IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-55945-4.html
   My bibliography  Save this article

Development and preclinical testing of a naloxone prodrug depot for extended protection against opioid overdose

Author

Listed:
  • Hala Aldawod

    (University of the Pacific)

  • Arjun D. Patel

    (University of the Pacific)

  • Rasha Emara

    (University of the Pacific)

  • Dengpan Liang

    (University of the Pacific)

  • Joshua S. Ho

    (University of the Pacific)

  • Toufiq Ul Amin

    (University of the Pacific)

  • Md Tariqul Haque Tuhin

    (University of the Pacific)

  • Abdulmalek Balgoname

    (University of the Pacific)

  • Avishan Kiani

    (University of the Pacific)

  • Jumana M. Ajlouny

    (University of the Pacific)

  • Melanie A. Felmlee

    (University of the Pacific)

  • Miki S. Park

    (University of the Pacific)

  • Bhaskara R. Jasti

    (University of the Pacific)

  • William K. Chan

    (University of the Pacific)

  • James A. Uchizono

    (University of the Pacific)

  • Mamoun M. Alhamadsheh

    (University of the Pacific)

Abstract

The opioid crisis, driven by synthetic opioids like fentanyl, demands innovative solutions. The opioid antidote naloxone has a short action ( ~ 1 hour), requiring repeated doses. To address this, we present a new and simple naloxone prodrug delivery system repurposing a hydrophilic derivative of acoramidis, a potent transthyretin ligand. When the fully soluble prodrug solution is administered subcutaneously, the prodrug forms a zwitterionic depot at physiological pH, enabling extended naloxone release. This non-polymeric depot-forming approach is rare and employs carboxylesterase 2 for selective bioactivation, ensuring controlled drug release. In male rats and cynomolgus monkeys, a single subcutaneous dose provides steady naloxone release over several days, reducing blood-brain barrier diffusion, withdrawal symptoms, and CNS toxicity. Preclinical studies demonstrated efficacy in rat overdose models and achieved monkey naloxone levels matching effective human therapeutic levels. Although monkey efficacy was not assessed, combined rat efficacy and monkey pharmacokinetics suggest strong potential for successful human translation.

Suggested Citation

  • Hala Aldawod & Arjun D. Patel & Rasha Emara & Dengpan Liang & Joshua S. Ho & Toufiq Ul Amin & Md Tariqul Haque Tuhin & Abdulmalek Balgoname & Avishan Kiani & Jumana M. Ajlouny & Melanie A. Felmlee & M, 2025. "Development and preclinical testing of a naloxone prodrug depot for extended protection against opioid overdose," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-55945-4
    DOI: 10.1038/s41467-025-55945-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-55945-4
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-55945-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Paul T. Bremer & Emily L. Burke & Andrew C. Barrett & Rajeev I. Desai, 2023. "Investigation of monoclonal antibody CSX-1004 for fentanyl overdose," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Ingrid A. Binswanger & Jason M. Glanz, 2018. "Potential Risk Window for Opioid Overdose Related to Treatment with Extended-Release Injectable Naltrexone," Drug Safety, Springer, vol. 41(10), pages 979-980, October.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.

      More about this item

      Statistics

      Access and download statistics

      Corrections

      All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-55945-4. See general information about how to correct material in RePEc.

      If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

      If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

      If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

      For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

      Please note that corrections may take a couple of weeks to filter through the various RePEc services.

      IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.