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. Schmidt; John F. Quinn; Michael R. Whittaker; Nicholas A. Veldhuis; Thomas P. Davis; Nigel W. Bunnett

doi:10.1038/s41565-019-0568-x

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 journal › Article › peer-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 language	English (US)
Pages (from-to)	1150-1159
Number of pages	10
Journal	Nature Nanotechnology
Volume	14
Issue number	12
DOIs	https://doi.org/10.1038/s41565-019-0568-x
State	Published - Dec 1 2019

ASJC Scopus subject areas

Bioengineering
Atomic and Molecular Physics, and Optics
Biomedical Engineering
General Materials Science
Condensed Matter Physics
Electrical and Electronic Engineering

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10.1038/s41565-019-0568-x

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Ramírez-García, P. D., Retamal, J. S., Shenoy, P., Imlach, W., Sykes, M., Truong, N., Constandil, L., Pelissier, T., Nowell, C. J., Khor, S. Y., Layani, L. M., Lumb, C., Poole, D. P., Lieu, T. M., Stewart, G. D., Mai, Q. N., Jensen, D. D., Latorre, R., Scheff, N. N., ... Bunnett, N. W. (2019). A pH-responsive nanoparticle targets the neurokinin 1 receptor in endosomes to prevent chronic pain. Nature Nanotechnology, 14(12), 1150-1159. https://doi.org/10.1038/s41565-019-0568-x

Ramírez-García, PD, Retamal, JS, Shenoy, P, Imlach, W, Sykes, M, Truong, N, Constandil, L, Pelissier, T, Nowell, CJ, Khor, SY, Layani, LM, Lumb, C, Poole, DP, Lieu, TM, Stewart, GD, Mai, QN, Jensen, DD, Latorre, R, Scheff, NN, Schmidt, BL, Quinn, JF, Whittaker, MR, Veldhuis, NA, Davis, TP & Bunnett, NW 2019, 'A pH-responsive nanoparticle targets the neurokinin 1 receptor in endosomes to prevent chronic pain', Nature Nanotechnology, vol. 14, no. 12, pp. 1150-1159. https://doi.org/10.1038/s41565-019-0568-x

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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.}",

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doi = "10.1038/s41565-019-0568-x",

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AU - Ramírez-García, Paulina D.

AU - Retamal, Jeffri S.

AU - Shenoy, Priyank

AU - Imlach, Wendy

AU - Sykes, Matthew

AU - Truong, Nghia

AU - Constandil, Luis

AU - Pelissier, Teresa

AU - Nowell, Cameron J.

AU - Khor, Song Y.

AU - Layani, Louis M.

AU - Lumb, Chris

AU - Poole, Daniel P.

AU - Lieu, Tina Marie

AU - Stewart, Gregory D.

AU - Mai, Quynh N.

AU - Jensen, Dane D.

AU - Latorre, Rocco

AU - Scheff, Nicole N.

AU - Schmidt, Brian L.

AU - Quinn, John F.

AU - Whittaker, Michael R.

AU - Veldhuis, Nicholas A.

AU - Davis, Thomas P.

AU - Bunnett, Nigel W.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

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

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