Biological Actions and Cellular Targeting of Nanoparticles for Medical Applicatio

描述(申请人提供)：纳米技术是一个多学科领域，涉及开发纳米范围(通常为1-100纳米)的原子、分子和大分子水平的工程设备。纳米技术的最新进展为将纳米材料应用于生物医学成像和靶向药物输送提供了令人兴奋的可能性。我们最近开发了一种新的纳米颗粒配方，对成骨细胞(负责骨形成的细胞)的形成具有强大的刺激作用，同时对负责骨破坏(吸收)的破骨细胞的形成具有伴随的抑制作用。这种纳米粒子有可能发展成为一种强大的双重抗代谢和促合成代谢药物，用于治疗多种骨质疏松疾病。然而，在任何试剂被开发成用于人类的药物之前，必须了解其调节细胞代谢的分子和细胞机制，以便评估其在体内可能的安全性，并了解对骨骼细胞和非骨骼细胞的潜在毒性或非特异性副作用。我们的初步研究表明，这种纳米制剂对成骨细胞的刺激作用和对破骨细胞的抑制作用是通过抑制核因子-kB转录因子的机制实现的。核因子-kB信号转导通路在体外和体内对骨吸收破骨细胞的产生起着至关重要的作用。相反，我们和其他人最近报道，在体外，核因子-kB途径对成骨细胞的分化和矿化具有有效的抑制作用。根据我们的初步数据，我们假设这种新的纳米制剂通过抑制核因子-kB信号转导途径来抑制破骨细胞的活性和刺激成骨细胞的活性。在特定目的1中，我们建议研究该纳米颗粒在分化破骨细胞和成骨细胞前体的过程中对核因子-kB信号转导通路的作用。在特定目标2中，我们将产生具有不同物理和化学性质的野生型纳米颗粒的变体，包括表面电荷、表面修饰和大小的变化，以确定哪些特定属性负责内化进入细胞，以及对核因子-kB途径的生物作用。最后，在特定的目标3中，我们将评估该纳米制剂在体内通过刺激成骨细胞骨形成和抑制破骨细胞性骨吸收来提高骨密度和骨结构的可能性。 与公共健康相关：纳米技术有能力给医学带来革命性的变化。我们最近开发了一种纳米颗粒，能够抑制骨骼分解，同时刺激新骨形成。我们现在寻求全面研究该颗粒对骨细胞的作用，并在体内测试其增强骨量的能力。

DESCRIPTION (provided by applicant): Nanotechnology is a multidisciplinary field involving the development of engineered devices at the atomic, molecular and macromolecular level, in the nanometer range (typically 1-100 nm). Recent advances in nanotechnology have raised exciting possibilities for the application of nanomaterials to biomedical imaging and the targeted delivery of drugs. We have recently developed a novel nanoparticle formulation with potent stimulatory effects on the formation of osteoblasts, the cells responsible for bone formation, and concomitant inhibitory effects on the formation of osteoclasts, the cells responsible for bone breakdown (resorption). This nanoparticle may have the potential to be developed into a powerful dual anticatabolic and proanabolic agent for the treatment of numerous osteoporotic diseases. However, before any reagent can be developed into a drug for use in humans it is imperative to understand the molecular and cellular mechanisms by which it regulates cell metabolism in order to assess its likely safety profile in vivo, and to understand potential toxic or non-specific side-effects on skeletal and non-skeletal cells. Our preliminary studies suggest that that this nanoparticle formulation achieves its stimulatory effects on osteoblasts, and inhibitory effects on osteoclasts, by a mechanism involving the suppression of the Nuclear Factor Kappa B (NF-kB) transcription factor. The NF-kB signal transduction pathway is established to be critical for production of bone resorbing osteoclasts in vitro and in vivo. By contrast, we and others have recently reported that the NF-kB pathway is potently inhibitory to osteoblastic differentiation and mineralization in vitro. Based on our preliminary data we hypothesize that this novel nanoparticle formulation inhibits osteoclast activity and stimulates osteoblast activity by suppressing the NF-kB signal transduction pathway. In Specific Aim 1 we propose to investigate the action of this nanoparticle on the NF-kB signal transduction pathway in differentiating osteoclast and osteoblast precursors. In Specific Aim 2 we will generate variants of the wild type nanoparticle possessing different physical and chemical properties including alterations to surface charge, surface decoration, and size, to determine which specific attributes are responsible for internalization entry into the cell, and biological action on the NF-kB pathway. Finally, in Specific Aim 3 we will evaluate the potential for this nanoparticle formulation to enhance bone mineral density and bone structure by stimulating osteoblastic bone formation and inhibiting osteoclastic bone resorption in mice in vivo. PUBLIC HEALTH RELEVANCE: Nanotechnology has the power to revolutionize medicine. We recently developed a nanoparticle capable of inhibiting bone breakdown, while simultaneously stimulating new bone formation. We now seek to fully investigate the action of this particle on bone cells, and test its capacity to enhance bone mass in vivo.