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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要局部麻醉是治疗术后疼痛的一种临床选择，这种疼痛通常会持续 5-7 年。天和持续超过 12 周的慢性疼痛表型。常规氨基酰胺和氨基酯局部麻醉药有效，但典型神经阻滞或浸润神经阻滞的持续时间相对较长。短（2-3小时）反映分子的清除。除了侵入性导管外，还有一种替代方案脂质体中布比卡因的商业制剂（Exaprel）被广泛使用。虽然增加了持续时间作用效果优于标准布比卡因，其持续时间通常少于 3-5 天。此外，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，以及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可以从单个神经周围产生可靠持续 7-14 天的局部麻醉持续时间的制剂注射或部位浸润，局部或全身副作用最小。为了实现这一目标，我们建议使用河鲀毒素 (TTX)，一种位点 1 钠通道阻滞剂，用于局部麻醉制剂。与相比 TTX 的神经阻滞效果比传统局部麻醉药强约一千倍，而且它不引起肌肉或神经毒性、癫痫发作或心律失常。 TTX 临床使用前的最后一个里程碑是解决其全身生物利用度，可导致神经阻滞和肌肉无力，导致膈肌麻痹，导致呼吸衰竭。以安全的方式长期使用 TTX 局部麻醉，我们开发了两阶段TTX输送系统，该系统集成了化学渗透增强剂（CPE）（第一阶段）和控释技术（第二阶段）整合到一个平台中。具体来说， TTX 将与聚（d,l-丙交酯-共-乙交酯）-嵌段-聚（乙二醇）（PLGA-PEG）共价缀合通过酯键，所得的 PLGA-PEG-TTX 缀合物随后将被制成纳米颗粒。我们假设 PLGA-PEG-TTX 纳米颗粒具有适当的亲水性和直径可穿透周围神经神经束膜，实现TTX靶向递送至神经，减少 TTX 的全身吸收，纳米粒子将驻留在神经内并充当药物库通过持续释放恒定量的 TTX，这足以随着时间的推移进行神经阻滞酯键的水解。两阶段 TTX 输送系统可安全输送更大剂量的神经周围 TTX 超过报告的剂量耐受极限，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与正常大鼠和原发性疼痛大鼠模型相比，PLGA-PEG-TTX 纳米颗粒脂质体布比卡因。该项目的预期结果是基于 TTX 的局部麻醉剂可能更加安全，并且将提供比快速清除所能安全实现的神经阻滞更长的时间目前使用的亲脂性麻醉剂。