Pufferfish toxin is "tamed" for up to 3 days or an alternative opioid

Opioids are usually systemic and primarily act on the central nervous system, which is the source of its main side effectsAs a result, there is growing interest in local treatments for painlocal anaesthetic can prevent the injury stimulation uploaded to the central nervous system, its effect is accurate, not easy to appear in the center, pain allergy and so onIn addition, due to local drug use of this method of administration, the concentration of blood medicine is low, in the absence of accidental blood, the systemic side effects are lessbut the existing clinical commonly used local anaesthetic action time is limited, the analgesic time of a single administration usually does not exceed 8 hours, although it can meet most of the surgery or invasive operation, but far from fully meet the needs of postoperative pain, chronic pain and so onTherefore, it has important clinical significance and broad market prospect to prolong the action time of local narcotic drugs and develop long-lasting local narcotic drugs to meet clinical needsrecently, researchers from Boston Children's Hospital, affiliated with Harvard Medical School, developed a new method to "tame" one of the world's most effective toxins, a naturally occurring sodium channel blocker (S1SCB), and a porpoise toxin (tetrodotoxin, TTX)the study reported a continuous release system that uses TTX for effective local anesthesia, which can provide anaesthetic in the target area for up to three days while ensuring safetyThe findings were published June 12 in Nature CommunicationsPicture: Nature Communications
TTX is an amino whole hydroquine compound, is one of the most toxic neurotoxins found in nature, after absorption and rapid action in the nerve endings and nerve centers, can be highly selective and affinity to block the sodium ion channels on the nerve excitatory membrane, hindering nerve conduction, resulting in nerve paralysis and deathHowever, it is precisely because of this unique mechanism of action that TTX has attracted the interest of some scientistsAt present, it can be used clinically for analgesia, local anesthesia, sedation, anti-hypertensive, anti-arrhythmia, etc, but because of the greater toxicity, the use of certain restrictionsDrDaniel SKohane, who led the study , has long been interested in neurotoxins in marine organisms such as pufferfish and algae His team has experimented with ways to encapsulate and transmit these compounds in the form of tiny particles, such as using ultrasound and near-infrared light to excite local drug releases In this new study, given the hydrophilic nature of S1SCBs, and the challenge of reducing toxicity through encapsulation, they did not load the pufferfish toxin into the particles as before, but chose a new method: combining TTX covalence with biodegradable and biodegradable polymers - polyglycosiumic acid - polyglycol (TDP) main chain through hydrolyzed estres This prevents the initial burst release of the TTX, and the slow hydrolysis of the ester key enables the continuous release of the TTX In addition, since the hydrophilic properties of polymers are the main determinant of the hydrolysis rate of ester bonds, the release of TTX can be adjusted by changing the hydrophilic properties of the polymer main chain in addition, based on the fact that only a small portion of the extra-nerve beam S1SCBs (possibly 0.05%) penetrate the axon surface, the researchers used chemical osmotic enhancers (CPEs, a multiphase molecule that helps the drug cross the biological barrier) to enhance TTX penetration of nerves, which can improve the effectiveness of the drug, thereby reducing the amount of TTX and improving the safety of the drug after testing factors such as TDP hydrophilicity, exosome release dynamics of TDP-TTX conjugate objects, and viscosity that affect shimmer performance, the Kohane team continued the study using rats first, they screened and confirmed that polyglycol 200 (PEG200) is a suitable chemical osmotic enhancer that effectively helps molecules penetrate the nerves; next, in order to improve safety and extend the release time of TDP-TTX under known loads, the researchers chose TgD8-TTX/PEG200 for inviva The results showed that combining TTX covalent to TgD8/PEG200 significantly improved effectiveness, safety, and the duration of nerve blocking was greatly extended where significant improvements in safety can be proved by local injection of high-dose TgD8-TTX/PEG200 without toxicity For example, with the injection of tgD8-TTX/PEG200, a formulation containing 80 ?g (480 ?M) TTX, the sensory nerve blocking effect lasts 71.5 to 6.9 hours (about 3 days) and no rat deaths This dose of TTX is 16 times higher than the free TTX, which is absolutely fatal After good experimental results, the researchers continued to evaluate the process of local retention of TDP in the organization They injected rats with TgD8/PEG200 in combination with Cy5.5, and observed that fluorescence signals could be seen in the sciatic nerves of all rats, with no detectable fluorescence elsewhere The signal gradually weakens within 4 weeks, indicating that TgD8 can gradually degrade in the body finally, the researchers also assessed the safety of intravenous TgD8-TTXH/PEG200, considering that accidental intravascular injections can lead to general anaesthetic toxicity Intravenous 0.5 ml in rats containing a formulation containing 20 ?g (120 m) TTX (12.5 mg TgD8-TTXH) found no neurobehavioral defects (reflecting systemic toxicity) or other signs of toxicity (including animal death) It is worth noting that the free TTX of 20 ?g of intravenous lynx is enough to kill many rats concluded that the Kohane team developed a local anaesthetic system that minimizes local or systemic toxicity of TTX in the event of nerve blockage for hours to days The design consists of two key parts: 1, TDP-TTX conjugate can accurately control the release of TTX at a safe rate, and 2, CPE can increase the amount of TTX into the nerve the local anaesthetic system successfully "tamed" the deadly pufferfish toxin, making the once-smelling poison a good medicine for the benefit of people.