| Literature DB >> 31686009 |
Paulina D Ramírez-García1,2, Jeffri S Retamal1,2, Priyank Shenoy1,2, Wendy Imlach3, Matthew Sykes3, Nghia Truong1,2, Luis Constandil4, Teresa Pelissier4, Cameron J Nowell1, Song Y Khor1,2, Louis M Layani1,2, Chris Lumb1,2, Daniel P Poole1,2, TinaMarie Lieu1,2, Gregory D Stewart1, Quynh N Mai1,2, Dane D Jensen5, Rocco Latorre5, Nicole N Scheff6, Brian L Schmidt6, John F Quinn1,2, Michael R Whittaker1,2, Nicholas A Veldhuis7,8, Thomas P Davis9,10,11, Nigel W Bunnett12,13,14,15.
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.Entities:
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Year: 2019 PMID： 31686009 DOI： 10.1038/s41565-019-0568-x
Source DB: PubMed Journal: Nat Nanotechnol ISSN： 1748-3387 Impact factor: 39.213