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.
