gate that opens to allow molecules to enter and interact with an enzyme (Nano Lett. 2015, DOI: 10.1021/acs.nanolett.5b03386). The system resembles biological cells, which control traffic using protein receptors and pores on their surfaces.

Many enzymes or other proteins that might be useful as drugs rapidly become inactivated inside the body, either denaturing or breaking down in the stomach or the blood, says Cornelia G. Palivan, a chemist at the University of Basel. Palivan wants to make it possible to use more proteins as drugs and to deliver them in better ways. To that end, she’s developing protective carriers that will allow proteins to react with their target tissues only under the right conditions. Biological cells do this with protein receptors on their membrane surface to receive signals from the environment and with protein pores to let things in and out.

Some groups have made synthetic cells with polymer membranes that break down in response to pH changes, releasing their contents. Palivan wanted to make synthetic cells that remain intact and can continue to carry out reactions. Her team made synthetic membranes out of a three-part block copolymer and combined them with a protein called outer-membrane protein F, which has a pore in the center that allows molecules to pass through. These components self-assemble into spherical membrane vesicles studded with protein pores. Palivan’s group then attached a cap over the pores with a pH-sensitive carbonyl group. When the pH drops to 5.5, the bond breaks, and the cap comes off, allowing molecules to flow in and out.

Palivan calls these 200-nm-diameter spheres nanoreactors because they can trap an enzyme within to carry out a reaction. To show that the gate works, the researchers made nanoreactors filled with horseradish peroxidase enzyme. This protein is too big to escape through the pore, but the molecule it interacts with can go in and out. In this case, the enzyme oxidizes a dye complex, and the enzyme’s activity can be monitored by measuring the intensity of light emitted. At pH 5.5, the enzyme’s activity increased by 23% compared with when the pH was 7.4, indicating that the gate opened at the lower pH, allowing reactants to enter.

Because tumors are commonly acidic, this kind of nanoreactor might be useful in treating cancer. It could protect a protein drug until it reaches a tumor site where the lower pH would open the pore channel. Palivan says next they need to figure out how to make a gate that not only will open but also will close in response to the environment, so that the drug’s activity can be stopped on demand.