Molecular mechanism of antiangiogenic properties of gold nanoparticle

金纳米粒子抗血管生成特性的分子机制

• 批准号: 8254463
• 负责人: Priyabrata Mukherjee
• 金额: $ 27.37万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8254463
• 关键词: Abdomen; Address; Angiogenesis Inhibitors; Angiogenic Factor; Angiogenic Switch; Animals; Antineoplastic Agents; Area; Ascites; Basic Science; Binding; Biochemical; Biodistribution; Biological; Biological Assay; Blood Circulation; Blood Vessels; Blood specimen; Cancer Patient; Canis familiaris; Chemicals; Clinic; Clinical Data; Color; Country; Coupled; Data; Diabetic Retinopathy; Disease; Disease-Free Survival; Drug Kinetics; Drug usage; Ear; Endostatins; Endothelial Cells; Epithelial ovarian cancer; Equilibrium; Excision; Exhibits; Extravasation; Feces; Female; Fibroblast Growth Factor 2; Genital system; Goals; Gold; Greater sac of peritoneum; Growth Factor; Half-Life; Heparin Binding; Heparin Binding Growth Factor; Housing; Human; In Vitro; Label; Lead; Macular degeneration; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mediator of activation protein; Medical; Metabolic; Metabolic Clearance Rate; Metabolism; Methods; Modeling; Molecular; Molecular Biology; Mouse Strains; Mus; Mutate; Nanotechnology; National Cancer Institute; Nature; Neoplasm Metastasis; Operative Surgical Procedures; Organ; PECAM1 gene; Pathway interactions; Peritoneal; Permeability; Physiological; Placental Growth Factor; Plasma; Plasma Proteins; Play; Process; Property; Protein Binding; Reporting; Research; Research Design; Rheumatoid Arthritis; Role; Science; Serum; Shapes; Somatostatin; Staging; Structure; Testing; Therapeutic Agents; Thrombospondin 1; Time; Toxic effect; Tracer; Urine; VEGF165; Vascular Endothelial Growth Factors; Vascular Permeabilities; Veins; Viola; Woman; angiogenesis; cancer cell; chemical property; chemotherapy; density; design; fluorescein isothiocyanate dextran; in vivo; insight; intraperitoneal; intravenous injection; metabolic abnormality assessment; molecular size; mouse model; multidisciplinary; nanoparticle; nanoscale; nanoscience; neoplastic cell; novel strategies; novel therapeutics; ovarian neoplasm; quantum; receptor; red wine; research study; time interval; treatment strategy; tumor; tumor growth; tumorigenesis

Nanotechnology is a burgeoning field and brings with it a myriad of opportunities and possibilities for advancing medical science and disease treatment. At the nano scale, the physico-chemical, and biological properties of materials differ fundamentally from their corresponding bulk counter part because of the quantum size effect. In fact, by creating nanometer- scale structures, it is possible to control the fundamental physico-chemical properties of a material without changing it's chemical composition, e.g. gold nanoparticles (AuNPs) have wine red color, whereas metallic gold is golden yellow and this wine red color can be tuned to either pink, or violet or blue by simply controlling the size and shape of AuNPs. In this proposal we will address a germane biomedical problem through basic research in nanotechnology. We have recently demonstrated that "bare" AuNPs bind to heparin binding growth factors such as VPF/VEGF165, bFGF and PlGF through their heparin-binding domain and inhibit their activities. Since these growth factors are pro-angiogenic in nature, therefore the unique antiangiogenic property of AuNPs will have significant impact in various angiogenesis-dependent disorders such as rheumatoid arthritis, macular degeneration, diabetic retinopathy, and cancer. The long-term goal of this proposal is to elucidate the molecular mechanisms by which gold nanoparticle inhibits the function of heparin-binding pro-angiogenic growth factors (HB-GFs). Also to determine the toxicity, pharmacokinetics, metabolism of AuNP and finally test its efficacy as anti-angiogenic agent to inhibit tumor growth and metastasis in advanced stage of ovarian tumor. It is well established that angiogenesis plays a central role in pathological disorders such as rheumatoid arthritis, macular degeneration and cancer. Under physiological conditions, angiogenesis is tightly regulated by a balance between endogenous pro-angiogenic factors such as VPF/VEGF165, PLGF, etc, and antiangiogenic factors such as thrombospondin-1 (TSP-1), somatostatin, endostatin, etc. Disruption of this equilibrium under pathological conditions turns on the "angiogenic switch". Some anti-angiogenic agents are being presently used in the clinics, but majority of them have been designed only to inhibit VPF/VEGF165 mediated processes. In addition, recent reports have indicated unexpected and serious toxicities of these agents. Furthermore, recent clinical data suggest that targeting a single pathway is not the most efficient or effective mode of treatment. In this context AuNPs might be more effective since it can target multiple pathways (by disrupting VPF/VEGF165, bFGF, PlGF dependent pathways). Moreover, unusual toxicities associated with conventional anti-angiogenic agents as mentioned above may be overcome when AuNPs alone can be efficacious as an anti-angiogenic agent. Therefore, the aims proposed in this study are designed to 1) Determine, in detail, pharmacological properties of gold nanoparticles, biodistribution, toxicity and plasma protein binding properties of AuNPs, and 2) Delineate the molecular mechanism of anti-angiogenic properties of AuNP in vivo. The significance of this proposal is that, when successful, this application will not only provide detailed insight into the mechanism of function of AuNPs, the first example of an inorganic anti-angiogenic nanoparticle, but also open a new area of research utilizing inorganic nanoparticles as novel therapeutic agents. The unusual toxicities associated with conventional anti-angiogenic agents as discussed above may also be overcome when AuNPs alone could be efficacious as anti-angiogenic agents. AuNPs not only inhibit the function of VPF/VEGF165, but bFGF as well. It is likely that it will bind to all the pro-angiogenic heparin-binding growth factors present in the ascites and inhibit their function. This method of inhibiting the function of multiple heparin-binding growth factors is a better approach, because heparin-binding growth factors other than VPF/VEGF165 and bFGF are also responsible for angiogenesis and peritoneal accumulation of ascites. Even if therapies directed against VEGF are effective initially, tumors may escape from inhibition after a time as they mutate to express other angiogenic growth factors. Furthermore, recent clinical data suggest that targeting multiple angiogenic pathways rather than a single pathway is a more effective mode of treatment. In this context AuNPs will be more effective as it can target multiple pathways. Epithelial ovarian cancer (EOC) is the most common malignancy of the female genital tract in western countries: 1-2 % of all women develop EOC at some time during their lives. This disease starts at and is limited to the peritoneal cavity. Currently, National Cancer Institute (NCI) is encouraging a dual mode of therapy for advanced ovarian cancer patients, after surgery. The combined methods, which deliver anti-cancer drugs into a vein and directly into the abdomen, extend overall survival for women with advanced ovarian cancer by about a year. We can use similar strategies for the treatment of advanced ovarian cancer patients. We can administer AuNPs directly into the abdomen as an anti-angiogenic agent and administer conventional anticancer drugs, used for advanced ovarian cancer, through intravenous injection. This mode of administration will not only block the angiogenesis but also sensitize the tumor cells to chemotherapy due to the normalization of tumor vasculature.

纳米技术是一个新兴的领域，并带来了无数的机会和可能性，为推进 医学和疾病治疗。在纳米尺度上， 由于量子尺寸效应，材料与它们相应的体计数器部件基本上不同。在 事实上，通过创造纳米尺度的结构， 在不改变其化学成分的情况下改变材料的性质，例如金纳米颗粒（AuNPs）具有葡萄酒 红色，而金属金是金黄色，这种酒红色可以调整到粉红色，或紫罗兰色， 通过简单地控制AuNPs的大小和形状，在本提案中，我们将讨论一个密切相关的生物医学 通过纳米技术的基础研究解决问题。我们最近已经证明，"裸"金纳米颗粒结合到 肝素结合生长因子如VPF/VEGF 165、bFGF和PlGF通过其肝素结合结构域 并抑制它们的活动。由于这些生长因子在性质上是促血管生成的，因此， AuNPs的抗血管生成特性将在各种血管生成依赖性疾病中具有显著影响 如类风湿性关节炎、黄斑变性、糖尿病性视网膜病和癌症。的长期目标 该方案旨在阐明金纳米颗粒抑制细胞功能的分子机制。 肝素结合促血管生成生长因子（HB-GF）。同时测定其毒性，药代动力学， AuNP的代谢，并最终测试其作为抗血管生成剂以抑制肿瘤生长和转移的功效 卵巢肿瘤晚期。 血管生成在病理性疾病如类风湿性关节炎中起着重要作用， 关节炎黄斑变性和癌症在生理条件下，血管生成受到 内源性促血管生成因子如VPF/VEGF 165、PLGF等与抗血管生成因子之间的平衡 因子如血小板反应蛋白-1（TSP-1）、生长抑素、内皮抑素等。 病理条件打开"血管生成开关"。目前，一些抗血管生成剂 在临床上使用，但它们中的大多数仅被设计用于抑制VPF/VEGF 165介导的过程。 此外，最近的报告表明，这些药物的意外和严重的毒性。此外，委员会认为， 最近的临床数据表明，靶向单一途径并不是最有效的治疗模式。 治疗在这种情况下，AuNP可能更有效，因为它可以靶向多个途径（通过破坏 VPF/VEGF165、bFGF、PlGF依赖性途径）。此外，与常规药物相关的不寻常毒性 当单独的AuNP可以有效地作为抗血管生成剂时，可以克服如上所述的抗血管生成剂。 抗血管生成剂。因此，本研究中提出的目标旨在：1）详细确定， 金纳米颗粒的药理学性质、生物分布、毒性和血浆蛋白结合 2）阐明金纳米粒子抗血管生成的分子机制 in vivo. 这一提议的意义在于，一旦成功，这一应用程序不仅将提供详细的见解， 金纳米粒子的功能机制，无机抗血管生成纳米粒子的第一个例子，但 也开辟了利用无机纳米颗粒作为新型治疗剂的新研究领域。不寻常的 也可以克服与上述常规抗血管生成剂相关的毒性 当单独的AuNP可以有效地作为抗血管生成剂时。AuNPs不仅抑制了 VPF/VEGF 165，但也有bFGF。它很可能会结合所有促血管生成的肝素结合生长 腹水中存在的因子并抑制其功能。这种抑制多功能的方法 肝素结合生长因子是一种更好的方法，因为肝素结合生长因子以外的 VPF/VEGF 165和bFGF也负责血管生成和腹水的腹膜积聚。甚至 如果针对VEGF的治疗最初是有效的，肿瘤可能在一段时间后逃脱抑制，因为它们 突变以表达其他血管生成生长因子。此外，最近的临床数据表明， 多个血管生成途径而不是单一途径是更有效的治疗模式。在这 上下文AuNP将更有效，因为它可以靶向多个途径。 上皮性卵巢癌（epithelial ovarian cancer，EOC）是西方女性生殖道最常见的恶性肿瘤， 国家：1 - 2%的妇女在其一生中的某个时候患上EOC。这种疾病开始于， 转移到腹膜腔目前，国家癌症研究所（NCI）正在鼓励一种双重治疗模式， 晚期卵巢癌患者，手术后。将抗癌药物输送到 静脉直接进入腹部，将晚期卵巢癌妇女的总生存期延长约 一年我们可以使用类似的策略来治疗晚期卵巢癌患者。我们可以 将AuNP直接施用到腹部作为抗血管生成剂，并施用常规的 抗癌药，用于晚期卵巢癌，通过静脉注射。的该模式 给药不仅会阻断血管生成，而且会使肿瘤细胞对化疗敏感， 肿瘤血管的正常化。