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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Chao Zhao & Andong Liu & Claudia M. Santamaria & Andre Shomorony & Tianjiao Ji & Tuo Wei & Akiva Gordon & Hannes Elofsson & Manisha Mehta & Rong Yang & Daniel S. Kohane, 2019. "Polymer-tetrodotoxin conjugates to induce prolonged duration local anesthesia with minimal toxicity," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10296-9
    DOI: 10.1038/s41467-019-10296-9
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    Cited by:

    1. Dali Wang & Yang Li & Xiaoran Deng & Matthew Torre & Zipei Zhang & Xiyu Li & Wei Zhang & Kathleen Cullion & Daniel S. Kohane & Christopher B. Weldon, 2023. "An aptamer-based depot system for sustained release of small molecule therapeutics," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

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