PAR2 on oral cancer cells and nociceptors contributes to oral cancer pain that can be relieved by nanoparticle-encapsulated AZ3451

Divya Bhansali; Nguyen H Tu; Kenji Inoue; Shavonne Teng; Tianyu Li; Hung D Tran; Dong H Kim; Jessy Dong; Chloe J Peach; Badr Sokrat; Dane D Jensen; John C Dolan; Seiichi Yamano; Valeria Mezzano Robinson; Nigel W Bunnett; Donna G Albertson; Kam W Leong; Brian L Schmidt

doi:10.1016/j.biomaterials.2024.122874

PAR₂ on oral cancer cells and nociceptors contributes to oral cancer pain that can be relieved by nanoparticle-encapsulated AZ3451

Biomaterials. 2024 Oct 2:314:122874. doi: 10.1016/j.biomaterials.2024.122874. Online ahead of print.

Authors

Divya Bhansali¹, Nguyen H Tu², Kenji Inoue³, Shavonne Teng⁴, Tianyu Li⁵, Hung D Tran⁶, Dong H Kim⁷, Jessy Dong⁸, Chloe J Peach⁹, Badr Sokrat¹⁰, Dane D Jensen¹¹, John C Dolan¹², Seiichi Yamano¹³, Valeria Mezzano Robinson¹⁴, Nigel W Bunnett¹⁵, Donna G Albertson¹⁶, Kam W Leong¹⁷, Brian L Schmidt¹⁸

Affiliations

¹ Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA. Electronic address: [email protected].
² New York University Dentistry Translational Research Center, New York University Dentistry, New York, NY, 10010, USA; Pain Research Center, New York University, New York, NY, 10010, USA. Electronic address: [email protected].
³ New York University Dentistry Translational Research Center, New York University Dentistry, New York, NY, 10010, USA; Pain Research Center, New York University, New York, NY, 10010, USA. Electronic address: [email protected].
⁴ Pain Research Center, New York University, New York, NY, 10010, USA; Department of Molecular Pathobiology, New York University Dentistry, New York, NY, 10010, USA; Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, 10032, USA. Electronic address: [email protected].
⁵ Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA. Electronic address: [email protected].
⁶ New York University Dentistry Translational Research Center, New York University Dentistry, New York, NY, 10010, USA. Electronic address: [email protected].
⁷ New York University Dentistry Translational Research Center, New York University Dentistry, New York, NY, 10010, USA. Electronic address: [email protected].
⁸ New York University Dentistry Translational Research Center, New York University Dentistry, New York, NY, 10010, USA. Electronic address: [email protected].
⁹ Pain Research Center, New York University, New York, NY, 10010, USA; Department of Molecular Pathobiology, New York University Dentistry, New York, NY, 10010, USA; Centre of Membrane Proteins and Receptors, School of Life Sciences, Queen's Medical Centre, University of Nottingham, UK. Electronic address: [email protected].
¹⁰ Pain Research Center, New York University, New York, NY, 10010, USA; Department of Molecular Pathobiology, New York University Dentistry, New York, NY, 10010, USA. Electronic address: [email protected].
¹¹ New York University Dentistry Translational Research Center, New York University Dentistry, New York, NY, 10010, USA; Pain Research Center, New York University, New York, NY, 10010, USA. Electronic address: [email protected].
¹² New York University Dentistry Translational Research Center, New York University Dentistry, New York, NY, 10010, USA. Electronic address: [email protected].
¹³ Department of Prosthodontics, New York University Dentistry, New York, NY, 10010, USA. Electronic address: [email protected].
¹⁴ Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA. Electronic address: [email protected].
¹⁵ Pain Research Center, New York University, New York, NY, 10010, USA; Department of Molecular Pathobiology, New York University Dentistry, New York, NY, 10010, USA; Neuroscience Institute, New York University Langone Health, New York, NY, 10016, USA; Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, NY, 10016, USA. Electronic address: [email protected].
¹⁶ New York University Dentistry Translational Research Center, New York University Dentistry, New York, NY, 10010, USA; Pain Research Center, New York University, New York, NY, 10010, USA. Electronic address: [email protected].
¹⁷ Department of Biomedical Engineering, Columbia University, New York, NY, 10027, USA. Electronic address: [email protected].
¹⁸ New York University Dentistry Translational Research Center, New York University Dentistry, New York, NY, 10010, USA; Pain Research Center, New York University, New York, NY, 10010, USA; Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, NY, 10016, USA. Electronic address: [email protected].

PMID: 39418848
DOI: 10.1016/j.biomaterials.2024.122874

Abstract

Oral cancer is notoriously painful. Activation of protease-activated receptor 2 (PAR₂, encoded by F2RL1) by proteases in the cancer microenvironment is implicated in oral cancer pain. PAR₂ is a G protein-coupled receptor (GPCR) expressed on neurons and cells in the cancer microenvironment. Sustained signaling of PAR₂ from endosomes of neurons mediates sensitization and nociception. We focused on the differential contribution of PAR₂ on oral cancer cells and neurons to oral cancer pain and whether encapsulation of a PAR₂ inhibitor, AZ3451 in nanoparticles (NP) more effectively reverses PAR₂ activation. We report that F2RL1 was overexpressed in human oral cancers and cancer cell lines. Deletion of F2RL1 on cancer cells reduced cancer-associated mechanical allodynia. A third-generation polyamidoamine dendrimer, functionalized with cholesterol was self-assembled into NPs encapsulating AZ3451. NP encapsulated AZ3451 (PAMAM-Chol-AZ NPs) more effectively reversed activation of PAR₂ at the plasma membrane and early endosomes than free drug. The PAMAM-Chol-AZ NPs showed greater efficacy in reversing nociception than free drug, with respect to both level and duration, in three preclinical mouse models of oral cancer pain. The antinociceptive efficacy was confirmed with an operant orofacial assay. Genetic deletion of F2RL1 on cancer cells or F2rl1 on neurons each partially reversed mechanical cancer allodynia. The remaining nociception could be effectively reversed by PAMAM-Chol-AZ NPs. These findings suggest that PAR₂ on oral cancer cells and neurons contribute to oral cancer nociception and NPs loaded with a PAR₂ antagonist provide increased antinociception and improved oral function compared to free drug.

Keywords: Nanoparticles; Oral cancer; Oral cancer pain; PAR(2); Protease-activated receptor 2.