Injectable Electrospun Fiber-Hydrogel Composite Delivery System for Prolonged and Nociceptive-Selective Analgesia

Abstract

Nociceptive-selective analgesia is often preferred over traditional methods, providing effective pain relief with minimum systemic side effects.The quaternary lidocaine derivative QX-314, is a promising local anesthetic for achieving selective analgesia. However, due to its inability to penetrate the cell membrane, its efficacy is limited to intracellular administration. In this study, we aimed to develop an injectable electrospun fiber-hydrogel composite comprising QX-314-loaded poly(ε-caprolactone) electrospun fiber and capsaicin (Cap)-loaded F127 hydrogel (Fiber-QX314/Gel-Cap composite) for long-term and nociceptive-selective analgesia. The sequential and sustained release mechanism of Cap and QX-314 helped remarkably extend the sensory blockade duration up to 44.0 h, and prevent motor blockade. Specifically, our findings indicated that QX-314 can traverse the cell membrane through the transient receptor potential vanilloid 1 channel activated by Cap, thus targeting the intracellular Na⁺ channel receptor to achieve selective analgesia. Moreover, the composite effectively alleviated incision pain by suppressing c-Fos expression in the dorsal root ganglion and reducing the activation of glial cells in the dorsal horn of the spinal cord. Consequently, the Fiber-QX314/Gel-Cap composite, designed for exceptional biosafety and sustained selective analgesia, holds great promise as a non-opioid analgesic.

Keywords

Nociceptive selective analgesia / QX-314 / TRPV1 / Electrospunfiber / Injectable hydrogel

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Funding

Joint Funds of National Natural Science Foundation of China(U22A20276); “Five and five” Project of the Third Affiliated Hospital of Sun Yat-Sen University(2023WW501); Guangdong Provincial Science and Technology Program(202201020429); Science and Technology Planning Project of Guangdong Province-Regional Innovation Capacity and Support System Construction(2023B110006); National Key Research and Development Program of China(2019YFA0111300); National Natural Science Foundation of China(32001012); Science and Technology Program of Guangzhou(202102010190); Guangdong Provincial Pearl River Talents Program(2019QN01Y131); Science and Technology Planning Project of Guangdong Province of China(2020A0505100035); Guangdong Basic and Applied Basic Research Foundation(2021A1515012318); Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(GZC20233217)