Site-1 sodium channel blockers (S1SCBs) act as potent local anaesthetics, but they can cause severe systemic toxicity. Delivery systems can be used to reduce the toxicity, but the hydrophilicity of S1SCBs makes their encapsulation challenging. Here, we report a self-assembling delivery system for S1SCBs whose design is inspired by the specific interactions of S1SCBs with two peptide sequences on the sodium channel. Specifically, the peptides were modified with hydrophobic domains so that they could assemble into nanofibres that facilitated specific binding with the S1SCBs tetrodotoxin, saxitoxin and dicarbamoyl saxitoxin. Injection of S1SCB-carrying nanofibres at the sciatic nerves of rats led to prolonged nerve blockade and to reduced systemic toxicity, with benign local-tissue reaction. The strategy of mimicking a molecular binding site via supramolecular interactions may be applicable more broadly to the design of drug delivery systems for receptor-mediated drugs.
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The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are available for research purposes from the corresponding author upon reasonable request.
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Support for this work was provided by NIH R35 GM131728 (to D.S.K.) and by the Anaesthesia Research Distinguished Trailblazer Award (to T.J. and Y.L.).
The authors declare no competing interests.
Peer review information Nature Biomedical Engineering thanks Matthew Webber and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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a) Release kinetics of ϕFFF-P1P2 + TTX formulations with TTX and different concentrations of peptides. The TTX concentration was 62.6 μM in each group. Data are means ± SD; n = 4. *p < 0.05, **p < 0.01. b) Data from panel (a) at 12 h to show relationship between peptide concentration and release of TTX. Data are mean ± SD; n = 4. *p < 0.01 vs. ϕFFF-P1P2 concentration at 62.6 µM. c) Representative TEM images showing the effect of the concentration of ϕFFF-P1P2 on morphology. The dashed red circles and yellow arrows indicated aggregations. Scale bar: 100 nm.
Extended Data Fig. 2 Laser scanning confocal microscopy of the fluorescence of Alexa- ϕFFF-P1P2 and Alexa-P1P2 injected at the sciatic nerve in rats.
Representative images are of sciatic nerves and surrounding tissues collected 15 min and 24 h after injection. Red: Alexa647, indicating formulations; blue: HOECHST33342, indicating nuclei.
a) Duration of sensory nerve blocks. Data are means ± SD; n = 4. b) Thermal latency in the uninjected (contralateral) extremity in the first 5 h. In both panels, the ϕFFF-P1P2 concentration was 626.4 μM, and the ratio of ϕFFF-P1: ϕFFF-P2 = 1:1. The STX concentration is as shown in the figures. Data are means ± SD; n = 4.
Scale bar for H&E-stained sections: 100 μm; for toluidine blue stained sections: 25 μm.
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Ji, T., Li, Y., Deng, X. et al. Delivery of local anaesthetics by a self-assembled supramolecular system mimicking their interactions with a sodium channel. Nat Biomed Eng 5, 1099–1109 (2021). https://doi.org/10.1038/s41551-021-00793-y