New slow-release drug delivery system provides weeks of pain-numbing anesthetic effects

Most local anesthetics used in medicine only last eight to 12 hours or a day tops. Now Boston Children's Hospital researchers have formulated a more effective slow-release injectable drug delivery system that achieved pain-numbing anesthetic effects lasting two to three weeks in rats compared to a commercial formulation lasting about four to eight hours. Given that nerve blocks in humans tend to work longer than in rats, this advancement, published today in Nature Biomedical Engineering, could blow the effective time of currently used anesthetics out of the water and have implications for other types of pain.

For decades physicians have used liposomes, which are tiny balls of fatty compounds known as lipids, as gradual drug delivery systems in the body. Liposome composition determines how fast drugs leak out, with faster leaking leading to a more potent drug effect over a shorter time period with potentially more toxicity. Up until now, researchers believed that molecules leaked fastest from liposomes made of more "fluid" lipids. However, Yuan Wang, PhD, a research engineer in the laboratory of Daniel Kohane, MD, PhD, overturned this theory by showing that liposomes made of more fluid lipids release drugs that mix well with or dissolve in water, known as "hydrophilic" drugs, extremely slowly. One way to make lipids more fluid is by adding many double chemical bonds to their tails. The double bonds mean that the lipids can't pack together as tightly.

With a series of complex experiments, the team demonstrated that the liposomes with many double bonds had a structure with multiple compartments, while those without had a simple spherical structure. As a result, in liposomes with many double bonds, hydrophilic drugs had more lipid barriers to cross leading to slower drug release.

The more fluid membranes in liposomes with many double bonds may be easier to cross, but the greater number of barriers slow down the drug's release. The more fluid liposomes with more double bonds may form concentric spheres that are like onions with many layers or could even potentially be even spheres within spheres."

Yuan Wang, PhD, research engineer, Boston Children’s Hospital

Knowing a hydrophilic drug will leak slower from a more fluid liposome, the researchers tested out a proof-of-principle experiment. The team filled their more fluid liposomes with potent tetrodotoxin - a powerful neurotoxin found in pufferfish and blue-ringed octopuses that serves as a powerful numbing agent. When injected near a nerve in the leg of rats, they showed very prolonged local anesthesia, but no toxicity at the injection site or throughout the body. This means the drug released slowly enough to be cleared by the body, but still at high enough levels to be an effective anesthetic. Tetrodotoxin isn't commercially used in patients yet but could one day be developed as a therapeutic.

"This extended-release combination could be used for longer term perioperative pain instead of opioids and we are starting to consider using these potentially for chronic pain, as well," says Kohane, senior associate in pediatric critical care at Boston Children's and director of Laboratory for Biomaterials and Drug Delivery. "These liposomes can also provide slow release of a wide range of hydrophilic molecules."