Polymer-tetrodotoxin conjugates for prolonged duration local anesthesia

用于延长局部麻醉时间的聚合物-河鲀毒素结合物

• 批准号: 10046799
• 负责人: Chao Zhao
• 金额: $ 42.95万
• 依托单位: UNIVERSITY OF ALABAMA IN TUSCALOOSA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046799
• 关键词: Address; Adverse effects; Amides; Analgesics; Anesthetics; Animals; Arrhythmia; Cardiovascular system; Cell Membrane Permeability; Cell surface; Cessation of life; Chemicals; Chronic; Clinical; Dose; Drug Delivery Systems; Drug Kinetics; Drug usage; Encapsulated; Esters; Formulation; Goals; Hour; Hydrolysis; Hydrophobicity; Inflammation; Injectable; Injections; Lead; Liposomes; Liquid substance; Local Anesthetics; Local anesthesia; Modeling; Muscle Weakness; Nerve; Nerve Block; Neural Conduction; Neurologic; Opioid; Overdose; Pain management; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Polyethylene Glycols; Polymers; Postoperative Pain; Property; Rattus; Reaction; Reporting; Research; Respiratory Paralysis; Risk; Safety; Seizures; Site; Sodium Channel; Sodium Channel Blockers; Syringes; System; Technology; Tetrodotoxin; Time; Tissues; Toxic effect; Vertebral column; addiction; biomaterial compatibility; chronic pain; compliance behavior; controlled release; covalent bond; efficacy study; improved; in vivo; nerve injury; neurobehavioral test; neurotoxicity; pharmacodynamic model; poly(glycerol-sebacate); prevent; respiratory; sciatic nerve; side effect; sodium ion; success; systemic toxicity

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.

开发局部麻醉剂制剂一直是一个长期目标，该制剂可产生长时间的局部麻醉效果。 麻醉（PDLA）副作用最小。河豚毒素 (TTX) 是一种位点 1 钠通道阻滞剂，可阻断 细胞表面 1 位点的钠通道是一种天然存在的化合物，具有极强的局部作用 麻醉特性。此外，TTX 不会引起肌肉或神经毒性。然而，主要原因是 尽管 TTX 具有强大的功效，但其相关的全身毒性令人担忧，但尚未实现临床应用。这 TTX 过量会导致神经阻滞和肌肉无力，导致膈肌麻痹，从而导致 呼吸停止和死亡。本研究的主要目的是利用药物控释 技术来解决 TTX 毒性带来的限制，并提供持续 2-4 周的 PDLA 单次注射。为了实现这一目标，我们建议 1) 将 TTX 共价结合到聚合物主链上 通过酯键水解，实现TTX的缓释； 2) 制作聚合物主链 成为液体、粘性和疏水性，可以实现增强的局部材料保留。一次 我们制作了配方，神经阻滞的持续时间和全身毒性将使用以下方法进行评估 大鼠坐骨神经阻滞模型和神经行为测试。药代动力学(PK)-药效学(PD) 还将研究持续释放 TTX 的模型和 PDLA 后的组织毒性。如果 如果成功的话，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 的安全裕度，由于麻醉给药频率降低而提高患者的依从性， 减少并可能消除疼痛治疗中阿片类药物的需求，以避免并发症并减轻疼痛 成瘾的风险。