Polymer-tetrodotoxin conjugates for prolonged duration local anesthesia

长期以来的目标是开发产生延长持续时间的局部麻醉剂制剂。 麻醉（PDLA），副作用最小。河豚毒素（TTX），一种位点1钠通道阻滞剂， 细胞表面位点1的钠通道是一种天然存在的化合物，具有极强的局部抑制作用， 麻醉特性。此外，TTX不会引起肌肉或神经毒性。然而， 尽管TTX具有很大的效力，但其相关的全身毒性令人担忧，但尚未实现临床应用。的 TTX过量导致神经阻滞和肌肉无力，导致横膈膜麻痹，导致 呼吸停止和死亡。本研究的主要目的是利用药物控制释放 技术，以解决TTX的毒性所施加的限制，并提供持续2-4周的PDLA， 一次注射为了实现这一目标，我们建议1）将TTX共价缀合到聚合物主链上 通过酯键的水解作用实现TTX的缓释; 2）使聚合物骨架 是液体、粘性和疏水的，其中可以实现增强的局部材料保持。一旦 我们制造了该制剂，将使用该制剂评估神经阻滞的持续时间和全身毒性。 大鼠坐骨神经阻滞模型和神经行为学测试。药代动力学（PK）-药效学（PD） 并对TTX缓释模型及PDLA后的组织毒性进行了研究。如果 如果成功，这项研究可能会产生重大的临床影响。TTX的缓释制剂将 增加TTX的安全范围，由于麻醉剂给药频率较低而提高患者依从性， 减少并可能消除疼痛治疗中对阿片类药物的需求，以避免并发症， 成瘾的风险。

It has been a long-standing goal to develop local anesthetic formulations producing prolonged duration local anesthesia (PDLA) with minimal side effects. Tetrodotoxin (TTX), a site 1 sodium-channel blocker, which blocks the sodium channel at site 1 on the cell surface, is a naturally occurring compound with extremely potent local anesthetic properties. Besides, TTX does not cause myo- or neurotoxicity. However, the principal reason that TTX has not achieved clinical use despite its great potency is concern over its associated systemic toxicity. The TTX overdose causes neural blockade and muscular weakness resulting in diaphragmatic paralysis leading to respiratory arrest and death. The primary objective of this research is to use the drug controlled release technology to address the limitations imposed by the toxicity of TTX and to provide PDLA lasting 2-4 weeks from a single injection. To achieve this goal, we propose to 1) covalently conjugate TTX onto polymer backbones through ester bonds, hydrolysis of which can achieve the slow release of TTX; 2) make the polymer backbone to be liquid, viscous and hydrophobic, where the enhanced local material retention can be accomplished. Once we fabricated the formulation, the duration of nerve blockade and systemic toxicity will be assessed using the rat sciatic nerve block model and neurobehavioral testing. Pharmacokinetics (PK)-pharmacodynamics (PD) models of the sustained-release TTX and the tissue toxicity following the PDLA will also be investigated. If successful, this research could have a substantial clinical impact. Sustained-release formulations of TTX would increase the safety margin of TTX, improve patient compliance due to less frequent anesthetic administration, reduce and possibly eliminate the need for opioids in pain treatment to avoid complications and to lessen the risk of addiction.