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

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, Miki S. Park, Bhaskara R. Jasti, William K. Chan, James A. Uchizono and Mamoun M. Alhamadsheh (malhamadsheh@pacific.edu)
Additional contact information
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

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-55945-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-55945-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-55945-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla (sonal.shukla@springer.com) and Springer Nature Abstracting and Indexing (indexing@springernature.com).