Supramolecular Brake for Slowing Fentanyl Into Brain to Ameliorate Its Therapeutic Outcome

Abstract

Fentanyl (Fen) analogs, clinically used anesthetic adjuvants, are often trouble with overdose-induced adverse effects due to rapid entry into the brain plus short retention time. Advanced approaches that can relieve related life-threatening symptoms without compromising their anesthetic efficacy are urgently needed to satisfy these special requirements. Herein, we propose that utilization of a well-matched macrocycle, terphen[3]arene sulfate (TP3S) as a molecular-level brake for Fen via the pharmacokinetic mode to execute this task. NMR and titration experiments confirm that TP3S possessed strong complexation ability toward Fen with an association constant of (1.36 ± 0.12) × 10⁶M⁻¹. Then, Transwell assays demonstrate that TP3S itself is unable to cross the blood–brain barrier, and codosed with Fen could effectively decelerate its velocity of entering the brain. Respiration-related evaluations and pharmacodynamics analyses reveal that administration of such a brake alleviates Fen-induced respiratory depression without losing its effectiveness. The therapeutic index of Fen/TP3S is calculated to be ~57% higher than that of Fen alone, and through pharmacokinetic studies, it has been clarified that ameliorating Fen's therapeutic outcome stemmed from reducing the initial brain concentration of Fen and maintaining its effective dose for a longer time. This supramolecular approach could also act on other opioids as long as strong binding was achieved.

Keywords

fentanyl / host–guest complexation / supramolecular brake / terphen[3]arene sulfate / therapeutic outcome

References

[1] J. P. Rathmell and M. S. Avidan, “Patient-Centered Outcomes After General and Spinal Anesthesia,” New England Journal of Medicine 385, no. 22 (2021): 2088–2089.

[2] A. Gawande, “Two Hundred Years of Surgery,” New England Journal of Medicine 366, no. 5 (2012): 1716–1723.

[3] L. A. Colvin, F. Bull, and T. G. Hales, “Perioperative Opioid Analgesia-When Is Enough Too Much? A Review of Opioid-Induced Tolerance and Hyperalgesia,” Lancet 393, no. 10180 (2019): 1558–1568.

[4] B. D. Wyke and E. Frayworth, “Use of Bemegride in Terminating Barbiturate Anæsthesia,” Lancet 270, no. 7004 (1957): 1025–1028.

[5] R. D. Dripps, “Pharmacology of General Anesthetic Agents,” Science 140, no. 3572 (1963): 1247.

[6] A. Faouzi, H. Wang, S. A. Zaidi, et al., “Structure-Based Design of Bitopic Ligands for the µ-Opioid Receptor,” Nature 613, no. 7945 (2022): 767–774.

[7] V. Fodale, F. Mafrica, and L. B. Santamaria, “Killer Fentanyl: A Lesson From Anaesthesiology,” Lancet 368, no. 9543 (2006): 1237–1238.

[8] Q. N. Vo, P. Mahinthichaichan, J. Shen, and C. R. Ellis, “How μ-Opioid Receptor Recognizes Fentanyl,” Nature Communications 12, no. 1 (2021): e984.

[9] J. K. Zubieta, Y. R. Smith, J. A. Bueller, et al., “Regional Mu Opioid Receptor Regulation of Sensory and Affective Dimensions of Pain,” Science 293, no. 5528 (2001): 311–315.

[10] C. A. Lipinski, F. Lombardo, B. W. Dominy, and P. J. Feeney, “Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings,” Advanced Drug Delivery Reviews 46, no. 1–3 (2001): 3–26.

[11] P. T. Bremer, E. L. Burke, A. C. Barrett, and R. I. Desai, “Investigation of Monoclonal Antibody CSX-1004 for Fentanyl Overdose,” Nature Communications 14, no. 1 (2023): e7700.

[12] P. W. H. Peng and A. N. Sandler, “A Review of the Use of Fentanyl Analgesia in the Management of Acute Pain in Adults,” Anesthesiology 90, no. 2 (1999): 576–599.

[13] S. M. Burns, C. W. Cunningham, and S. L. Mercer, “DARK Classics in Chemical Neuroscience: Fentanyl,” ACS Chemical Neuroscience 9, no. 10 (2018): 2428–2437.

[14] A. Dahan, M. Boon, M. van Velzen, and M. Niesters, “From Breathtaking to Encapsulation: A Novel Approach to Reverse Respiratory Depression From Opioid Overdosing,” British Journal of Anaesthesia 125, no. 1 (2020): e16–e17.

[15] M. T. H. Tuhin, D. Liang, F. Liu, et al., “Peripherally Restricted Transthyretin-Based Delivery System for Probes and Therapeutics Avoiding Opioid-Related Side Effects,” Nature Communications 13, no. 1 (2022): e3590.

[16] R. Hill, R. Santhakumar, W. Dewey, E. Kelly, and G. Henderson, “Fentanyl Depression of Respiration: Comparison With Heroin and Morphine,” British Journal of Pharmacology 177, no. 2 (2019): 254–265.

[17] W. Jeal and P. Benfield, “Transdermal Fentanyl. A Review of Its Pharmacological Properties and Therapeutic Efficacy in Pain Control,” Drugs 53, no. 1 (1997): 109–138.

[18] R. Benyamin, A. M. Trescot, S. Datta, et al., “Opioid Complications and Side Effects,” Pain Physician 11, no. 2 (2008): 105–120.

[19] The Lancet, “Take-Home Naloxone: A Life Saver in Opioid Overdose,” Lancet 393, no. 10169 (2019): e296.

[20] U. G. Khatri, K. Viner, and J. Perrone, “Lethal Fentanyl and Cocaine Intoxication,” New England Journal of Medicine 379, no. 18 (2018): 1782.

[21] N. Gao and C. Pan, “Intelligent Ion Gels: Design, Performance, and Applications,” SmartMat 5, no. 1 (2024): e1215.

[22] C. Li, Z. Xie, Q. Chen, et al., “Supramolecular Hunter Stationed on Red Blood Cells for Detoxification Based on Specific Molecular Recognition,” ACS Nano 14, no. 4 (2020): 4950–4962.

[23] Y. C. Pan, Y. X. Yu, X. Y. Hu, H. B. Li, and D. S. Guo, “Supramolecular Antidote to Macromolecular Toxins Prepared Through Co-Assembly of Macrocyclic Amphiphiles,” Advanced Materials 33, no. 40 (2021): 2104310.

[24] A. T. Brockett, W. Xue, D. King, et al., “Pillar[6]MaxQ: A Potent Supramolecular Host for In Vivo Sequestration of Methamphetamine and Fentanyl,” Chem 9, no. 4 (2023): 881–900.

[25] L. Chen, J. Chen, F. Wang, et al., “Host–Guest Formulation of Carboxylatopillar[6]arene With Ergothioneine as a New Antidote for Combinational Detoxification of Paraquat,” ACS Applied Materials & Interfaces 15, no. 22 (2023): 26407–26416.

[26] Z. Q. Wang, X. Wang, and Y. W. Yang, “Pillararene-Based Supramolecular Polymers for Adsorption and Separation,” Advanced Materials 36, no. 4 (2024): 2301721.

[27] C. Y. Shi, Q. Zhang, H. Tian, and D. H. Qu, “Supramolecular Adhesive Materials From Small-Molecule Self-Assembly,” SmartMat 1, no. 1 (2020): e1012.

[28] J. Gao, J. Li, W. C. Geng, et al., “Biomarker Displacement Activation: A General Host–Guest Strategy for Targeted Phototheranostics In Vivo,” Journal of the American Chemical Society 140, no. 14 (2018): 4945–4953.

[29] S. Li, R. Ma, X. Y. Hu, et al., “Drug in Drug: A Host–Guest Formulation of Azocalixarene With Hydroxychloroquine for Synergistic Anti-Inflammation,” Advanced Materials 34, no. 32 (2022): 2203765.

[30] Z. Qi, Q. Wang, H. Xu, Y. Lei, X. Li, and D. H. Qu, “Dynamic Hydrogel via Temporally Controlled Supramolecular Host–Guest Complex Crosslinkers for Information Self-Erasing Materials,” Materials Today 76, no. 76 (2024): 64–71.

[31] L. Yue, K. Yang, X. Y. Lou, Y. W. Yang, and R. Wang, “Versatile Roles of Macrocycles in Organic-Inorganic Hybrid Materials for Biomedical Applications,” Matter 3, no. 5 (2020): 1557–1588.

[32] C. L. Deng, S. L. Murkli, and L. D. Isaacs, “Supramolecular Hosts as In Vivo Sequestration Agents for Pharmaceuticals and Toxins,” Chemical Society Reviews 49, no. 21 (2020): 7516–7532.

[33] Z. Li and Y. W. Yang, “Functional Materials With Pillarene Struts,” Accounts of Materials Research 2, no. 4 (2021): 292–305.

[34] Z. Y. Zhang and C. Li, “Biphen[n]arenes: Modular Synthesis, Customizable Cavity Sizes, and Diverse Skeletons,” Accounts of Chemical Research 55, no. 6 (2022): 916–929.

[35] K. Xu, Z. Y. Zhang, C. Yu, et al., “A Modular Synthetic Strategy for Functional Macrocycles,” Angewandte Chemie International Edition 59, no. 18 (2020): 7214–7218.

[36] L. Zhao, J. Chen, L. Tian, et al., “Supramolecular Detoxification of Macromolecular Biotoxin Through the Complexation by a Large-Sized Macrocycle,” Advanced Healthcare Materials 11, no. 14 (2022): 2200270–2200277.

[37] Z. X. Li, J. Wang, Z. Y. Ning, et al., “Synthesis of the Fluorine-Edged Macrocycle for Promoting High-Resolution Gas Chromatographic Separation,” Chemistry of Materials 36, no. 23 (2024): 11628–11634.

[38] C. M. Yu, X. Meng, X. Liu, Z. Y. Zhang, and C. Li, “Switchable Supramolecular Jalousie Constructed From a Fluorenone Macrocycle,” Chemistry of Materials 34, no. 1 (2022): 358–365.

[39] M. N. He, X. M. Zhang, X. Ran, et al., “Black Phosphorus Nanosheets Protect Neurons Degrading Aggregative α-syn and Clearing ROS in Parkinson's Disease,” Advanced Materials 36, no. 30 (2024): 2404576.

[40] Y. Wang, X. Mao, D. Li, et al., “Functional Injectable Hydrogel for Bone Regeneration: Regulation of the circSRPK1/miR-320a Axis and Targeting Multiple Osteogenic Pathways via CDH2 and Osterix Genes,” SmartMat 6, no. 1 (2025): e1319.

[41] A. Xie, G. Cheng, J. Wu, et al., “Highly BBB-Permeable Nanomedicine Reverses Neuroapoptosis and Neuroinflammation to Treat Alzheimer's Disease,” Biomaterials 312 (2025): 122749.

[42] M. Xin, T. Yu, Y. Jiang, et al., “Multi-Vital on-Skin Optoelectronic Biosensor for Assessing Regional Tissue Hemodynamics,” SmartMat 4, no. 3 (2023): e1157.

[43] Y. Z. Fan, W. Liu, Z. Yong, and R. Su, “Pre-Treatment With Tandospirone Attenuates Fentanyl-Induced Respiratory Depression Without Affecting the Analgesic Effects of Fentanyl in Rodents,” Neuroscience Letters 771 (2022): e136459.

[44] S. Buonvino, M. Ciocci, F. Nanni, I. Cacciotti, and S. Melino, “New Vegetable-Waste Biomaterials by Lupin albus L. as Cellular Scaffolds for Applications in Biomedicine and Food,” Biomaterials 293 (2023): 121984.

[45] C. Yang, X. Liao, K. Zhou, et al., “Multifunctional Nanoparticles and Collagenase Dual Loaded Thermosensitive Hydrogel System for Enhanced Tumor-Penetration, Reversed Immune Suppression and Photodynamic-Immunotherapy,” Bioactive Materials 48 (2025): 1–17.

[46] X. Zhang, D. Mehvish, and H. Yang, “Implantable and Biodegradable Closed-Loop Devices for Autonomous Electrotherapy,” SmartMat 4, no. 3 (2023): e1172.

RIGHTS & PERMISSIONS

2025 The Author(s). SmartMat published by Tianjin University and John Wiley & Sons Australia, Ltd.