Covalent Poly(lactic acid) Nanoparticles for the Sustained Delivery of Naloxone

Andrew J. Kassick, Heather N. Allen, Saigopalakrishna S. Yerneni, Fathima Pary, Marina Kovaliov, Cooper Cheng, Marco Pravetoni, Nestor D. Tomycz, Donald M. Whiting, Toby L. Nelson, Michael Feasel, Phil G. Campbell, Benedict Kolber, Saadyah Averick

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

The opioid epidemic currently plaguing the United States has been exacerbated by an alarming rise in fatal overdoses as a result of the proliferated abuse of synthetic mu opioid receptor (MOR) agonists, such as fentanyl and its related analogues. Attempts to manage this crisis have focused primarily on widespread distribution of the clinically approved opioid reversal agent naloxone (Narcan); however, due to the intrinsic metabolic lability of naloxone, these measures have demonstrated limited effectiveness against synthetic opioid toxicity. This work reports a novel polymer-based strategy to create a long-acting formulation of naloxone with the potential to address this critical issue by utilizing covalent nanoparticle (cNP) drug delivery technology. Covalently loaded naloxone nanoparticles (Nal-cNPs) were prepared via the naloxone-initiated, ring-opening polymerization (ROP) of l-lactide in the presence of a bifunctional thiourea organocatalyst with subsequent precipitation of the resulting naloxone-poly(l-lactic acid) polymer. This protocol afforded well-defined nanoparticles possessing a drug loading of approximately 7% w/w. The resulting Nal-cNPs demonstrated excellent biocompatibility, while exhibiting sustained linear release kinetics in vitro and blocking the effects of high dose (10 mg/kg) acute morphine for up to 98 h in an in vivo rodent model of neuropathic pain.

Original languageEnglish (US)
Pages (from-to)3418-3428
Number of pages11
JournalACS Applied Bio Materials
Volume2
Issue number8
DOIs
StatePublished - Aug 19 2019

Bibliographical note

Funding Information:
We gratefully acknowledge The Army Research Office (award no. 68271-CH) Young Investigator Program (W911NF-17-1-0015) and the Neuroscience Institute at AHN for funding. NMR measurements and instrumentation at CMU, which was partially supported by NSF (CHE-0130903 and CHE-1039870), the National Institutes of Health (UL1TR001857) and through a Pain Research Challenge Grant (to B.J.K. and H.N.A.), were supported by the Clinical and Translational Science Institute at the University of Pittsburgh.

Publisher Copyright:
© 2019 American Chemical Society.

Keywords

  • controlled release
  • covalent nanoparticles
  • drug delivery
  • naloxone
  • ring-opening polymerization

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