Emulsion‐Induced Polymersomes Taming Tetrodotoxin for Prolonged Duration Local Anesthesia

Abstract

Injectable local anesthetics that can provide a continuous nerve block approximating the duration of a pain state would be a life‐changing solution for patients experiencing post‐operative pain or chronic pain. Tetrodotoxin (TTX) is a site 1 sodium channel blocker that is extremely potent compared to clinically used local anesthetics. Challengingly, TTX doses are limited by its associated systemic toxicity, thus shortening the achievable duration of nerve blocks. Here, emulsion‐induced polymersomes (EIP) are explored as a drug delivery system to safely use TTX for local anesthesia. By emulsifying hyperbranched polyglycerol‐poly (propylene glycol)‐hyperbranched polyglycerol (HPG‐PPG‐HPG) in TTX aqueous solution, HPG‐PPG‐HPG self‐assembles into micrometer‐sized polymersomes within seconds. The formed polymersomes have microscopically visible internal aqueous pockets that encapsulate TTX with an encapsulation efficiency of up to 94%. Moreover, the polymersomes are structurally stable, enabling sustained TTX release. In vivo, the freshly prepared EIP/TTX formulation can be directly injected and increase the tolerated dose of TTX in Sprague–Dawley rats to 11.5 µg without causing any TTX‐related systemic toxicity. In the presence of the chemical penetration enhancer sodium octyl sulfate (SOS), a single perineural injection of EIP/TTX/SOS formulation produces a reliable sciatic nerve block for 22 days with minimal local toxicity.

Hydration‐Induced Void‐Containing Hydrogels for Encapsulation and Sustained Release of Small Hydrophilic Molecules

“…All reactants and by-products (such as pure HPG) can be easily removed by dialysis against water and methanol to achieve high purity. [15] The chemical structure of the synthesized HPG-PPG-HPG was confirmed by proton nuclear magnetic resonance spectroscopy ( 1 H NMR) and Carbon-13 nuclear magnetic resonance spectroscopy ( 13 C NMR) (Figure 1b). Specifically, the peak at 1.1 ppm represents the CH 3 group of PPG, and the peak at 3.5 ppm represents the CH 2 group of PPG.…”

“…Analysis of 1 H NMR and inverse gated 13 C NMR spectra and calculation of molecular weights followed previously established methods. [15,36] Preparation of Hydrogels: A predetermined amount of the copolymer and DI water or aqueous solution (see details in Table S1, Supporting Information) were placed in a syringe or test tube and incubated overnight at 4 °C until the polymer was fully hydrated.…”

“…The vortex process created HPG-PPG-HPG polymersomes with aqueous pockets through a water-in-oil-in-water (w/o/w) emulsion, as previously reported. [15] Upon centrifugation, the polymersomes underwent precipitation and packed together to form a hydrogel. More specifically, under centrifugal pressure, the polymersomes came into close contact with each other, and the polymersome shells merged together, ultimately forming a 3D network that maintained the aqueous pockets, thus converting the polymersomes into hydrogel precursors.…”

“…In recent decades, hydrogels have been widely used as drug delivery vehicles due to their excellent biocompatibility, storage, this can result in depletion of the vehicles' drug content; concerning in vivo, this can manifest as burst release and systemic toxicity, which is especially problematic with ultrapotent drugs. [12][13][14][15] Given the advantages of hydrogels in biomedical engineering applications, if the above challenges of small hydrophilic molecule delivery are addressed, hydrogels could have an extensive clinical impact on the local delivery of small hydrophilic molecules.…”

“…Based on the integrated intensity analysis of 13 C NMR spectrum, the HPG molecular weight was calculated as previously reported. [15] The synthesized HPG-PPG-HPG copolymers…”