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Opioids are usually the mainstay of perioperative and chronic pain, and even local pain treatment, but these drugs have many side effects, including nausea, irritations, itching, urinary retention, constipation, etc., and more serious tolerance. , addiction and the risk of overuse of death.

Opioids are usually administered systemically, primarily in the central nervous system, which is the source of their major side effects. Therefore, there is growing interest in methods for locally treating pain.


Local anesthetics can prevent noxious stimuli from being uploaded to the central nervous system, and the effect is exact, and it is not easy to have centralization and pain allergy. In addition, due to the administration method of topical administration, the blood drug concentration is low, and systemic side effects are small in the case of no accidental blood injection.


However, the existing clinically used local anesthetics have limited action time. The analgesic time of a single administration usually does not exceed 8 hours. Although it can satisfy most operations or invasive operations, it is far from fully satisfying postoperative pain and chronicity. Pain and so on. Therefore, prolonging the action time of local anesthetics and developing long-acting local anesthetics that meet clinical needs have important clinical significance and broad market prospects.


Recently, researchers from Boston Children’s Hospital affiliated with Harvard Medical School have developed a new method for “taming” one of the world’s most effective toxins, a naturally occurring sodium channel blocker (S1SCB), tetrodotoxin (TTX).

The study reported a sustained release system that uses TTX for effective local anesthesia, which allows the target area to be anesthetized for up to 3 days while ensuring safety. Related research results were published on Nature Communications on June 12.

TTX is an aminohydroquinazoline type compound, which is one of the most toxic neurotoxins found in nature. It quickly acts on nerve endings and nerve centers after absorption, and blocks nerve excitation membrane with high selectivity and high affinity. The upper sodium channel blocks the nerve conduction, causing nerve paralysis and death.


However, it is precisely because of this unique mechanism of action that TTX has attracted the interest of some scientists. At present, it can be used clinically for analgesia, local anesthesia, sedation, antihypertensive, antiarrhythmia, etc., but due to its toxicity, it is limited in its use.


Dr. Daniel S. Kohane, who led the research, has long been interested in neurotoxins in marine organisms such as pufferfish and algae. His team has tried various methods of encapsulating and delivering these compounds in the form of tiny particles, such as the use of ultrasound and near-infrared light to excite local drug release.


However, in this new study, considering the hydrophilicity of S1SCBs, it is a big challenge to reduce toxicity by encapsulation. Instead of loading tetrodotoxin into the granules as before, they chose a new method: The hydrolyzable ester bond covalently binds TTX to the biodegradable and biocompatible polymer-poly(trimer dicarboxylic acid)-copolyethylene glycol (TDP) backbone. This prevents the initial burst release of TTX and the slow hydrolysis of the ester bond can achieve sustained release of TTX. In addition, since the hydrophilicity of the polymer is a major determinant of the hydrolysis rate of the ester bond, the amount of TTX released can be adjusted by changing the hydrophilicity of the polymer backbone.


In addition, based on the fact that only a small fraction (possibly 0.05%) of the S1SCBs outside the nerve bundle penetrates the axon surface, the researchers used chemical penetration enhancers (CPEs, a multiphase that helps drugs cross the biological barrier). Small molecules) to enhance the penetration of TTX into the nerve, which can improve the effectiveness of the drug, thereby reducing the amount of TTX and improving the safety of the drug.

After testing for the hydrophilicity of TDP, the release kinetics of the TDP-TTX conjugated object, and the viscosity affecting the injection performance, the Kohane team continued the study using the rat.


First, they screened and confirmed that polyethylene glycol 200 (PEG200) is a suitable chemical penetration enhancer that effectively helps molecules penetrate into the nerve; in addition, it has been demonstrated that when covalently bound to the polymer backbone, TTX is not biologically active.



Next, in order to improve safety and extend the release time of TDP-TTX under known loading, the researchers selected TgD8-TTX/PEG200 for in vivo experiments. The results showed that the covalent binding of TTX to TgD8/PEG200 significantly improved the efficacy and safety, and the duration of nerve block was also greatly prolonged.


Among them, a significant increase in safety can be demonstrated by local injection of large doses of TgD8-TTX/PEG200 without toxicity. For example, the injection of TgD8-TTXH/PEG200 containing 80 μg (480 μM) TTX, the sensory nerve block effect lasted 71.5 ± 6.9 hours (about 3 days), and no rats died. This dose of TTX is 16 times higher than free TTX, which is absolutely fatal.


After obtaining good experimental results, the researchers continued to evaluate the time course of TDP local retention in tissues. They injected TgD8/PEG200 covalently bound to Cy5.5 and observed fluorescence signals on the sciatic nerve of all rats, with no detectable fluorescence elsewhere. This signal gradually weakened within 4 weeks, indicating that TgD8 can gradually degrade in vivo.


Finally, the investigators also evaluated the safety of intravenous TgD8–TTXH/PEG200, considering that accidental intravascular injections can cause general anesthetic toxicity. Intravenous injection of 0.5 ml of a formulation containing 20 μg (120 μM) of TTX (12.5 mg TgD8-TTXH) in rats revealed no neurobehavioral defects (reflecting systemic toxicity) or other signs of toxicity (including animal death). It is worth noting that 20 μg of intravenous TTX is sufficient to kill many rats.


In summary, the Kohane team developed a local anesthesia system that minimizes TTX local or systemic toxicity from a few hours to several days of nerve block. The design consists of two key components: 1. The TDP-TTX conjugate can precisely control the release of TTX at a safe rate; 2. CPE can increase the amount of TTX entering the nerve.


The local anesthesia system successfully “tamed” the deadly tetrodotoxin, making this once-fascinating poison a good medicine for the benefit of people.



Drug: Tetrodotoxin

Magazine: Nature Communications

Highlights: Researchers from Boston Children’s Hospital affiliated with Harvard Medical School have developed a local anesthesia system that precisely controls TTX release through TDP-TTX conjugates and increases TTX penetration of nerves through CPE. This system not only overcomes the highly toxic of TTX, but also solves the shortcomings of traditional anesthetics, making it a highly effective, safe and long-acting local anesthetic.

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