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

Chao Zhao, Andong Liu, Claudia M. Santamaria, Andre Shomorony, Tianjiao Ji, Tuo Wei, Akiva Gordon, Hannes Elofsson, Manisha Mehta, Rong Yang and Daniel S. Kohane ()
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Chao Zhao: Harvard Medical School
Andong Liu: Harvard Medical School
Claudia M. Santamaria: Harvard Medical School
Andre Shomorony: Harvard Medical School
Tianjiao Ji: Harvard Medical School
Tuo Wei: Harvard Medical School
Akiva Gordon: Harvard Medical School
Hannes Elofsson: Harvard Medical School
Manisha Mehta: Harvard Medical School
Rong Yang: Harvard Medical School
Daniel S. Kohane: Harvard Medical School

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10296-9

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