Molecular mechanism of antiangiogenic properties of gold nanoparticle

纳米技术是一个新兴的领域，它带来了无数的机会和发展的可能性 医学和疾病治疗。在纳米尺度上，它的物理化学和生物学特性 由于量子尺寸效应，材料从根本上不同于其对应的大块对应物。在……里面 事实上，通过创造纳米级的结构，有可能控制基本的物理化学 在不改变其化学成分的情况下材料的性质，例如，金纳米颗粒(AuNPs)具有酒 红色，而金属金色是金黄色，这种葡萄酒的红色可以调整为粉色或紫色或 只需控制AuNPs的大小和形状，即可获得蓝色。在这项提案中，我们将讨论一种密切相关的生物医学 通过纳米技术的基础研究来解决这一问题。我们最近证明了“裸露的”AuNPs结合到 VPF/VEGF165、bFGF和PlGF等肝素结合生长因子通过其肝素结合区 并抑制它们的活动。由于这些生长因子本质上是促血管生成的，因此独特的 金纳米粒的抗血管生成特性将在各种血管生成依赖性疾病中产生重大影响 如类风湿性关节炎、黄斑变性、糖尿病视网膜病变和癌症。的长期目标是 本研究旨在阐明纳米金颗粒抑制血管紧张素转换酶功能的分子机制。 肝素结合促血管生成生长因子(HB-GFS)。也是为了确定毒性，药代动力学， AuNP的代谢，并最终检测其作为抗血管生成剂抑制肿瘤生长和转移的效果 卵巢肿瘤晚期。 众所周知，血管生成在类风湿等病理性疾病中起着核心作用。 关节炎、黄斑变性和癌症。在生理条件下，血管生成受到严格的 内源性促血管生成因子如VPF/VEGF165、PLGF等与抗血管生成因子之间的平衡 凝血酶反应蛋白-1(TSP-1)、生长抑素、内皮抑素等因子在 病理条件开启了“血管生成开关”。一些抗血管生成剂目前正在研制中。 在临床上使用，但大多数都是为了抑制VPF/VEGF165介导的过程而设计的。 此外，最近的报告表明，这些药物具有意想不到的严重毒性。此外， 最近的临床数据表明，靶向单一途径不是最有效或最有效的治疗模式 治疗。在这种情况下，AuNPs可能更有效，因为它可以靶向多条路径(通过干扰 VPF/VEGF165、bFGF、PlGF依赖通路)。此外，与常规药物相关的异常毒性 当AuNPs单独作为一种有效的血管生成药物时，上述抗血管生成药物可能会被克服 抗血管生成剂。因此，这项研究中提出的目标旨在1)详细确定， 金纳米粒的药理性质、生物分布、毒性和血浆蛋白结合 AuNP的性质，以及2)AuNP抗血管生成的分子机制 在活体内。 这项建议的意义在于，当成功时，这项应用不仅将提供详细的见解 第一个无机抗血管生成纳米颗粒的例子--AuNPs的作用机制，但 还开辟了利用无机纳米粒子作为新的治疗剂的新研究领域。不同寻常的 与上述常规抗血管生成药物相关的毒性也可能被克服 当AUNPs单独作为抗血管生成药物时。AuNPs不仅抑制细胞的功能 VPF/VEGF165，但也包括bFGF165。它很可能会与所有促血管生成的肝素结合生长结合。 腹水中存在的因子并抑制其功能。这种抑制多倍体功能的方法 肝素结合生长因子是更好的方法，因为肝素结合生长因子不是 VPF/VEGF165和bFGF165也参与了血管生成和腹水积聚。连 如果针对血管内皮生长因子的治疗最初是有效的，那么肿瘤可能会在一段时间后摆脱抑制，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，靶向 多条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AuNPs将更有效，因为它可以针对多个路径。 上皮性卵巢癌(EOC)是西方女性生殖道最常见的恶性肿瘤 国家：1%-2%的女性在一生中的某个时候会出现EoC。这种疾病始于并局限于 转移到腹膜腔。目前，美国国家癌症研究所(NCI)正在鼓励一种双重治疗模式 晚期卵巢癌患者，手术后。这种联合方法将抗癌药物输送到 静脉和直接进入腹部，使晚期卵巢癌妇女的总体生存期延长约 一年。我们可以使用类似的策略来治疗晚期卵巢癌患者。我们可以的 将AuNPs作为抗血管生成剂直接注入腹部，并给予常规 抗癌药物，用于晚期卵巢癌，通过静脉注射。这种模式 给药不仅会阻止血管生成，而且会使肿瘤细胞对化疗敏感，这是因为 肿瘤血管的正常化。

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.