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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All data generated or analysed during this study are available in this Article and its Supplementary Information or from the corresponding authors upon request.
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This work was supported by the National Institutes of Health (NS102722, DE026806, DK118971), the Department of Defense (PR170507), the National Health and Medical Research Council (63303, 1049682, 1031886; N.W.B.), the Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology (N.W.B. and T.P.D.), the Center for the Development of Nanoscience and Nanotechnology (CEDENNA, Fondecyt no. 1181622, L.C.) and Takeda Pharmaceuticals Inc. (N.W.B., N.A.V and D.P.P.). We thank F. Chiu for mass spectrometry analysis of aprepitant loading and P. Zhao for advice about signalling assays.
Research in N.A.V.'s, D.P.P.’s and N.W.B.’s laboratories is funded, in part, by Takeda Pharmaceuticals. N.W.B. is a founding scientist of Endosome Therapeutics.
Peer review information Nature Nanotechnology thanks Jean-Pierre Vilardaga and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Methods, Supplementary Figs. 1–8, Supplementary Video titles and legends 1–7 and Supplementary refs. 1–4.
Localization of DIPMA-Cy5 nanoparticles and Rab5a-GFP in HEK-293 cells.
Localization of DIPMA-Cy5 nanoparticles and Rab7a-GFP in HEK-293 cells.
Localization of DIPMA-Cy5 nanoparticles and NK1R-GFP in HEK-293 cells.
Localization of DIPMA-Cy5 nanoparticles in the mouse dorsal horn.
Localization of BMA-Cy5 nanoparticles in the mouse dorsal horn.
Localization of NK1R-IR in the rat dorsal horn after sham surgery.
Localization of NK1R-IR in the rat dorsal horn after SNS surgery.
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Ramírez-García, P.D., Retamal, J.S., Shenoy, P. et al. A pH-responsive nanoparticle targets the neurokinin 1 receptor in endosomes to prevent chronic pain. Nat. Nanotechnol. (2019) doi:10.1038/s41565-019-0568-x