Amine Functionalized Trimetallic Nitride Endohedral Fullerenes: A Class of Nanoparticle to Tackle Low Back/Leg Pain

Low back pain is the most common health problem with a prevalence of over 80% worldwide and an estimated annual cost of $100 billion in the United States. Intervertebral disc degeneration accounts for a major cause of low back pain. However, there is still a lack of safe and effective treatment to tackle this devastating condition. In this study, we synthesized four functionalized trimetallic nitride endohedral metallofullerenes (carboxyl-f-Sc₃N@C₈₀, carboxyl-f-Gd₃N@C₈₀, amino-f-Sc₃N@C₈₀, and amino-f-Gd₃N@C₈₀) and characterized them with X-ray photoelectron spectroscopy, matrix-assisted laser desorption/ionization-time of flight mass spectrometry, and UV-vis. Via electron paramagnetic resonance, all four metallofullerene derivatives possessed dose-dependent radical scavenging capabilities (hydroxyl radicals and superoxide anions), with the most promising radical scavenging properties shown in the amine functionalized C₈₀ metallofullerenes. Both amino-f-Sc₃N@C₈₀ and amino-f-Gd₃N@C₈₀ at 1 μM significantly reduced lipopolysaccharide induced reactive oxygen species production and mRNA expressions of pro-inflammatory mediators (inos, tnf-α, il-1, and cox-2) in macrophages without apparent cytotoxicity through regulating activity of p38 MAPK, p65, and nuclear translocation of NF-κB. Furthermore, in an established mouse model of lumbar radiculopathy, amino-f-Sc₃N@C₈₀ and amino-f-Gd₃N@C₈₀ effectively alleviated ipsilateral mechanical hyperalgesia for up to 2 weeks. In dorsal root ganglia explant culture, we also showed that amino-f-Sc₃N@C₈₀ and amino-f-Gd₃N@C₈₀ ameliorated TNF-α elicited neuroinflammation. In summary, we presented results for a potent radical scavenging, anti-inflammatory and analgesic nanoparticle, amino-functionalized eighty-carbon metallofullerenes in vitro and in vivo. Our study provides important assets for developing pleiotropic treatment strategies to tackle the inflammation, a significant pathological hallmark in the intervertebral disc degeneration and associated pain.