Saturday, April 20, 2024
4/20/2024
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.
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