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

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 inh...

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Bibliographic Details
Published in:	Nature nanotechnology Vol. 14; no. 12; pp. 1150 - 1159
Main Authors:	Ramírez-García, Paulina D., Retamal, Jeffri S., Shenoy, Priyank, Imlach, Wendy, Sykes, Matthew, Truong, Nghia, Constandil, Luis, Pelissier, Teresa, Nowell, Cameron J., Khor, Song Y., Layani, Louis M., Lumb, Chris, Poole, Daniel P., Lieu, TinaMarie, Stewart, Gregory D., Mai, Quynh N., Jensen, Dane D., Latorre, Rocco, Scheff, Nicole N., Schmidt, Brian L., Quinn, John F., Whittaker, Michael R., Veldhuis, Nicholas A., Davis, Thomas P., Bunnett, Nigel W.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-12-2019 Nature Publishing Group
Subjects:	631/61 631/61/350/354 Acidification Animals Aprepitant - administration & dosage Aprepitant - pharmacokinetics Aprepitant - therapeutic use Cell Line Chemistry and Materials Science Chronic pain Chronic Pain - drug therapy Chronic Pain - metabolism Clathrin Delayed-Action Preparations - metabolism Drug delivery Drug Delivery Systems Dynamin Endocytosis Endosomes Endosomes - metabolism HEK293 Cells Humans Hydrogen-Ion Concentration Inflammation Male Materials Science Mice, Inbred C57BL Nanoparticles Nanoparticles - metabolism Nanotechnology Nanotechnology and Microengineering Neurokinin Neurokinin NK1 receptors Neurokinin-1 Receptor Antagonists - administration & dosage Neurokinin-1 Receptor Antagonists - pharmacokinetics Neurokinin-1 Receptor Antagonists - therapeutic use Opioids Pain Pain perception pH effects Rats Receptors, Neurokinin-1 - metabolism Substance P
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Summary:	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 (NK 1 R) redistributes from the plasma membrane to acidified endosomes, where it signals to maintain pain. Therefore, the NK 1 R in endosomes provides an important target for pain relief. The pH-responsive nanoparticles enter cells by clathrin- and dynamin-dependent endocytosis and accumulate in NK 1 R-containing endosomes. Following intrathecal injection into rodents, the nanoparticles, containing the FDA-approved NK 1 R 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. A pH-responsive, soft polymeric nanoparticle targets the neurokinin 1 receptor in acidified endosomes to inhibit signalling events leading to chronic pain.
Bibliography:	P.D.R.-G. prepared and characterized nanoparticles, examined nanoparticle uptake and disassembly, studied SP signalling in model cells and wrote the manuscript. J.S.R. studied the biodistribution and anti-nociceptive and in vivo electrophysiological actions of nanoparticles. P.S. studied the biodistribution and anti-nociceptive actions of nanoparticles. W.I. conceived and designed electrophysiological studies on spinal neurons. M.S. studied the excitation of spinal neurons, and N.T. prepared and characterized nanoparticles. L.C. conceived and designed neuropathic nociception and in vivo electrophysiological studies. T.P. conceived and designed neuropathic nociception. C.J.N. provided expertise in the analysis of confocal images and S.Y.K. obtained transmission electron microscopy images. L.M.L. characterized the critical micellar concentration and pH-disassembly of nanoparticles. C.L. studied SP signalling in model cells and D.P.P. studied nanoparticle uptake. T.M.L. studied anti-nociceptive actions of nanoparticles, G.D.S. prepared striatal neurons, and Q.N.M. prepared and characterized nanoparticles. D.D.J. examined NK1R endocytosis, nanoparticle uptake into spinal neurons, and SP signalling in model cells and striatal neurons. R.L. examined NK1R endocytosis and nanoparticle uptake into spinal neurons. N.S.N. studied NK1R endocytosis in rats. B.L.S. designed experiments to examine NK1R endocytosis in rats. J.F.Q. designed nanoparticles and wrote the manuscript. M.R.W. designed nanoparticles. N.A.V. conceived experiments, studied SP signalling in neurons, interpreted the results and wrote the manuscript. T.P.D. conceived the experiments and designed the nanoparticles. N.W.B. conceived and designed the experiments, interpreted the results and wrote the manuscript. Author contributions
ISSN:	1748-3387 1748-3395
DOI:	10.1038/s41565-019-0568-x