Journal
NATURE NANOTECHNOLOGY
Volume 14, Issue 12, Pages 1150-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41565-019-0568-x
Keywords
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Funding
- National Institutes of Health [NS102722, DE026806, DK118971]
- Department of Defense [PR170507]
- National Health and Medical Research Council [63303, 1049682, 1031886]
- Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology
- Center for the Development of Nanoscience and Nanotechnology (CEDENNA, Fondecyt) [1181622]
- Takeda Pharmaceuticals Inc.
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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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