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

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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.

Graphical abstract

Injectable composite comprising QX-314-loaded electrospun fiber and capsaicin-loaded thermosensitive hydrogel sequentially releasing drugs for prolonged and nociceptive-selective local analgesia.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Skolnick P. The opioid epidemic: crisis and solutions. Annu Rev Pharmacol Toxicol. 2018;58:143.

    Article  CAS  PubMed  Google Scholar 

  2. Zhang WJ, Ning C, Xu W, Hu H, Li MQ, Zhao GQ, Ding JX, Chen XS. Precision-guided long-acting analgesia by gel-immobilized bupivacaine-loaded microsphere. Theranostics. 2018;8:3331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Macfarlane AJR, Gitman M, Bornstein KJ, El-Boghdadly K, Weinberg G. Updates in our understanding of local anaesthetic systemic toxicity: a narrative review. Anaesthesia. 2021;76(Suppl 1):27.

    Article  PubMed  Google Scholar 

  4. Zhang QS, Ren YM, Mo YQ, Guo PP, Liao P, Luo YC, Mu J, Chen Z, Zhang Y, Li Y, Yang LH, Liao DQ, Fu J, Shen JW, Huang W, Xu XW, Guo YY, Mei LH, Zuo YX, Liu J, Yang HY, Jiang RT. Inhibiting Hv1 channel in peripheral sensory neurons attenuates chronic inflammatory pain and opioid side effects. Cell Res. 2022;32:461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Shen HZ, Liu DL, Wu K, Lei JL, Yan NE. Structures of human Na(v)1.7 channel in complex with auxiliary subunits and animal toxins. Science. 2019;363:1303.

    Article  CAS  PubMed  Google Scholar 

  6. Osteen JD, Herzig V, Gilchrist J, Emrick JJ, Zhang CC, Wang XD, Castro J, Garcia-Caraballo S, Grundy L, Rychkov GY, Weyer AD, Dekan Z, Undheim EA, Alewood P, Stucky CL, Brierley SM, Basbaum AI, Bosmans F, King GF, Julius D. Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain. Nature. 2016;534:494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Binshtok AM, Bean BP, Woolf CJ. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature. 2007;449:607.

    Article  CAS  PubMed  Google Scholar 

  8. Xu ZZ, Kim YH, Bang SS, Zhang Y, Berta T, Wang F, Oh SB, Ji RR. Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade. Nat Med. 2015;21:1326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhang Q, Luo P, Xia F, Tang H, Chen JY, Zhang JZ, Liu DD, Zhu YP, Liu YQ, Gu LW, Zheng LH, Li ZJ, Yang F, Dai LY, Liao FL, Xu CC, Wang JA. Capsaicin ameliorates inflammation in a TRPV1-independent mechanism by inhibiting PKM2-LDHA-mediated Warburg effect in sepsis. Cell Chem Biol. 2022;29:1248.

    Article  CAS  PubMed  Google Scholar 

  10. Liao MF, Cao EH, Julius D, Cheng YF. Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature. 2013;504:107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang KH, Julius D, Cheng YF. Structural snapshots of TRPV1 reveal mechanism of polymodal functionality. Cell. 2021;184:5138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Blake KJ, Baral P, Voisin T, Lubkin A, Pinho-Ribeiro FA, Adams KL, Roberson DP, Ma YC, Otto M, Woolf CJ, Torres VJ, Chiu IM. Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314. Nat Commun. 2018;9:37.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Arora V, Campbell JN, Chung MK. Fight fire with fire: neurobiology of capsaicin-induced analgesia for chronic pain. Pharmacol Ther. 2021;220: 107743.

    Article  CAS  PubMed  Google Scholar 

  14. Ries CR, Pillai R, Chung CC, Wang JT, MacLeod BA, Schwarz SK. QX-314 produces long-lasting local anesthesia modulated by transient receptor potential vanilloid receptors in mice. Anesthesiology. 2009;111:122.

    Article  CAS  PubMed  Google Scholar 

  15. Stueber T, Eberhardt MJ, Hadamitzky C, Jangra A, Schenk S, Dick F, Stoetzer C, Kistner K, Reeh PW, Binshtok AM, Leffler A. Quaternary lidocaine derivative QX-314 activates and permeates human TRPV1 and TRPA1 to produce inhibition of sodium channels and cytotoxicity. Anesthesiology. 2016;124:1153.

    Article  CAS  PubMed  Google Scholar 

  16. Zhou C, Huang JQ, Yang Q, Li T, Liu J, Qian ZY. Gold nanorods-based thermosensitive hydrogel produces selective long-lasting regional anesthesia triggered by photothermal activation of transient receptor potential vanilloid type-1 channels. Colloids Surf B. 2018;171:17.

    Article  CAS  Google Scholar 

  17. Kopach O, Zheng K, Dong L, Sapelkin A, Voitenko N, Sukhorukov GB, Rusakov DA. Nano-engineered microcapsules boost the treatment of persistent pain. Drug Deliv. 2018;25:435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hu YW, Xu YT, Mintz RL, Luo X, Fang YQ, Lao YH, Chan HF, Li K, Lv SX, Chen GJ, Tao Y, Luo Y, Li MQ. Self-intensified synergy of a versatile biomimetic nanozyme and doxorubicin on electrospun fibers to inhibit postsurgical tumor recurrence and metastasis. Biomaterials. 2023;293: 121942.

    Article  CAS  PubMed  Google Scholar 

  19. Fang YQ, Luo X, Xu YT, Liu Z, Mintz RL, Yu HY, Yu X, Li K, Ju EG, Wang HX, Tang ZH, Tao Y, Li MQ. Sandwich-structured implants to obstruct multipath energy supply and trigger self-enhanced hypoxia-initiated chemotherapy against postsurgical tumor recurrence and metastasis. Adv Sci. 2023;10: e2300899.

    Article  Google Scholar 

  20. Lin ZJ, Liu BL, Wang HX, Zhan HL, Huang Y, Lu JX, Tao Y, Li MQ, Zhou XF. Nanoparticle-mediated intravesical delivery of conditioned medium derived from mesenchymal stem cells for interstitial cystitis/bladder pain syndrome treatment. Appl Mater Today. 2021;24: 101144.

    Article  Google Scholar 

  21. Chen SF, Yao WF, Wang HX, Wang TN, Xiao X, Sun GL, Yang J, Guan Y, Zhang Z, Xia ZY, Li MQ, Tao Y, Hei ZQ. Injectable electrospun fiber-hydrogel composite sequentially releasing clonidine and ropivacaine for prolonged and walking regional analgesia. Theranostics. 2022;12:4904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wang L, Li T, Wang ZH, Hou JD, Liu ST, Yang Q, Yu L, Guo WH, Wang YJ, Guo BL, Huang WH, Wu YB. Injectable remote magnetic nanofiber/hydrogel multiscale scaffold for functional anisotropic skeletal muscle regeneration. Biomaterials. 2022;285: 121537.

    Article  CAS  PubMed  Google Scholar 

  23. Zhou XH, He XL, Shi K, Yuan LP, Yang Y, Liu QY, Ming Y, Yi C, Qian ZY. Injectable thermosensitive hydrogel containing erlotinib-loaded hollow mesoporous silica nanoparticles as a localized drug delivery system for NSCLC therapy. Adv Sci. 2020;7:2001442.

    Article  CAS  Google Scholar 

  24. Li M, Chen D, Sun X, Xu ZS, Yang YT, Song YM, Jiang F. An environmentally tolerant, highly stable, cellulose nanofiber-reinforced, conductive hydrogel multifunctional sensor. Carbohydr Polym. 2022;284: 119199.

    Article  CAS  PubMed  Google Scholar 

  25. Jin YY, Zhang JB, Xu YT, Yi K, Li FF, Zhou HC, Wang HX, Chan HF, Lao YH, Lv SX, Tao Y, Li MQ. Stem cell-derived hepatocyte therapy using versatile biomimetic nanozyme incorporated nanofiber-reinforced decellularized extracellular matrix hydrogels for the treatment of acute liver failure. Bioact Mater. 2023;28:112–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. He JX, Wu XL, Xie YF, Gao Y, McClements DJ, Zhang L, Zou LQ, Liu W. Capsaicin encapsulated in W/O/W double emulsions fabricated via ethanol-induced pectin gelling: improvement of bioaccessibility and reduction of irritation. Int J Biol Macromol. 2023;235: 123899.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang YJ, Yang J, Yin QQ, Yang LH, Liu J, Zhang WS. QX-OH, a QX-314 derivative agent, produces long-acting local anesthesia in rats. Eur J Pharm Sci. 2017;105:212.

    Article  CAS  PubMed  Google Scholar 

  28. Wang Q, Zhang Y, Liu J, Zhang W. Quaternary lidocaine derivatives: past, present, and future. Drug Des Dev Ther. 2021;15:195.

    Article  Google Scholar 

  29. Gao Y, Cao EH, Julius D, Cheng YF. TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action. Nature. 2016;534:347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. García-Cáceres C, Balland E, Prevot V, Luquet S, Woods SC, Koch M, Horvath TL, Yi CX, Chowen JA, Verkhratsky A, Araque A, Bechmann I, Tschöp MH. Role of astrocytes, microglia, and tanycytes in brain control of systemic metabolism. Nat Neurosci. 2019;22:7.

    Article  PubMed  Google Scholar 

  31. Li J, Wei YY, Zhou JL, Zou HL, Ma LL, Liu CX, Xiao Z, Liu XF, Tan XR, Yu T, Cao S. Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn. J Neuroinflammation. 2022;19:123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yin SQ, Gao P, Yu LD, Zhu L, Yu WF, Chen Y, Yang LQ. Engineering 2D silicene-based mesoporous nanomedicine for in vivo near-infrared-triggered analgesia. Adv Sci. 2022;9: e2202735.

    Article  Google Scholar 

  33. Qiao B, Song XY, Zhang WY, Xu M, Zhuang BW, Li W, Guo HL, Wu WX, Huang GL, Zhang MR, Xie XY, Zhang N, Luan Y, Zhang CY. Intensity-adjustable pain management with prolonged duration based on phase-transitional nanoparticles-assisted ultrasound imaging-guided nerve blockade. J Nanobiotechnol. 2022;20:498.

    Article  CAS  Google Scholar 

  34. Ebbinghaus M, Müller S, Segond von Banchet G, Eitner A, Wank I, Hess A, Hilger I, Kamradt T, Schaible HG. Contribution of inflammation and bone destruction to pain in arthritis: a study in murine glucose-6-phosphate isomerase-induced arthritis. Arthritis Rheumatol. 2019;2016:71.

    Google Scholar 

  35. Sajid M, Khan MR, Ismail H, Latif S, Rahim AA, Mehboob R, Shah SA. Antidiabetic and antioxidant potential of Alnus nitida leaves in alloxan induced diabetic rats. J Ethnopharmacol. 2020;251: 112544.

    Article  CAS  PubMed  Google Scholar 

  36. Zhang HR, Tao JL, Bai H, Yang EM, Zhong ZH, Liu XT, Gu YH, Lu SF. Changes in the serum metabolome of acute myocardial ischemia rat pretreatment with electroacupuncture. Am J Chin Med. 2019;47:1025.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the Joint Funds of National Natural Science Foundation of China (U22A20276), the “Five and five” Project of the Third Affiliated Hospital of Sun Yat-Sen University (2023WW501), the Guangdong Provincial Science and Technology Program (202201020429), the Science and Technology Planning Project of Guangdong Province-Regional Innovation Capacity and Support System Construction (2023B110006), the National Key Research and Development Program of China (2019YFA0111300), the National Natural Science Foundation of China (52373166, 22277155, 32001012), the Science and Technology Program of Guangzhou (2024A04J6572, 202102010217, 202102010190), the Guangdong Provincial Pearl River Talents Program (2019QN01Y131), the Science and Technology Planning Project of Guangdong Province of China (2020A0505100035), the Guangdong Basic and Applied Basic Research Foundation (2019A1515011852, 2021A1515012318), the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation (GZC20233217), the Natural Science Foundation of Guangdong Province for Distinguished Young Scholar (2024B1515020025), and the China Primary Health Care Foundation (2022-003).

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Author notes

  1. Sufang Chen, Weifeng Yao, and Zhendong Ding, have contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology and Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China

    Sufang Chen, Weifeng Yao, Zhendong Ding, Jingyi Du, Tienan Wang, Xue Xiao, Linan Zhang, Jing Yang, Yu Guan, Chaojin Chen, Yu Tao, Mingqiang Li, Haixia Wang & Ziqing Hei

  2. Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China

    Sufang Chen, Yu Tao, Mingqiang Li & Haixia Wang

  3. Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, China

    Yu Tao, Mingqiang Li & Haixia Wang

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  1. Sufang Chen
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Contributions

Sufang Chen: Conceptualization, Investigation, Methodology, Data curation and analysis, Writing-original draft, Funding acquisition. Weifeng Yao: Conceptualization, Investigation, Methodology, Data curation and analysis, Writing-review & editing, Funding acquisition. Zhendong Ding: Investigation, Methodology, Data curation. Jingyi Du: Investigation. Tienan Wang: Investigation. Xue Xiao: Investigation. Linan Zhang: Investigation. Jing Yang: Investigation. Yu Guan: Investigation. Chaojin Chen: Investigation. Yu Tao: Validation, Writing-review & editing, Funding acquisition. Mingqiang Li: Conceptualization, Project administration, Writing-review & editing, Funding acquisition. Haixia Wang: Conceptualization, Project administration, Writing-review & editing, Funding acquisition. Ziqing Hei: Conceptualization, Project administration, Writing-review & editing, Funding acquisition.

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Correspondence to Mingqiang Li, Haixia Wang or Ziqing Hei.

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Chen, S., Yao, W., Ding, Z. et al. Injectable Electrospun Fiber-Hydrogel Composite Delivery System for Prolonged and Nociceptive-Selective Analgesia. Adv. Fiber Mater. (2024). https://doi.org/10.1007/s42765-024-00422-8

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