How deadly pufferfish toxin led to a breakthrough long-lasting local anesthetic
An impressive new study, led by scientists from the Boston Children's Hospital, has developed a novel method to tame one of the world's most potent toxins, tetrodotoxin, commonly found in the pufferfish. The research demonstrates a way to control the spread of the toxin and harness it into an effective local anesthetic that can numb targeted regions for up to three days.
Tetrodotoxin is a somewhat notorious poison, known for killing hundreds of people. In Japan a sashimi dish, made from a species of pufferfish known as fugu, is so controlled that there are strict regulations over its service. Chefs must train for at least three years, and obtain a license, before being allowed to serve the dish. If it is incorrectly prepared the dish can be easily contaminated with tetrodotoxin, swiftly poisoning those hungry diners.
Tetrodotoxin is such a potent toxin due to its incredibly efficient ability at inducing paralysis. It is this exact mechanism that has attracted scientists looking to develop novel forms of painkilling and anesthetic agents. The challenge in harnessing this toxin is in finding a safe way to deliver it to a specific area of the body and control the volume of release.
The new research describes a slow-release formulation that bounds the tetrodotoxin particles to a biodegradable polymer that degrades at a slow and controlled rate. This allows for the release of the tetrodotoxin into a localized area at a safe speed.
"A lesson we learned is that with our previous delivery systems, the drug can leak out too quickly, leading to systemic toxicity," explains Daniel Kohane. "In this system, we gave an amount of tetrodotoxin intravenously that would be enough to kill a rat several times over if given in the unbound state, and the animals didn't even seem to notice it."
To add to the localized efficacy of the technique the researchers incorporated a compound called a chemical permeation enhancer, which helps the tetrodotoxin easily permeate nerve tissue. This addition allows the toxin to more specifically enter the local tissue, meaning a lower dose can be just as effective as a higher concentration.
"With the enhancer, drug concentrations that are ineffective become effective, without increasing systemic toxicity," says Kohane. "Each bit of drug you put in packs the most punch possible."
So far the technique has only been validated in animal tests, however, the early results are incredibly positive. As well as proving to be safe and non-toxic, the composition of the polymer can be modulated to control the release rate and duration of anesthesia. In rat models, the sciatic nerve was effectively blocked for anywhere from a few hours to three days depending on the polymer backbone utilized. Kohane suggests in humans this duration could theoretically be extended up to several weeks depending on the condition being targeted.
"We could think about very long durations of nerve block for patients with cancer pain, for example," says Kohane. "Certainly for days, and maybe for weeks."
There is still plenty of work ahead for the researchers before this innovation is translated to humans, but early indications are promising that this technique can effectively scale up into human treatment. Considering the devastating opioid crisis ongoing around the world any new way to target chronic pain could be profoundly helpful, and this novel approach for a local anesthetic offers a compelling new way to approach blocking specific nerve clusters.
The research was published in the journal Nature Communications.
Source: Boston Children's Hospital