Cold triggered Local Anesthesia for Pain Management

项目总结 临床上和科学上都有兴趣开发按需局部麻醉，其中局部麻醉药可以 仅在第一次给药后需要时由外部触发器释放。在过去的几年里 多年来，已开发出可注射局部麻醉剂配方，可按需产生局部麻醉剂 由光和超声波触发的麻醉。然而，它们的临床应用受到缺点的阻碍， 如基础药物释放时不应用触发，少量重复触发事件为一 注射(通常4至6次)，触发事件仅在注射后几个小时内发生，潜在的局部 由外部诱因引起的组织毒性，以及昂贵的制备程序。在这项研究中，为了 为了克服这些缺点，我们的目标是探索冷触发局部麻醉。配方设计 由三种成分组成：河豚毒素(TTX)、冷疗和温度响应性多聚体。我们 假设TTX是一种非常有效的局部麻醉剂，少量就可以成功地产生局部麻醉剂 麻醉，从而提高每次触发的效果并增加触发事件的数量；冷 治疗是亚低温在医学治疗中的一种常用方法，具有成本低、操作简便等特点 可操作，非侵入性；温度响应性多聚体可以有效地将TTX包裹在体内 温度，但由于冷处理下多聚体的解构而释放TTX。此外, 微米级的聚合体可以在注射部位停留很长时间，作为药物储存库来实现 长期影响。具体地说，具有各种结构(大小和孔隙度)的聚合体的大型文库和 性能(结构稳定性和外壳刚度)将被制造出来。这样的图书馆将是 候选人。将进行迭代筛选以鉴定具有所需体外冷的聚合体 可触发的TTX释放，增强了组织中的局部滞留，以及出色的生物相容性(细胞毒性， 炎症、肌肉毒性、器官毒性)。然后，建立大鼠足垫麻醉模型和大鼠足爪切开创面模型。 渗透模型将用于评价所选多聚体在冷条件下的体内有效性和安全性。 触发了局部麻醉。本项目的预期成果是一个方便、适用的按需本地 麻醉剂配方。这样的系统将使患者能够根据需要调整局部止痛的程度 他们不断变化的需求和条件，并将最大限度地减少全身止痛药的使用 比如阿片类药物。

PROJECT SUMMARY There is clinical and scientific interest in developing on-demand local anesthesia, in which local anesthetics can only be released by an external trigger when and where needed after the first administration. In the past few years, injectable local anesthetic formulations have been developed that can generate on-demand local anesthesia triggered by light and ultrasound. However, their clinical application is hindered by shortcomings, such as basal drug release when the trigger is not applied, a small number of repetitive trigger events for one injection (usually 4 to 6 times), the trigger event only occurs within a few hours after the injection, potential local tissue toxicity caused by the external triggers, and expensive preparation procedures. In this research, in order to overcome these shortcomings, we aim to explore cold triggered local anesthesia. The formulation design consists of three components: tetrodotoxin (TTX), cold therapy, and thermo-responsive polymersomes. We hypothesize that TTX is an extremely potent local anesthetic, a small amount can successfully produce local anesthesia, thereby improving the efficacy of each trigger and increasing the number of trigger events; cold treatment is a common use of hypothermia in medical therapy, which has the characteristics of low cost, easy operation, and non-invasiveness; thermo-responsive polymersomes can efficiently encapsulate TTX at body temperature, but release TTX due to the deconstruction of the polymersomes under cold treatment. In addition, the micron-sized polymersomes can stay at the injection site for a long time, acting as a drug reservoir to achieve long-term effects. Specifically, a large library of polymersomes with various structures (size and porosity) and properties (structurally stability and shell stiffness) will be fabricated. Such a library will be a collection of candidates. Iterative screening will be conducted to identify the polymersomes with the desired in vitro cold triggerable TTX release, enhanced local retention in tissues, and excellent biocompatibility (cytotoxicity, inflammation, myotoxicity, organ toxicity). Then, the rat footpad anesthesia model and rat paw incision wound infiltration model will be used to evaluate the in vivo efficacy and safety of the selected polymersomes in cold triggered local anesthesia. The expected outcome of this project is a convenient and applicable on-demand local anesthetic formulation. Such a system will enable patients to adjust the degree of local analgesia according to their changing needs and conditions, and will minimize the administration of systemic analgesic medications such as opioids.