A pH-responsive nanoparticle targets the neurokinin 1 receptor in endosomes to prevent chronic pain

Paulina D. Ramírez-García, Jeffri S. Retamal, Priyank Shenoy, Wendy Imlach, Matthew Sykes, Nghia Truong, Luis Constandil, Teresa Pelissier, Cameron J. Nowell, Song Y. Khor, Louis M. Layani, Chris Lumb, Daniel P. Poole, Tina Marie Lieu, Gregory D. Stewart, Quynh N. Mai, Dane D. Jensen, Rocco Latorre, Nicole N. Scheff, Brian L. SchmidtJohn F. Quinn, Michael R. Whittaker, Nicholas A. Veldhuis, Thomas P. Davis, Nigel W. Bunnett

Research output: Contribution to journalArticlepeer-review

Abstract

Nanoparticle-mediated drug delivery is especially useful for targets within endosomes because of the endosomal transport mechanisms of many nanomedicines within cells. Here, we report the design of a pH-responsive, soft polymeric nanoparticle for the targeting of acidified endosomes to precisely inhibit endosomal signalling events leading to chronic pain. In chronic pain, the substance P (SP) neurokinin 1 receptor (NK1R) redistributes from the plasma membrane to acidified endosomes, where it signals to maintain pain. Therefore, the NK1R in endosomes provides an important target for pain relief. The pH-responsive nanoparticles enter cells by clathrin- and dynamin-dependent endocytosis and accumulate in NK1R-containing endosomes. Following intrathecal injection into rodents, the nanoparticles, containing the FDA-approved NK1R antagonist aprepitant, inhibit SP-induced activation of spinal neurons and thus prevent pain transmission. Treatment with the nanoparticles leads to complete and persistent relief from nociceptive, inflammatory and neuropathic nociception and offers a much-needed non-opioid treatment option for chronic pain.

Original languageEnglish (US)
Pages (from-to)1150-1159
Number of pages10
JournalNature Nanotechnology
Volume14
Issue number12
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Bioengineering
  • Atomic and Molecular Physics, and Optics
  • Biomedical Engineering
  • Materials Science(all)
  • Condensed Matter Physics
  • Electrical and Electronic Engineering

Fingerprint Dive into the research topics of 'A pH-responsive nanoparticle targets the neurokinin 1 receptor in endosomes to prevent chronic pain'. Together they form a unique fingerprint.

Cite this