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: 8061627
• 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/8061627
• 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; Health; 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：纳米技术是一个新兴的领域，带来了无数的机会和可能性来推进医学和疾病治疗的机会。在纳米尺度上，由于量子尺寸的效应，材料的物理化学和生物学特性与相应的散装柜台的根本不同。实际上，通过创建纳米尺度结构，可以控制材料的基本物理化学特性，而不会改变其化学成分，例如金纳米颗粒（Aunps）具有红色，而金属金是金黄色的，并且可以通过简单地控制Aunps的大小和形状来调节这种葡萄酒红色。在此提案中，我们将通过纳米技术的基础研究来解决一个德国生物医学问题。我们最近证明，“裸” AuNP与肝素结合生长因子（例如VPF/VEGF165，BFGF和PLGF）结合，并通过其肝素结合域结合并抑制其活性。由于这些生长因子本质上是促血管生成的，因此AUNP的独特抗血管生成特性将对各种血管生成依赖性疾病产生重大影响，例如类风湿关节炎，黄斑变性，糖尿病性视网膜病变和癌症。该提案的长期目标是阐明黄金纳米颗粒抑制肝素结合促血管生成生长因子（HB-GFS）功能的分子机制。还要确定AUNP的毒性，药代动力学，代谢的代谢，并最终检验其作为抗血管生成剂的功效，可抑制卵巢肿瘤晚期肿瘤生长和转移。众所周知，血管生成在类风湿关节炎，黄斑变性和癌症等病理疾病中起着核心作用。在生理条件下，血管生成受到内源性促血管生成因子（例如VPF/VEGF165，PLGF等）之间的平衡，以及抗血管生成因子，例如血小板传播-1（TSP-1），生成抑制素，内皮抑素等。在病理条件下的平衡打开了“血管生成开关”。目前在诊所中使用了一些抗血管生成剂，但其中大多数仅设计用于抑制VPF/VEGF165介导的过程。此外，最近的报告表明这些药物的意外毒性和严重的毒性。此外，最近的临床数据表明，针对单个途径不是最有效或有效的治疗方式。在这种情况下，AUNPS可能更有效，因为它可以针对多个途径（通过破坏VPF/VEGF165，BFGF，PLGF依赖途径）。此外，当单独使用AUNPs作为抗血管生成剂有效时，可能会克服与上述常规抗血管生成剂相关的异常毒性。因此，本研究中提出的目的是为1）详细确定金纳米颗粒的药理特性，生物分布，毒性和血浆蛋白蛋白蛋白的结合特性，2）描述了AUNP抗氧特性的分子机制。体内。该提议的重要性是，在成功的情况下，该应用不仅将提供详细的见解，了解AUNP的功能机理，这是无机抗血管生成纳米粒子的第一个例子，而且还开设了利用无机纳米颗粒的新研究领域新颖的治疗剂。与上述常规抗血管生成剂相关的异常毒性也可以在单独使用AUNPs作为抗血管生成剂有效时也可以克服。 AUNP不仅抑制VPF/VEGF165的功能，还可以抑制BFGF的功能。它可能会与腹水中存在的所有促肝素结合生长因子结合并抑制其功能。这种抑制多种肝素结合生长因子功能的方法是一种更好的方法，因为除VPF/VEGF165和BFGF以外的肝素结合生长因子和BFGF外，还负责血管生成和腹膜的腹膜积累。即使针对VEGF的疗法最初是有效的，肿瘤在突变以表达其他血管生长因子时可能会逃脱。此外，最近的临床数据表明，针对多个血管生成途径而不是单个途径是一种更有效的治疗方式。在这种情况下，Aunps将更有效，因为它可以针对多个途径。上皮卵巢癌（EOC）是西方国家生殖道最常见的恶性肿瘤：1-2％的妇女在她一生中的某个时候发展了EOC。该疾病始于并仅限于腹膜腔。目前，在手术后，国家癌症研究所（NCI）鼓励对晚期卵巢癌患者进行双重治疗。将抗癌药物输送到静脉并直接进入腹部的合并方法将晚期卵巢癌女性的总体生存扩大了大约一年。我们可以使用类似的策略来治疗晚期卵巢癌患者。我们可以通过静脉注射直接将AUNP作为抗血管生成剂作为抗血管生成剂，并通过静脉注射施用用于晚期卵巢癌的常规抗癌药物。这种给药方式不仅会阻止血管生成，而且还将由于肿瘤脉管系统的归一化而使肿瘤细胞对化学疗法敏感。