Nanoparticles with Two-Stage Delivery of Tetrodotoxin for Prolonged Duration Local Anesthesia

具有两阶段输送河豚毒素的纳米颗粒用于延长局部麻醉时间

• 批准号: 10434389
• 负责人: Chao Zhao
• 金额: $ 32.21万
• 依托单位: UNIVERSITY OF ALABAMA IN TUSCALOOSA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-21 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434389
• 关键词: Address; Adjuvant; Adverse effects; Amides; Anesthetics; Arrhythmia; Biological Availability; Buffers; Bupivacaine; Caliber; Cardiovascular system; Catheters; Chemicals; Clinical; Clinical Trials; Development; Dose; Drug Kinetics; Enhancers; Esters; Feasibility Studies; Formulation; Glycolic-Lactic Acid Polyester; Goals; Hour; Hydrolysis; Infiltration; Infiltration Anesthesias; Inflammation; Injections; Kinetics; Ligation; Light; Liposomes; Local Anesthetics; Local anesthesia; Measures; Meta-Analysis; Modeling; Molecular Weight; Morbidity - disease rate; Motor; Movement; Muscle; Muscle Weakness; Nerve; Nerve Block; Neurologic; Operative Surgical Procedures; Outcome; Pain; Pain management; Penetration; Perineuriums; Peripheral Nerves; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phenotype; Plasma; Polymers; Postoperative Pain; Postoperative Period; Preparation; Rattus; Reaction; Reporting; Research; Respiratory Failure; Respiratory Paralysis; Risk; Safety; Seizures; Sensory; Silicon Dioxide; Site; Sodium Channel Blockers; Stimulus; Surgical incisions; System; Technology; Tetrodotoxin; Time; Tissues; Touch sensation; Toxic effect; base; biomaterial compatibility; chronic pain; clinical efficacy; clinically significant; controlled release; efficacy evaluation; ethylene glycol; hydrophilicity; in vivo; in vivo evaluation; lipophilicity; nanoparticle; neurotoxicity; pain score; perineural; poly(D,L-lactide-co-glycolide); poly(glycerol-sebacate); prospective; sciatic nerve; side effect; systemic toxicity; uptake; wound

PROJECT SUMMARY Local anesthesia is a clinical option for the treatment of post-operative pain that may typically persist for 5-7 days and chronic pain phenotype that lasts longer than 12 weeks. Conventional amino-amide and amino-ester local anesthetics are effective, but the duration of a typical nerve block or infiltrations nerve block is relatively short (2-3 hours) reflecting clearance of the molecule. Aside from an invasive catheter, an alternative commercial formulation of bupivacaine in liposomes (Exaprel) is widely used. While an increased duration of action is achieved over standard bupivacaine, its duration is typically less than 3-5 days. In addition, the extended duration of bupivacaine exposure increases risk of intrinsic muscle and nerve toxicity, as well as cardiovascular and neurologic systemic side effects. The goal of our research is to develop a local anesthetic preparation that can produce a duration of local anesthesia reliably lasting 7-14 days from a single perineural injection or site infiltration with minimal local or systemic side effects. To pursue this goal, we propose to employ tetrodotoxin (TTX), a site 1 sodium-channel blocker, for local anesthetic formulations. Compared with conventional local anesthetics, TTX is around one thousand-fold more potent in nerve block, and it does not cause myo- or neurotoxicity, seizures, or arrhythmias. The final milestone before TTX clinical use is to address its systemic bioavailability, which can cause neural blockade and muscular weakness, resulting in diaphragmatic paralysis, leading to respiratory failure. To use TTX in a safe manner for prolonged duration of local anesthesia, we developed a two-stage TTX delivery system, which integrates the chemical penetration enhancer (CPE) (first stage) and controlled release technology (second stage) into one platform. Specifically, TTX will be covalently conjugated with poly(d,l-lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-PEG) through ester bonds, and the resulting PLGA-PEG-TTX conjugates will be subsequently fabricated into nanoparticles. We hypothesize that PLGA-PEG-TTX nanoparticles with appropriate hydrophilicity and diameter can penetrate the peripheral nerve perineurium to achieve the targeted TTX delivery to the nerve and reduce the systemic uptake of TTX, and that the nanoparticles will reside inside the nerve and act as a drug depot to continuously release a constant amount of TTX, which is adequate for the nerve block over time, via the hydrolysis of the ester bonds. The two-stage TTX delivery system allows safe delivery of larger doses of perineural TTX than the reported dose tolerance limit, minimizing TTX toxicity, and greatly extending duration of local anesthesia. We will assess sciatic nerve block, wound infiltration anesthesia, and systemic toxicity of the PLGA-PEG-TTX nanoparticles in both normal rats and rat models of primary pain as compared with liposomal bupivacaine. The expected outcome of this project is that TTX-based local anesthetics are likely to be even safer and will provide longer nerve blocks than can be safely achieved with the rapidly cleared lipophilic anesthetics currently in use.

项目摘要 局部麻醉是治疗术后疼痛的临床选择，通常持续5-7 持续时间超过12周的慢性疼痛表型。常规氨基酰胺和氨基酯 局部麻醉剂是有效的，但典型的神经阻滞或浸润性神经阻滞的持续时间相对较长。 短（2-3小时），反映了分子的清除。除了侵入性导管，还有一种替代方法 广泛使用脂质体中的布比卡因的商业制剂（Exaprel）。虽然持续时间增加， 作用超过标准布比卡因，其持续时间通常小于3-5天。此外该 布比卡因暴露时间延长会增加内在肌肉和神经毒性的风险， 心血管和神经系统副作用。我们研究的目标是开发一种局部麻醉剂 一种制剂，可以产生持续时间的局部麻醉，可靠地持续7-14天，从单一的神经周围 注射或部位渗透，局部或全身副作用最小。为了实现这一目标，我们建议 使用河豚毒素（TTX），一种部位1钠通道阻滞剂，用于局部麻醉制剂。较 传统的局部麻醉剂，TTX在神经阻滞中的效力大约是传统局部麻醉剂的一千倍，并且它不 引起肌肉或神经毒性癫痫或心律失常。TTX临床使用前的最后一个里程碑是解决 它的全身生物利用度，可引起神经阻滞和肌肉无力， 神经麻痹，导致呼吸衰竭。以安全的方式使用TTX， 局部麻醉下，我们开发了一种两阶段TTX输送系统，它集成了化学渗透 增强剂（CPE）（第一阶段）和控制释放技术（第二阶段）整合为一个平台。具体地说， TTX将与聚（d，l-丙交酯-共-乙交酯）-嵌段-聚（乙二醇）（PLGA-PEG）共价结合 通过酯键，将得到的PLGA-PEG-TTX缀合物随后制成 纳米粒子我们假设具有适当亲水性和直径的PLGA-PEG-TTX纳米粒 可穿透周围神经束膜，实现TTX靶向递送至神经， TTX的全身摄取，并且纳米颗粒将驻留在神经内并作为药物储存库， 持续释放恒定量的TTX，这是足够的神经阻滞随着时间的推移，通过 酯键的水解。两阶段TTX输送系统允许安全输送较大剂量的 神经周围TTX比报告的剂量耐受限度，最大限度地减少TTX毒性，并大大延长持续时间 局部麻醉我们将评估坐骨神经阻滞、伤口浸润麻醉和全身毒性。 PLGA-PEG-TTX纳米粒在正常大鼠和大鼠原发性疼痛模型中的作用， 脂质体布比卡因。该项目的预期结果是，基于TTX的局部麻醉剂很可能 甚至更安全，并且将提供比快速清除的 目前使用的亲脂性麻醉剂。