Development and preclinical testing of a naloxone prodrug depot for extended protection against opioid overdose
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 derivati...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55945-4 |
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| author | 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 Mamoun M. Alhamadsheh |
| author_facet | 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 Mamoun M. Alhamadsheh |
| author_sort | Hala Aldawod |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-f716c7d929e74f248d449573822994c2 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-f716c7d929e74f248d449573822994c22025-01-26T12:41:44ZengNature PortfolioNature Communications2041-17232025-01-0116111810.1038/s41467-025-55945-4Development and preclinical testing of a naloxone prodrug depot for extended protection against opioid overdoseHala Aldawod0Arjun D. Patel1Rasha Emara2Dengpan Liang3Joshua S. Ho4Toufiq Ul Amin5Md Tariqul Haque Tuhin6Abdulmalek Balgoname7Avishan Kiani8Jumana M. Ajlouny9Melanie A. Felmlee10Miki S. Park11Bhaskara R. Jasti12William K. Chan13James A. Uchizono14Mamoun M. Alhamadsheh15Department of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy, University of the PacificDepartment of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy, University of the PacificDepartment of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy, University of the PacificDepartment of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy, University of the PacificDepartment of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy, University of the PacificDepartment of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy, University of the PacificDepartment of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy, University of the PacificDepartment of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy, University of the PacificDepartment of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy, University of the PacificDepartment of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy, University of the PacificDepartment of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy, University of the PacificDepartment of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy, University of the PacificDepartment of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy, University of the PacificDepartment of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy, University of the PacificDepartment of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy, University of the PacificDepartment of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy, University of the PacificAbstract 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.https://doi.org/10.1038/s41467-025-55945-4 |
| spellingShingle | 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 Mamoun M. Alhamadsheh Development and preclinical testing of a naloxone prodrug depot for extended protection against opioid overdose Nature Communications |
| title | Development and preclinical testing of a naloxone prodrug depot for extended protection against opioid overdose |
| title_full | Development and preclinical testing of a naloxone prodrug depot for extended protection against opioid overdose |
| title_fullStr | Development and preclinical testing of a naloxone prodrug depot for extended protection against opioid overdose |
| title_full_unstemmed | Development and preclinical testing of a naloxone prodrug depot for extended protection against opioid overdose |
| title_short | Development and preclinical testing of a naloxone prodrug depot for extended protection against opioid overdose |
| title_sort | development and preclinical testing of a naloxone prodrug depot for extended protection against opioid overdose |
| url | https://doi.org/10.1038/s41467-025-55945-4 |
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