Inspired by the natural bonding between a class of potent local anesthetics called site-1 sodium channel blockers (S1SCBs) and peptide sequences on the sodium channel in the nerve cell membrane, scientists at Boston Children’s Hospital and Harvard Medical School, have developed a self-assembling delivery system that releases the anesthetic over a prolonged period.

S1SCBs such as tetrodotoxin and saxitoxin are highly hydrophilic and therefore diffuse quickly when injected, causing severe systemic toxicity.

“The toxicity becomes dose-limiting, and you can’t get a long-lasting nerve block,” said Daniel Kohane, MD, PhD, director of the Laboratory for Biomaterials and Drug Delivery at Boston Children’s Hospital and vice-chair for research in the department of anesthesiology, critical care, and pain medicine.

The water solubility of S1SCBs also makes their encapsulation difficult. However, these potent pain relievers are an attractive alternative to opioids and ways to deliver them safely are of prime interest in anesthesiology and can be broadly applied in the design of drug delivery systems for receptor-mediated drugs.

In the current study, published in the Nature Biomedical Engineering article, “Delivery of local anesthetics by a self-assembled supramolecular system mimicking their interactions with a sodium channel,” the researchers exploited the specific interactions of S1SCBs with two peptide sequences on the sodium channel.

Tianjiao Ji, PhD, a former postdoc in Daniel Kohane’s lab at the Boston Children’s Hospital, came up with the idea for the biomimetic drug delivery system and is first author of the paper.

Tianjiao Ji, PhD, a former postdoc in Kohane’s lab, came up with the idea for a biomimetic system that would release local anesthetics slowly, prolonging their effect.

“By hijacking nature’s design, we created a synthetic receptor for anesthetic drugs that acts as a delivery and release system,” said Ji.

Ji, co-first author Yang Li, PhD, and their team modified the two sodium channel peptides with hydrophobic domains so that they assembled into nanofibers with the two peptides positioned together, mimicking the way they’re positioned on the sodium channel. These modified peptide pairs bind to tetrodotoxin simultaneously just as they would on the sodium channel itself and release the anesthetic when the nanofibers are in the proximity of the nerve, providing prolonged local anesthesia.

“When you add the hydrophobic chains, the peptides form a long fiber with thousands of P1s and P2s waving around,” Kohane explained. “Each set of peptides binds one tetrodotoxin molecule. Think of the peptides like hands—if you’re trying to catch tetrodotoxin, you need two hands to come together to hold it.”

Peptides P1 and P2 with hydrophobic modifications self-assemble into nanostructures that bind to tetrodotoxin (TTX). (Source: Tianjiao Ji, PhD, Kohane lab in Nature Biomedical Engineering)

The authors tested the S1SCB-carrying nanofibers by injecting them at the sciatic nerves of Sprague–Dawley rats and demonstrates successful prolonged sensory nerve blockade through a modified hotplate test and motor nerve blockade through a weight-bearing test. The neurobehavioral tests showed that the nerve block lasted for as long as 16 hours. The authors also showed minimal systemic toxicity and benign local-tissue reaction.

Although in the current study the team tested tetrodotoxin and saxitoxin, the approach can potentially be applied to other drug delivery systems that rely on receptor-drug interactions.

The study was funded by the National Institutes of Health and an Anesthesia Research Distinguished Trailblazer Award.