@article{9e8d6ec62f564004830f8a7f8d692406,
title = "Sustained endosomal release of a neurokinin-1 receptor antagonist from nanostars provides long-lasting relief of chronic pain",
abstract = "Soft polymer nanoparticles designed to disassemble and release an antagonist of the neurokinin 1 receptor (NK1R) in endosomes provide efficacious yet transient relief from chronic pain. These micellar nanoparticles are unstable and rapidly release cargo, which may limit the duration of analgesia. We examined the efficacy of stable star polymer nanostars containing the NK1R antagonist aprepitant-amine for the treatment of chronic pain in mice. Nanostars continually released cargo for 24 h, trafficked through the endosomal system, and disrupted NK1R endosomal signaling. After intrathecal injection, nanostars accumulated in endosomes of spinal neurons. Nanostar-aprepitant reversed mechanical, thermal and cold allodynia and normalized nociceptive behavior more efficaciously than free aprepitant in preclinical models of neuropathic and inflammatory pain. Analgesia was maintained for >10 h. The sustained endosomal delivery of antagonists from slow-release nanostars provides effective and long-lasting reversal of chronic pain.",
keywords = "Endosomes, Nociception, Pain, Receptors, Signal transduction",
author = "Rocco Latorre and Ram{\'i}rez-Garcia, {Paulina D.} and Alan Hegron and Grace, {James L.} and Retamal, {Jeffri S.} and Priyank Shenoy and Mai Tran and Luigi Aurelio and Bernard Flynn and Poole, {Daniel P.} and Rafael Klein-Cloud and Jensen, {Dane D.} and Davis, {Thomas P.} and Schmidt, {Brian L.} and Quinn, {John F.} and Whittaker, {Michael R.} and Veldhuis, {Nicholas A.} and Bunnett, {Nigel W.}",
note = "Funding Information: Supported by grants from: National Institutes of Health ( NS102722 , DE026806 , DK118971 , DE029951 , NWB, BLS) and Department of Defense ( W81XWH1810431 , W81XWH-22-1-0239 , Expansion Award, NWB, BLS). We thank Eric Le for help with Ca 2+ mobilization assays and Joseph B. Guttenplan and Shavonne Teng for help with the HPLC analysis of AP-NH 2 . Funding Information: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nigel W. Bunnett reports financial support was provided by Endosome Therapeutics Inc and Takeda Pharmaceuticals International. Nigel W Bunnett reports a relationship with Endosome Therapeutics Inc and Takeda Pharmaceuticals International that includes: board membership, equity or stocks, funding grants, and travel reimbursement. Declaration of competing interest. NWB is a founding scientist of Endosome Therapeutics Inc. Research in NWB's laboratory is funded, in part, by Takeda Pharmaceuticals International. Publisher Copyright: {\textcopyright} 2022 Elsevier Ltd",
year = "2022",
month = jun,
doi = "10.1016/j.biomaterials.2022.121536",
language = "English",
volume = "285",
journal = "Biomaterials",
issn = "0142-9612",
publisher = "Elsevier BV",
}