Controlled drug delivery using engineered nanoparticles offers a potential route for targeted medical treatment. The main challenge is designing and synthesizing particles that deliver the drug at the right time and to the right place.

Frank Caruso and colleagues at the University of Melbourne in Australia1 have now fabricated nanoporous polymer microspheres that can be loaded with drugs to be released only within the simulated environment inside cells. This highly specific approach should mean that the drugs achieve full efficacy within the cells whilst minimizing negative effects on the rest of the body.

Fig. 1: Confocal laser scanning microscopy image of drug-loaded capsules.

The researchers produced microspheres using an approach known as ‘click’ chemistry, which is characterized by efficient and specific reactions under mild conditions. They filled mesoporous silica spheres with a brush poly(ethylene glycol) (PEG) polymer that was prefunctionalized with alkyne groups to allow it to be crosslinked. A drug — in this case the model compound doxorubicin modified with an azide and a cleavable disulfide group — was then linked to the polymer inside the spheres via click chemistry, and the silica template was finally dissolved to leave naked polymer spheres.

The disulfide linkages are key to the delivery of the drug. The conditions inside cells are very different to those in the bloodstream. The researchers showed that the disulfide linkages degrade only under the simulated reducing conditions found within cells. They also showed that the spheres were not toxic to cells.

“Our bio-responsive particles are based on a low-fouling polymer, which is of significance for a range of biomedical applications as it is known that PEG-based coatings aid in increasing the circulation times of particulates and delivery systems in vivo,” says Caruso.

Caruso emphasizes that their drug delivery system potentially allows the negative effects of drugs to be minimized by only delivering drugs once they are inside the cell. “The disulfide cleavage mechanism means the capsules are stable in the oxidizing environment of the blood stream, but are degraded in the reducing conditions of the cellular cytoplasm,” he says.