Department of Chemistry , Virginia Polytechnic Institute and State University , Blacksburg , Virginia 24061 United States.
Biomedical Imaging Research Institute , Cedars-Sinai Medical Center , Los Angeles , California 90048 , United States.
ACS Appl Mater Interfaces. 2019 Oct 23;11(42):38405-38416. doi: 10.1021/acsami.9b11783. Epub 2019 Oct 8.
Intervertebral disc degeneration associated back pain is the most common cause of disability worldwide; however, no safe and effective treatments have been available. Here, we report a new functionalized nanofullerene conjugated with a peptide that binds specifically to a formyl peptide receptor-1 (FPR-1) expressed on activated macrophages. The new nanoparticle (aka FT-C) was synthesized by conjugating carboxyl-C with the primary amine group of the peptide with a fluorescence dye for easy detection. The new nanoparticle was characterized by X-ray photoelectron spectroscopy, mass spectroscopy, and gel electrophoresis. It possessed effective radical (hydroxyl and superoxide anions) scavenging capabilities in electron paramagnetic resonance spectroscopy. In cultured cells, the nanoparticle FT-C demonstrated preferential binding to FPR-1 on activated macrophages and significantly attenuated mRNA expressions of proinflammatory factors including interleukin-6, interleukin-1, tumor necrosis factor-alpha, and cyclooxygenase-2. In vivo animal studies exhibited that a single intravenous injection of FT-C effectively alleviated pain in an established mouse model of radiculopathy for up to post-operation day (POD) 12. Ex vivo near-infrared fluorescence imaging of the mouse spine confirmed the targeting property of FT-C toward the injured disc on POD 14. Quantitative analysis of histological staining on spine sections showed that nanoparticle FT-C dramatically reduced inflammation at the local injury site compared to injury only on POD 7. In summary, we developed a novel targeted nanoparticle for treatment of lumbar radiculopathy by systemic delivery. This is a first-of-its-kind study for developing a novel class of targeted and systemic nanoparticle therapeutics to treat degenerative disc diseases.
椎间盘退变相关腰痛是全球最常见的致残原因；然而，目前尚无安全有效的治疗方法。在这里，我们报告了一种新的功能化富勒烯与一种肽结合，该肽特异性结合到激活的巨噬细胞上表达的甲酰肽受体-1（FPR-1）。新的纳米颗粒（又名 FT-C）是通过将羧基-C 与肽的伯胺基团缀合，并带有荧光染料以方便检测而合成的。新的纳米颗粒通过 X 射线光电子能谱、质谱和凝胶电泳进行了表征。它在电子顺磁共振光谱中具有有效的自由基（羟基和超氧阴离子）清除能力。在培养的细胞中，纳米颗粒 FT-C 优先与激活的巨噬细胞上的 FPR-1 结合，并显著减弱包括白细胞介素-6、白细胞介素-1、肿瘤坏死因子-α和环氧化酶-2 在内的促炎因子的 mRNA 表达。体内动物研究表明，单次静脉注射 FT-C 可有效缓解已建立的神经根病小鼠模型的疼痛，持续时间长达术后第 12 天（POD）。在 POD 14 时对小鼠脊柱进行的近红外荧光体外成像证实了 FT-C 对损伤椎间盘的靶向特性。脊柱切片的组织学染色定量分析表明，与仅在 POD 7 时的损伤相比，纳米颗粒 FT-C 可大大减少局部损伤部位的炎症。总之，我们通过系统给药开发了一种治疗腰椎神经根病的新型靶向纳米颗粒。这是首例开发新型靶向和系统纳米颗粒疗法治疗退行性椎间盘疾病的研究。
