Anesthetics that have prolonged duration from a single injection such as local anesthetics wear off quickly but can affect the brain and heart. A new rat study from Boston Children’s Hospital and Harvard Medical School may have found an alternative stemming from a compound that is found in a relatively infamous but unusual source: the pufferfish, as published in Nature Communications.
The scientists report a system that results in the slow release of tetrodotoxin that occurs as a result of the hydrolysis of ester linkages that conjugate the TTX to a biocompatible and biodegradable polymer, poly(triol dicarboxylic acid)-co-poly(ethylene glycol).
Pufferfish have a claim of fame as being the beautiful and delicate little fish that balloons up when in danger that carries a lethal toxin. Sometimes called fugu the pufferfish also is a most dangerous choice off of the menu at many sushi restaurants due to the production of TTX, neither freezing or cooking can destroy the toxin, if not prepared correctly ingesting it can cause severe illness and death; symptoms typically start minutes after eating the toxic fish can include but are limited to tingling of lips/mouth/extremities, dizziness, problems speaking, balance issues, muscle weakness and paralysis, and vomiting.
In small amounts neurotoxins found in marine organisms can potentially provide pain relief by blocking sodium channels that conduct pain messages. Daniel Kohane, MD, PhD, and Professor of anaesthesia at Harvard medical School has experimented with various ways of packaging/delivering these compounds in tiny particles; in tiny amounts and slow release formulations it efficentle penetrates nerves to provide safe, highly targeted and long lived nerve block.
“A lesson we learned is that with our previous delivery systems, the drug can leak out too quickly, leading to systemic toxicity.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.” says Kohane.
The team bound the tetrodotoxin chemically to a polymer backbone that is slowly degraded to release the drug at a safe rate, and experimented with different drug loading and polymer formations to achieve the longest possible nerve block with the least toxicity. The tetrodotoxin polymer combination was paired with a chemical penetration enhancer to make nerve tissue more permeable to further increase safety, which allowed the use of smaller amounts of the toxin while still achieving nerve block.
Nerve block was achieved for up to 3 days with minimal local or systemic toxicity and no apparent signs of tissue injury by injecting the cocktail near the sciatic nerve in rats. Nerve block in humans may last even longer since it could be administered more safely than in rats, and using polymers with longer retention time in tissue could also prolong effects, in theory, according to Kohane.
“We can modulate the polymer composition to control the release rate. With the enhancer, drug concentrations that are ineffective become effective. Each bit of drug you put in packs the most punch possible. We show that both the penetration enhancer and the reversible bonding of toxin to polymer are crucial to achieving such prolonged anesthesia. We could think about very long durations of nerve block for patients with cancer pain, for example. Certainly for days, and maybe for weeks.” note the researchers.
