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: 10650400
• 负责人: Chao Zhao
• 金额: $ 33.05万
• 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/10650400
• 关键词: Address; Adjuvant; Adverse effects; Amides; Anesthetics; Arrhythmia; Biological Availability; Buffers; Bupivacaine; Cardiovascular system; Catheters; Chemicals; Clinical; Clinical Trials; Development; Diameter; Dose; Drug Kinetics; Enhancers; Esters; Feasibility Studies; Formulation; Glycolic-Lactic Acid Polyester; Goals; Hour; Hydrolysis; Infiltration; Infiltration Anesthesias; Inflammation; Injections; Integrated Delivery Systems; 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; biomaterial compatibility; chronic pain; clinical efficacy; clinically significant; controlled release; efficacy evaluation; ethylene glycol; hydrophilicity; improved; in vivo; in vivo evaluation; lipophilicity; liposomal formulation; 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，通常可能持续5-7 天数和慢性疼痛表型持续超过12周。常规的氨基酰胺和氨基酯 局部麻醉剂是有效的，但是典型神经阻滞或浸润神经阻滞的持续时间相对 短（2-3小时）反映分子清除率。除了侵入性导管，另一种选择 布比卡因在脂质体（Exaprel）中的商业配方被广泛使用。而持续时间增加 在标准的布比卡因实现了行动，其持续时间通常不到3-5天。另外， 延长布比卡因暴露持续时间增加了内在肌肉和神经毒性的风险， 心血管和神经系统副作用。我们研究的目的是开发局部麻醉 可以从单个会周围可靠地可靠地持续7-14天的局部麻醉持续时间的准备工作 注射或现场渗透，最小的局部或全身副作用。为了实现这一目标，我们建议 使用Tetrodotoxin（TTX）（TTX），一种位点1钠通道阻滞剂，用于局部麻醉配方。与 常规的局部麻醉药，TTX在神经阻滞中的效力约为一千倍，而不是 引起肌毒性，癫痫发作或心律不齐。 TTX临床使用之前的最后一个里程碑是解决 它的系统性生物利用性，可能导致神经阻滞和肌肉无力，导致 dia肌瘫痪，导致呼吸衰竭。长时间以安全的方式使用TTX 局部麻醉，我们开发了一个两阶段的TTX输送系统，该系统整合了化学渗透率 增强器（CPE）（第一阶段）和受控释放技术（第二阶段）进入一个平台。具体来说， TTX将与poly（d，l-lactide-co-glycolide）-Block-Poly（乙二醇）（PLGA-PEG）共价共轭 通过酯键，随后将所得的PLGA-PEG-TTX结合物用于 纳米颗粒。我们假设具有适当亲水性和直径的PLGA-PEG-TTX纳米颗粒 可以穿透周围神经会不会以实现靶向的TTX递送到神经并减少 TTX的系统性摄取，纳米颗粒将位于神经内部，并充当药物库 连续释放恒定数量的TTX，这是随着时间的流逝而适合神经阻滞的足够的 酯键的水解。两阶段的TTX输送系统允许安全交付更大的剂量 周围的TTX大于报告的剂量耐受性极限，最小化TTX毒性，并且大大延长了持续时间 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 与 脂质体布比卡因。该项目的预期结果是，基于TTX的局部麻醉剂可能可能 更安全，将提供更长的神经阻滞 目前正在使用的亲脂性麻醉药。