@article{ecfb227a1bf44310ab588d73400b3ccb,
title = "A pH-responsive nanoparticle targets the neurokinin 1 receptor in endosomes to prevent chronic pain",
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.",
author = "Ram{\'i}rez-Garc{\'i}a, {Paulina D.} and Retamal, {Jeffri S.} and Priyank Shenoy and Wendy Imlach and Matthew Sykes and Nghia Truong and Luis Constandil and Teresa Pelissier and Nowell, {Cameron J.} and Khor, {Song Y.} and Layani, {Louis M.} and Chris Lumb and Poole, {Daniel P.} and Lieu, {Tina Marie} and Stewart, {Gregory D.} and Mai, {Quynh N.} and Jensen, {Dane D.} and Rocco Latorre and Scheff, {Nicole N.} and Schmidt, {Brian L.} and Quinn, {John F.} and Whittaker, {Michael R.} and Veldhuis, {Nicholas A.} and Davis, {Thomas P.} and Bunnett, {Nigel W.}",
note = "Funding Information: Research in N.A.V.'s, D.P.P.{\textquoteright}s and N.W.B.{\textquoteright}s laboratories is funded, in part, by Takeda Pharmaceuticals. N.W.B. is a founding scientist of Endosome Therapeutics. Funding Information: This work was supported by the National Institutes of Health (NS102722, DE026806, DK118971), the Department of Defense (PR170507), the National Health and Medical Research Council (63303, 1049682, 1031886; N.W.B.), the Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology (N.W.B. and T.P.D.), the Center for the Development of Nanoscience and Nanotechnology (CEDENNA, Fondecyt no. 1181622, L.C.) and Takeda Pharmaceuticals Inc. (N.W.B., N.A.V and D.P.P.). We thank F. Chiu for mass spectrometry analysis of aprepitant loading and P. Zhao for advice about signalling assays. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2019",
month = dec,
day = "1",
doi = "10.1038/s41565-019-0568-x",
language = "English (US)",
volume = "14",
pages = "1150--1159",
journal = "Nature Nanotechnology",
issn = "1748-3387",
publisher = "Nature Publishing Group",
number = "12",
}