Sustained endosomal release of a neurokinin-1 receptor antagonist from nanostars provides long-lasting relief of chronic pain

Rocco Latorre; Paulina D Ramírez-Garcia; Alan Hegron; James L Grace; Jeffri S Retamal; Priyank Shenoy; Mai Tran; Luigi Aurelio; Bernard Flynn; Daniel P Poole; Rafael Klein-Cloud; Dane D Jensen; Thomas P Davis; Brian L Schmidt; John F Quinn; Michael R Whittaker; Nicholas A Veldhuis; Nigel W Bunnett

doi:10.1016/j.biomaterials.2022.121536

Sustained endosomal release of a neurokinin-1 receptor antagonist from nanostars provides long-lasting relief of chronic pain

Biomaterials. 2022 Jun:285:121536. doi: 10.1016/j.biomaterials.2022.121536. Epub 2022 Apr 28.

Authors

Rocco Latorre¹, Paulina D Ramírez-Garcia², Alan Hegron¹, James L Grace², Jeffri S Retamal², Priyank Shenoy², Mai Tran², Luigi Aurelio², Bernard Flynn², Daniel P Poole², Rafael Klein-Cloud¹, Dane D Jensen³, Thomas P Davis⁴, Brian L Schmidt⁵, John F Quinn², Michael R Whittaker⁶, Nicholas A Veldhuis⁷, Nigel W Bunnett⁸

Affiliations

¹ Department of Molecular Pathobiology, New York University, New York, 10010, USA; Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, 10010, USA.
² Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.
³ Department of Molecular Pathobiology, New York University, New York, 10010, USA; Bluestone Center for Clinical Research, New York University College of Dentistry, New York, 10010, USA.
⁴ Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, 4072, Australia.
⁵ Department of Molecular Pathobiology, New York University, New York, 10010, USA; Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, 10010, USA; Bluestone Center for Clinical Research, New York University College of Dentistry, New York, 10010, USA.
⁶ Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. Electronic address: [email protected].
⁷ Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia. Electronic address: [email protected].
⁸ Department of Molecular Pathobiology, New York University, New York, 10010, USA; Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, 10010, USA. Electronic address: [email protected].

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Animals
Aprepitant / pharmacology
Aprepitant / therapeutic use
Chronic Pain* / drug therapy
Endosomes
Mice
Neurokinin-1 Receptor Antagonists* / pharmacology
Neurokinin-1 Receptor Antagonists* / therapeutic use
Polymers / pharmacology

Substances

Neurokinin-1 Receptor Antagonists
Polymers
Aprepitant

Abstract

Publication types

MeSH terms

Substances

Grants and funding