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 |
|---|---|
| Number of pages | 10 |
| Journal | Nature Nanotechnology |
| DOIs | |
| Publication status | Accepted/In press - 4 Nov 2019 |
Keywords
- biotechnology
- nanoparticles
Cite this
}
A pH-responsive nanoparticle targets the neurokinin 1 receptor in endosomes to prevent chronic pain. / Ramirez Garcia, 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.
In: Nature Nanotechnology, 04.11.2019.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - A pH-responsive nanoparticle targets the neurokinin 1 receptor in endosomes to prevent chronic pain
AU - Ramirez Garcia, 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, TinaMarie
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 - 2019/11/4
Y1 - 2019/11/4
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.
AB - 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.
KW - biotechnology
KW - nanoparticles
UR - http://www.scopus.com/inward/record.url?scp=85074752061&partnerID=8YFLogxK
U2 - 10.1038/s41565-019-0568-x
DO - 10.1038/s41565-019-0568-x
M3 - Article
JO - Nature Nanotechnology
JF - Nature Nanotechnology
SN - 1748-3387
ER -