• Transcranial ultrasound combin...

Treffer: Transcranial ultrasound combined with intravenous metformin-loaded oxygenated microbubbles attenuates noise-induced hearing loss in mice.

Title:
Transcranial ultrasound combined with intravenous metformin-loaded oxygenated microbubbles attenuates noise-induced hearing loss in mice.
Authors:
Liao AH; Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei, Taiwan.; Department of Biomedical Engineering, National Defense Medical University, Taipei, Taiwan., Wang CH; Department of Otolaryngology, Taipei City Hospital, Taipei, Taiwan.; Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan.; Graduate Institute of Medical Sciences, National Defense Medical University, Taipei, Taiwan., Chou LY; Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei, Taiwan., Hung YC; Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei, Taiwan., Lin YC; Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan., Chuang HC; Department of Mechanical Engineering, National Taipei University of Technology, Taipei, Taiwan., Ma KH; Department of Biology and Anatomy, National Defense Medical University, Taipei, Taiwan., Liu HL; Department of Electrical Engineering, National Taiwan University, Taipei, Taiwan., Wang JK; Department of Biochemistry, National Defense Medical University, Taipei, Taiwan., Shih CP; Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical University, Taipei, Taiwan.
Source:
Drug delivery [Drug Deliv] 2025 Dec 31; Vol. 32 (1), pp. 2576220. Date of Electronic Publication: 2025 Nov 05.
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: Taylor & Francis Country of Publication: England NLM ID: 9417471 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0464 (Electronic) Linking ISSN: 10717544 NLM ISO Abbreviation: Drug Deliv Subsets: MEDLINE
Imprint Name(s):
Publication: 2015->: Abingdon, Oxford : Taylor & Francis
Original Publication: Orlando, FL : Academic Press, c1993-
MeSH Terms:
Metformin*/administration & dosage , Metformin*/pharmacology , Hearing Loss, Noise-Induced*/drug therapy , Microbubbles* , Oxygen*/metabolism , Oxygen*/chemistry , Oxygen*/administration & dosage, Animals ; Mice ; Reactive Oxygen Species/metabolism ; Male ; Cochlea/drug effects ; Cochlea/metabolism ; Evoked Potentials, Auditory, Brain Stem/drug effects ; Oxidative Stress/drug effects ; Disease Models, Animal ; Mice, Inbred C57BL ; Hair Cells, Auditory, Outer/drug effects
References:
Front Pharmacol. 2021 Jun 28;12:689032. (PMID: 34262458)
Neuroreport. 2005 May 31;16(8):799-802. (PMID: 15891573)
Otolaryngol Head Neck Surg. 2019 Aug;161(1_suppl):S1-S45. (PMID: 31369359)
Brain Res Bull. 2025 Feb;221:111214. (PMID: 39826756)
EXCLI J. 2020 Aug 05;19:1124-1140. (PMID: 33088250)
Otol Neurotol. 2023 Oct 1;44(9):956-963. (PMID: 37641232)
Neuroreport. 2002 Dec 20;13(18):2459-62. (PMID: 12499849)
Theranostics. 2016 Apr 11;6(6):817-27. (PMID: 27162552)
Hear Res. 2003 Aug;182(1-2):2-8. (PMID: 12948595)
Sci Rep. 2018 May 29;8(1):8327. (PMID: 29844469)
Hear Res. 2000 Mar;141(1-2):199-219. (PMID: 10713508)
Front Cell Neurosci. 2019 Apr 24;13:155. (PMID: 31068792)
J Control Release. 2023 Apr;356:481-492. (PMID: 36921723)
Mol Neurobiol. 2023 Feb;60(2):629-642. (PMID: 36334193)
J Control Release. 2021 Mar 10;331:376-389. (PMID: 33508351)
Langmuir. 2022 May 3;38(17):5040-5051. (PMID: 34096296)
Otolaryngol Head Neck Surg. 2023 Jun;168(6):1389-1400. (PMID: 36939574)
J Neuroinflammation. 2019 Jul 27;16(1):156. (PMID: 31351490)
J Assoc Res Otolaryngol. 2014 Apr;15(2):149-58. (PMID: 24297263)
Am J Otolaryngol. 2020 Jan - Feb;41(1):102328. (PMID: 31732304)
JCI Insight. 2020 Feb 13;5(3):. (PMID: 31895697)
Biochem Biophys Res Commun. 2018 Sep 5;503(2):665-670. (PMID: 29908183)
Nanotheranostics. 2024 Mar 9;8(3):285-297. (PMID: 38577322)
Audiol Neurootol. 1999 Sep-Oct;4(5):219-28. (PMID: 10436314)
Adv Drug Deliv Rev. 2024 Jan;204:115145. (PMID: 38042259)
Neurosci Lett. 2010 Aug 2;479(3):249-52. (PMID: 20561939)
Diab Vasc Dis Res. 2019 Jul;16(4):324-327. (PMID: 30712377)
PLoS One. 2020 May 21;15(5):e0232617. (PMID: 32438389)
ACS Nano. 2023 Dec 26;17(24):25157-25174. (PMID: 38063490)
Hear Res. 2015 Sep;327:58-68. (PMID: 25987500)
J Control Release. 2013 Apr 28;167(2):167-74. (PMID: 23391441)
J Neurophysiol. 2021 Apr 1;125(4):1202-1212. (PMID: 33625942)
Sci Transl Med. 2019 Mar 6;11(482):. (PMID: 30842313)
Neuroreport. 2010 Oct 27;21(15):968-75. (PMID: 20802354)
Pharmaceuticals (Basel). 2023 Aug 09;16(8):. (PMID: 37631036)
Perfusion. 2014 Nov;29(6):539-43. (PMID: 24803489)
Ann N Y Acad Sci. 1999 Nov 28;884:226-32. (PMID: 10842596)
Semin Respir Crit Care Med. 2016 Feb;37(1):16-22. (PMID: 26820270)
J Control Release. 2024 Aug;372:318-330. (PMID: 38906419)
Sci Rep. 2017 Jan 24;7:41325. (PMID: 28117399)
Hear Res. 2016 May;335:105-117. (PMID: 26930622)
J Biomed Mater Res B Appl Biomater. 2021 Nov;109(11):1796-1806. (PMID: 33838006)
J Neurosci. 2008 Jan 30;28(5):1236-45. (PMID: 18234901)
Ultrasound Med Biol. 2018 Feb;44(2):416-425. (PMID: 29174042)
Nanotheranostics. 2020 Feb 28;4(2):83-90. (PMID: 32190535)
Biomater Sci. 2021 Mar 21;9(6):2082-2089. (PMID: 33475656)
Eur Arch Otorhinolaryngol. 2018 Dec;275(12):2957-2966. (PMID: 30306316)
J Comp Neurol. 2003 Feb 3;456(2):105-11. (PMID: 12509868)
J Biomol Struct Dyn. 2015;33(3):513-33. (PMID: 24720899)
Front Pharmacol. 2021 Apr 27;12:668754. (PMID: 33986689)
Cell Tissue Res. 2021 Nov;386(2):239-247. (PMID: 34155579)
Contributed Indexing:
Keywords: Blood–labyrinthine barrier; hearing loss; ischemia; metformin; oxidative stress; oxygenated microbubbles; ultrasound
Substance Nomenclature:
9100L32L2N (Metformin)
0 (Reactive Oxygen Species)
S88TT14065 (Oxygen)
Entry Date(s):
Date Created: 20251106 Date Completed: 20251106 Latest Revision: 20251112
Update Code:
20251112
PubMed Central ID:
PMC12599344
DOI:
10.1080/10717544.2025.2576220
PMID:
41194422
Database:
MEDLINE

Weitere Informationen

Noise-induced hearing loss (NIHL) involves a biphasic pathophysiology. Intense noise exposure causes immediate cochlear vasoconstriction and ischemia, leading to transient hypoxia. Subsequent reperfusion triggers excess reactive oxygen species (ROS) production, resulting in oxidative stress and hair cell injury. This study therefore developed two oxygenated albumin microbubble (OMB) formulations-ionic-bond metformin-coated (iMet-OMBs) and covalent-bond metformin-encapsulated (cMet-OMBs)-and combined them with transcranial ultrasound (US) to enhance targeted delivery to the cochlea. This approach aims to provide transient oxygen supplementation while simultaneously reducing ROS-mediated injury. Microbubbles were characterized for morphology, oxygen loading, and metformin content. Based on their superior stability and drug-loading profile, cMet-OMBs were selected for in vivo evaluation. In a mouse NIHL model, animals were administered cMet-OMBs systemically via retro-orbital injection, followed by US triggering over the temporal bone. Auditory brainstem response (ABR) thresholds, cochlear oxygen tension, and outer hair cell (OHC) survival were assessed. US-mediated cMet-OMBs rupture transiently increased intracochlear oxygen tension, counteracting early hypoxia after noise exposure. Metformin released from cMet-OMBs attenuated ROS production through mitochondrial complex I inhibition and antioxidant pathway activation. Mice treated with cMet-OMBs + US showed significantly lower ABR threshold shifts and better OHC preservation compared with controls. This dual-action strategy combines transient oxygen supplementation from OMBs with sustained antioxidant protection from metformin. While oxygen delivery raises intracochlear oxygen tension, metformin suppresses ROS generation through mitochondrial complex I inhibition and AMPK/Nrf2 activation. This controlled, US-triggered release achieves net cochlear protection against NIHL without excessive oxidative burden.