A Covalent Poly(Lactic Acid) Naloxone Nanoparticle Reduces Fentanyl-Induced Poisoning In Rats

Accidental and deliberate exposure to fentanyl and related synthetic opioid analogs are the primary catalysts behind the exponential rise in opioid-related fatal overdose in the US and worldwide. These synthetic opioids are either misused or added as adulterants in counterfeit prescription opioid and non-opioid medications. Although the opioid antagonist naloxone (NLX) is very effective at reversing opioid overdose, multiple doses of NLX may need to be administered to avoid renarcotization and death due to the apparent rapid metabolism of NLX compared to synthetic opioids. To circumvent this shortcoming of NLX and provide greater protection against overdose, this study developed covalent poly(lactic acid-co-glycolic acid) naloxone nanoparticle (NP-NLX) as a delivery platform for sustained-release of naloxone. In the current study, rats were exposed to repeated subcutaneous challenges of fentanyl at 0, 4, 24, and 48 hr timepoints and tested for respiratory depression via oximetry and antinociception via the hotplate test of central analgesia. Immediately following testing only after the t=0 hr timepoint, rats were rescued using either NLX or NP-NLX and tested 15 minutes later on the oximeter and hotplate. During all subsequent timepoints, rats did not receive NLX or NP-NLX. Data showed that NP-NLX was as effective as NLX at reversing fentanyl-induced effects 15 minutes after the initial fentanyl exposure. However, no effect of fentanyl was seen during subsequent fentanyl treatments due to the establishment of tolerance. To circumvent fentanyl-induced tolerance and to demonstrate efficacy at later timepoints, an independent follow-up study involved rats receiving NLX or NP-NLX 0 hr, but not fentanyl. Fentanyl challenges at subsequent timepoints showed that NP-NLX protected against fentanyl effects during the 4 and 24 hr timepoints, while NLX did not. These results suggest that NP-NLX could be an effective alternative to NLX to reverse fentanyl-induced overdose and prevent renarcotization, and that covalent poly(lactic acid-co-glycolic acid) nanoparticles are an attractive delivery platform for opioid antagonists or other small molecules used in treatment of toxicity.