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Opioids remain a pillar of the treatment of chronic and surgical pain, despite their side effects and their risk of addiction and overdose. Conventional local anesthetics block pain very effectively, but they quickly disappear and can affect the heart and brain. Today, a rat study offers a possible alternative, involving an otherwise deadly pufferfish toxin.
In a small amount, in a slow-release formulation that effectively penetrates the nerves, the toxin has provided secure, highly targeted, long-lasting nerve blockade, researchers said today. Nature Communications. The study was led by Daniel Kohane, MD, Ph.D., director of the Laboratory of Biomaterials and Drug Administration at Boston Children's Hospital.
Kohane has long been interested in neurotoxins found in marine organisms such as puffer fish and algae. In small amounts, they can potentially provide powerful pain relief by blocking the sodium channels that transmit pain messages. Kohane's laboratory has experimented with different methods of packaging and administering these compounds into tiny particles, for example activating the local drug release by ultrasound and near-infrared light.
For the new study, the team chose tetrodotoxin, a potent commercially available compound derived from puffer fish. (Tetrodotoxin is known to have caused fugu intoxication by poorly prepared sashimi.)
Taming a deadly toxin
Rather than loading the tetrodotoxin into particles as before, the team chemically bonded it to a "skeletal" polymer. The body very slowly degrades the bond between the tetrodotoxin and the polymer by hydrolysis (natural breakdown of chemical bonds by water). This releases the drug at a slow and safe pace.
One lesson we learned is that with our previous delivery systems, the drug can leak too quickly, resulting in systemic toxicity. In this system, we administered intravenously a quantity of tetrodotoxin sufficient to kill a rat several times if it was administered in the unbound state, and the animals did not even seem to realize it. "
Daniel Kohane, MD, Ph.D., director of the Laboratory of Biomaterials and Drug Administration at Boston Children's Hospital
Kohane Fellows, Chao Zhao, PhD, and Andong Liu, PhD, have experimented with different drug fillers and polymer formulations to achieve the longest possible nerve block with as little toxicity as possible.
"We can modulate the polymer composition to control the release rate," says Zhao.
Improve permeation
To further increase safety, the team combined the tetrodotoxin-polymer combination with a chemical penetration enhancer, a compound that makes nerve tissue more permeable. This allowed them to use smaller amounts of tetrodotoxin while maintaining a nerve block.
"With the amplifier, ineffective drug concentrations become effective without increasing systemic toxicity," says Kohane. "Every piece of drugs you put in the most powerful package possible."
"We show that the penetration enhancer and the reversible binding of the toxin to the polymer are essential to achieve such prolonged anesthesia," Liu adds.
Good results early
When the researchers injected the combination near the sciatic nerve in the rat, they reached a nerve block for up to three days, with minimal local or systemic toxicity and no evidence of tissue damage.
In theory, nerve blockage in humans could last longer, since it could be administered more safely than in rats, says Kohane. The use of polymers with a longer retention time in the tissues would also prolong the effects.
"We could think of very long periods of nerve blockage in cancer patients, for example," he says. "Certainly for days and maybe weeks."
The investigators and the Boston Children's Hospital have filed a patent application covering the technology. For more information on licensing, contact [email protected] at the Boston Children's Technology and Innovation Development Office.
Source:
Boston Children & # 39; s Hospital
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