Functionalized nanoparticles containing MKP-1 agonists reduce periodontal bone loss

Background: Progress over of the past several years has elucidated a role for mitogen-activated protein kinase phosphatase to regulate periodontal inflammation yielding new possibilities for treatment of periodontal diseases. These studies aimed to determine if nanoparticles (NPs) loaded with a pharmacological agent that induces mitogen-activated protein kinase phosphatase have potential clinical utility for management of periodontal inflammation and alveolar bone. Methods: Polyethylene glycol (PEG)-polylactide (PLA) (PEG-PLA) NPs were loaded with auranofin (ARN), an antirheumatic drug, to induce mitogen-activated protein kinase phosphatase (MKP)-1 expression in vitro and in vivo. Release kinetics of ARN from NPs was performed by high performance liquid chromatogra-phy (HPLC). Fluorescent-labeled NPs were used to show uptake into macrophages by flow cytometry. Real-time quantitative polymerase chain reaction (qPCR) was used to determine dual specificity protein phosphatase (Dusp)-1 mRNA induction by Auranofin-loaded nanoparticles (ARN-NPs) and viability of ARN-NPs was determined by colorimetric in vitro assays. Functional in vitro assays were used to measure functional MKP-1 induction and preclinical models using Aggregatibacter actinomycetemcomitans lipopolysaccharide-induced alveolar bone loss and microcomputed tomography was used to determine in vivo efficacy of functionalized ARN-NPs. Results: Data indicated that ARN-NPs had reduced cytotoxicity compared with free ARN and Dusp1 mRNA and MKP-1 activity was significantly increased by ARN-NPs in vitro. Flow cytometry indicated rapid uptake into macrophages. Finally, significant bone loss reduction was observed with ARN-NPs compared with control NPs in vivo using an lipopolysaccharide-induced rat model of periodontitis. Conclusion: Results from these studies suggest that developing NPs functionalized with ARN have anti-inflammatory activities and may be a novel adjuvant therapeutic strategy to significantly improve periodontitis therapy and outcomes.