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; Daniel S Kohane

doi:10.1038/s41467-019-10296-9

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

Nat Commun. 2019 Jun 12;10(1):2566. doi: 10.1038/s41467-019-10296-9.

Authors

Affiliations

¹ Laboratory for Biomaterials and Drug Delivery, Division of Critical Care Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA.
² Laboratory for Biomaterials and Drug Delivery, Division of Critical Care Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA. Daniel.Kohane@childrens.harvard.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Anesthesia, Local / methods
Anesthetics, Local / administration & dosage*
Anesthetics, Local / pharmacokinetics
Animals
Biocompatible Materials / chemistry
Biocompatible Materials / toxicity
Biodegradable Plastics / chemistry
Biodegradable Plastics / toxicity
Cell Line
Cell Survival / drug effects
Delayed-Action Preparations / administration & dosage
Drug Carriers / chemistry*
Drug Carriers / toxicity
Drug Compounding / methods
Drug Evaluation, Preclinical
Drug Liberation
Male
Mice
Nerve Block / methods*
Permeability
Rats
Rats, Sprague-Dawley
Sciatic Nerve / drug effects
Sodium Channel Blockers / administration & dosage*
Sodium Channel Blockers / pharmacokinetics
Tetrodotoxin / administration & dosage*
Tetrodotoxin / pharmacokinetics
Time Factors
Treatment Outcome

Substances

Anesthetics, Local
Biocompatible Materials
Biodegradable Plastics
Delayed-Action Preparations
Drug Carriers
Sodium Channel Blockers
Tetrodotoxin

Grants and funding

R35 GM131728/GM/NIGMS NIH HHS/United States