Polymer-tetrodotoxin conjugates to induce prolonged duration local anesthesia with minimal toxicity

Abstract

There is clinical and scientific interest in developing local anesthetics with prolonged durations of effect from single injections. The need for such is highlighted by the current opioid epidemic. Site 1 sodium channel blockers such as tetrodotoxin (TTX) are extremely potent, and can provide very long nerve blocks but the duration is limited by the associated systemic toxicity. Here we report a system where slow release of TTX conjugated to a biocompatible and biodegradable polymer, poly(triol dicarboxylic acid)-co-poly(ethylene glycol) (TDP), is achieved by hydrolysis of ester linkages. Nerve block by the released TTX is enhanced by administration in a carrier with chemical permeation enhancer (CPE) properties. TTX release can be adjusted by tuning the hydrophilicity of the TDP polymer backbone. In vivo, 1.0–80.0 µg of TTX released from these polymers produced a range of durations of nerve block, from several hours to 3 days, with minimal systemic or local toxicity.

Strategies to Obtain Encapsulation and Controlled Release of Small Hydrophilic Molecules

“…Conjugate delivery systems overcome the main drawbacks of non-covalent physical methods, unfavorable leakage and burst release, due to stable linkers between drugs and polymers (Chen et al, 2014). Zhao et al (2019) synthesized a range of rationally designed PEGylated and non-PEGylated polymers to which the ultra-potent local anesthetic TTX was conjugated by hydrolysable ester bonds. Zhao demonstrated that TTX was released in its native form, and the release rate can be regulated by manipulating the polymer composition (the TTX release rate is proportional to the hydrophilicity of polymer backbone).…”

Correction of amblyopia in cats and mice after the critical period

“…In humans, 30 μg of TTX administered subcutaneously twice a day for 4 days was reported to be safe and well tolerated (Hagen et al, 2017). In addition, new biodegradable polymers have recently been developed for therapeutic delivery of TTX to achieve prolonged and local sodium channel blockade without detectable systemic toxicity (Zhao et al, 2019). Thus, there may be a path forward to apply this strategy for the treatment of deprivation amblyopia in adult patients.…”

Applications of capillary action in drug delivery

“…The release rate can be tuned by adjusting the chemical linker type and the large molecules' chemical composition. For example, when a drug binds to a polymer through an ester bond, the drug is released by hydrolysis of the ester bond, and the hydrolysis rate can be reduced by increasing the hydrophobicity of the polymer chain (Zhao et al, 2019). Covalent bonds are more stable than non-covalent bonds; therefore, less drug is released prematurely, and sudden initial drug release is reduced.…”

“…In addition to the carrier itself, solvent residues in the carrier can also cause biocompatibility issues. Organic solvents are used usually in the manufacturing or processing of formulations, such as dissolving polymers for emulsification to prepare nanoparticles (Zhang et al, 2016), dissolving lipids to prepare liposomes through the film hydration method (Shomorony et al, 2019), and in the reactions to covalently bind drug to the large molecules (Zhang et al, 2020;Zhao et al, 2019). The solvents present in the final product must be below the limits set by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) as they are potentially harmful to those consuming these products.…”

“…Besides, TTX has a very narrow therapeutic window (e.g., there is a small difference between the toxic and therapeutic levels of TTX for blocking nerves). For example, a single injection of 4 mg TTX in phosphate-buffered saline (PBS, pH 7.4) can produce sensory sciatic nerve block in rats for 2 hr and a single injection of 5 mg TTX is fatal to rats (Liu et al, 2018;Zhao et al, 2019).…”