Testing the therapeutic potential of carbon nanodots in bone mineralization diseases

测试碳纳米点在骨矿化疾病中的治疗潜力

• 批准号: 9373531
• 负责人: Isaac Skromne
• 金额: $ 18.92万
• 依托单位: UNIVERSITY OF RICHMOND
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9373531
• 关键词: Adult; Affinity; Amination; Amines; Binding; Biological; Biological Assay; Bone Density; Bone Development; Bone Diseases; Bone Matrix; Bone Mineralization Regulation Pathway; Bone Regeneration; Bone Tissue; Carbon; Carbon nanoparticle; Cell Differentiation process; Cell physiology; Chemical Structure; Chemicals; Chemistry; Data; Development; Disease; Drug Delivery Systems; Drug Targeting; Duct (organ) structure; Equilibrium; FDA approved; Fluorescence; Future; Generations; Goals; Grant; Heart; Homeostasis; Human; Malignant Neoplasms; Measures; Methods; Minerals; Modeling; Molecular; Mutation; Natural regeneration; Nervous system structure; Osteocytes; Osteogenesis; Osteoid; Osteoporosis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phenotype; Physiologic calcification; Physiological; Process; Production; Quality of life; Reagent; Recruitment Activity; Regulation; Scheme; Signal Pathway; Signal Transduction; Specificity; Staining method; Stains; Sulfhydryl Compounds; Surface; Techniques; Testing; Therapeutic; Tissues; Tretinoin; Work; Zebrafish; base; biomaterial compatibility; blind; bone; bone health; chemical property; functional group; human disease; improved; inhibitor/antagonist; innovation; insight; mineralization; nanoparticle; novel; novel therapeutics; osteosarcoma; particle; prevent; targeted delivery; therapeutic evaluation; tool

Project Summary Traditional methods to deliver drugs to bones for the treatment of mineralization diseases, such as Osteoporosis, can also disrupt homeostasis in other tissues. To overcome this important problem it is critical to develop novel drug delivery methods that precisely deliver drugs exclusively to the bones. One novel method of drug delivery uses Carbon nanodots (C-dots), an emerging class of nanoparticles with high stability and excellent biocompatibility. Our work in zebrafish has identified a particular class of C-dots that bind with high affinity and specificity to larval and adult bones, without binding to other tissues. Based on this and additional preliminary evidence, here we seek to develop C-dots as a novel method for the precise delivery of drugs exclusively to bones. By systematically defining the chemical properties of C-dots that are essential for bone binding and drug delivery, we will determine the mechanism of C-dot's binding specificity and affinity to bones, while developing a novel and versatile set of carriers for delivering drugs precisely to bones. As proof of principle that C-dots can be used as novel therapeutic drug delivery system, we are targeting the Retinoic Acid signaling pathway involved in the homeostatic regulation of bone mineralization. Rare mutations in humans have identified Retinoic Acid as a key regulator of bone mineralization. These mutations, which can be faithfully recapitulated in the zebrafish, cause excessive Retinoic Acid accumulation, promote excessive osteocyte cell differentiation, and trigger bone fusions. Thus, recruiting the Retinoic Acid signaling pathway to regulate osteocyte production represents a novel and largely unexplored approach to regulating bone mineralization for disease treatment. We are combining our expertise in carbon-based material chemistry and Retinoic Acid signaling in zebrafish to determine the mechanisms of C-dots binding to bones, and improve their efficiency as a bone-specific drug delivery system. The aims of this project are: 1) to determine C-dots' range of function as bone-specific, drug delivery agents; by loading C-dots with a variety of Retinoic Acid activator and inhibitor drugs and measuring changes in osteocyte cell differentiation and bone mineralization in developing, mature, and regenerating bones; 2) to increase the repertoire of drugs that C-dots can deliver to bones; by chemically changing the linkers and functional groups on the C-dots surface and testing their activity in our osteocyte cell differentiation and bone mineralization paradigm. The development of C-dots as tools for the study and precise treatment of bone mineralization diseases will help increase our understanding of the function of cell signaling in promoting and preventing osteocyte differentiation. By expanding the repertoire of drugs that C-dots can carry, this novel drug-delivery platform will also allow, in future work, to target other processes altering bone homeostasis, including cancer. Thus, cellular and molecular data emerging from the use of C-dot-based reagents will lead to new biological insights and the development of innovative bone therapies.

项目摘要 将药物递送到骨骼以治疗矿化疾病（例如骨质疏松症）的传统方法可以 也会破坏其他组织的体内平衡。为了克服这一重要问题，开发新型药物递送系统至关重要 精确地将药物输送到骨骼的方法。一种新的药物输送方法使用碳纳米点 （C-dots），一种新兴的具有高稳定性和优异生物相容性的纳米颗粒。我们对斑马鱼的研究 鉴定了一类特殊的C点，它们以高亲和力和特异性与幼虫和成虫的骨骼结合， 其他组织。基于这一点和额外的初步证据，在这里，我们寻求开发C点作为一种新的方法， 精确地将药物输送到骨骼。通过系统地定义C点的化学性质， 对于骨结合和药物递送至关重要，我们将确定C-dot结合特异性和亲和力的机制 同时开发一种新颖的多功能载体，用于将药物精确地输送到骨骼。 作为C点可用作新型治疗药物递送系统的原理证明，我们的目标是维甲酸 酸性信号通路参与骨矿化的稳态调节。人类的罕见突变 确定视黄酸是骨矿化的关键调节剂。这些突变，可以忠实地概括为 在斑马鱼中，引起过量的视黄酸积累，促进骨细胞过度分化，并引发 骨融合因此，招募维甲酸信号通路来调节骨细胞的产生代表了一种新的 并且很大程度上未探索的调节骨矿化用于疾病治疗的方法。我们正在结合我们的专业知识 在碳基材料化学和视黄酸信号在斑马鱼，以确定机制的C点 与骨骼结合，并提高其作为骨特异性药物递送系统的效率。 本项目的目的是：1）确定C-dots作为骨特异性药物递送剂的功能范围; 用多种视黄酸激活剂和抑制剂药物负载C-点，并测量骨细胞中的变化， 分化和骨矿化的发展，成熟，和再生骨; 2）增加剧目， C点可以传递到骨骼的药物;通过化学改变C点表面的连接体和官能团 并在我们的骨细胞分化和骨矿化范例中测试它们的活性。 C-dots作为研究和精确治疗骨矿化疾病的工具的发展将有助于 增加我们对细胞信号在促进和阻止骨细胞分化中的作用的理解。通过 这种新型的药物输送平台扩大了C-dots可以携带的药物种类，在未来的工作中， 以改变骨稳态的其他过程为目标，包括癌症。因此，细胞和分子数据来自 基于C-dot的试剂的使用将导致新的生物学见解和创新骨疗法的发展。