Drug delivery system reduces nerve-blocker toxicity in rats

A new self-assembling drug delivery system releases the nerve-blocker tetrodotoxin more slowly and with less toxicity than direct injection of the anesthetic compound in rats. A team led by Daniel S. Kohane, an anesthesiologist at Boston Children’s Hospital and Harvard Medical School, used modified versions of peptides from the same voltage-gated sodium channels that tetrodotoxin targets to deliver the drug (Nat. Biomed. Eng. 2021, DOI: 10.1038/s41551-021-00793-y). Tetrodotoxin, produced by some fish including pufferfish, is not currently used clinically. It is attractive as a local anesthetic because of its potency, but its systemic toxicity limits the concentration range over which it could be used.

Tetrodotoxin works by binding to peptides in sodium channels and plugging the channels. Postdoctoral researcher Tianjiao Ji, a member of Kohane’s lab, wondered whether they could deliver it using two of the peptides that tetrodotoxin interacts with on the sodium channel.

The peptides alone couldn’t encapsulate the drug. So the researchers added hydrophobic regions to the peptides, causing the peptides to self-assemble into nanofibers. The tetrodotoxin then interacts with its peptide binding sites in the fibers. “This turned out to be an injectable system that gave prolonged release with reduced toxicity,” Kohane says. It blocked the sciatic nerve of rats 3.6 times as long as free tetrodotoxin did.

The system is sequence specific. If the researchers change the sequence of the peptides from the sodium channel, the fibers no longer encapsulate tetrodotoxin. But the assembly works with other drugs, like saxitoxin, that interact with the sodium channel at the same site. It doesn’t deliver drugs that target other sites in the sodium channel.

The work “is a great example of the enormous potential of peptide-based supramolecular polymers to transform drug delivery,” says Samuel I. Stupp, an expert on supramolecular chemistry at Northwestern University. “They can be tailored to be highly bioactive and biodegrade safely, and their filamentous shape can help target and localize their medicinal cargo.”

The same approach may be generalizable to other drugs that target well-understood receptors, Kohane says. “There are so many drugs where their action is based on interactions with a receptor.”