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: 7725603
• 负责人: Priyabrata Mukherjee
• 金额: $ 28.22万
• 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/7725603
• 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; Life; Living Wills; 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; 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; public health relevance; 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. PUBLIC HEALTH RELEVANCE: It is well established that angiogenesis plays a central role in a number of pathological disorders such as rheumatoid arthritis, macular degeneration and cancer. We have recently demonstrated that "bare" gold nanoparticles (AuNPs) bind to heparin binding growth factors such as vascular permeability factor/vascular endothelial growth factor 165 (VPF/VEGF165), basic fibroblast growth factor (bFGF) and placental growth factor (PlGF) through their heparin-binding domain and inhibit their activities. It also reduced ascites accumulation and increased survival in mouse ovarian tumor (MOT) bearing mice. However, molecular mechanism underlying such an activity of gold nanoparticles is unknown. Therefore, in this proposal we will elucidate the mechanisms by which AuNPs inhibit the function of heparin binding pro-angiogenic growth factors, determine plasma protein-binding property, pharmacokinetics, toxicity and metabolism of AuNPs and finally use it as an anti-angiogenic molecule to inhibit tumorigenesis in vivo. This study will provide the first example of an inorganic nanoparticle as a therapeutic agent to inhibit angiogenesis in tumor. This multidisciplinary study will integrate expertise in nanoscience and basic science that may lead to novel strategies to treat angiogenesis-dependent disorders.

描述（由申请人提供）：纳米技术是一个新兴的领域，它为推进医学科学和疾病治疗带来了无数的机会和可能性。在纳米尺度上，由于量子尺寸效应，材料的物理化学和生物特性与其相应的块状对应部分有着根本的不同。事实上，通过创建纳米级结构，可以在不改变化学成分的情况下控制材料的基本物理化学性质，例如，金纳米粒子（AuNPs）具有酒红色，而金属金是金黄色的，这种酒红色可以通过简单地控制AuNPs的大小和形状来调整为粉红色，紫色或蓝色。在这个建议中，我们将通过纳米技术的基础研究来解决一个密切相关的生物医学问题。我们最近证明，“裸”AuNPs通过肝素结合域与肝素结合生长因子（如VPF/VEGF165、bFGF和PlGF）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AuNPs独特的抗血管生成特性将对各种血管生成依赖性疾病（如类风湿关节炎、黄斑变性、糖尿病视网膜病变和癌症）产生重大影响。本研究的长期目标是阐明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。测定AuNP的毒性、药代动力学和代谢，最后检验其作为抗血管生成剂抑制晚期卵巢肿瘤生长和转移的功效。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重要作用。在生理条件下，血管生成受到内源性促血管生成因子（如VPF/VEGF165、PLGF等）和抗血管生成因子（如血栓反应蛋白-1 （TSP-1）、生长抑素、内皮抑素等）之间平衡的严格调控。在病理条件下，这种平衡的破坏打开了“血管生成开关”。目前临床上正在使用一些抗血管生成药物，但大多数药物仅用于抑制VPF/VEGF165介导的过程。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，针对单一途径并不是最有效或最有效的治疗模式。在这种情况下，AuNPs可能更有效，因为它可以靶向多种途径（通过破坏VPF/VEGF165， bFGF， PlGF依赖途径）。此外，如上所述，当AuNPs单独作为抗血管生成药物有效时，与常规抗血管生成药物相关的异常毒性可能会被克服。因此，本研究的目的是：1)详细确定金纳米颗粒的药理学性质、AuNP的生物分布、毒性和血浆蛋白结合特性；2)阐明AuNP体内抗血管生成特性的分子机制。该提议的意义在于，如果成功，该应用不仅将提供对AuNPs功能机制的详细了解，这是无机抗血管生成纳米颗粒的第一个例子，而且还将开辟利用无机纳米颗粒作为新型治疗剂的新研究领域。如上所述，当AuNPs单独作为抗血管生成药物有效时，与常规抗血管生成药物相关的不寻常毒性也可能被克服。AuNPs不仅抑制VPF/VEGF165的功能，还抑制bFGF的功能。它很可能与腹水中存在的所有促血管生成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，因为除了VPF/VEGF165和bFGF之外，肝素结合生长因子也负责血管生成和腹水的腹膜积聚。即使针对VEGF的治疗最初是有效的，肿瘤也可能在一段时间后摆脱抑制，因为它们会突变表达其他血管生成生长因子。此外，最近的临床数据表明，针对多种血管生成途径而不是单一途径是一种更有效的治疗模式。在这种情况下，aunp将更有效，因为它可以靶向多种途径。上皮性卵巢癌（EOC）是西方国家女性生殖道最常见的恶性肿瘤：1- 2%的女性在一生中的某个时候会患上EOC。这种疾病起源于并局限于腹膜腔。目前，美国国家癌症研究所（NCI）正在鼓励晚期卵巢癌患者在手术后采用双重治疗模式。将抗癌药物注入静脉并直接进入腹部的综合方法，将晚期卵巢癌女性的总体生存期延长了大约一年。我们可以使用类似的策略来治疗晚期卵巢癌患者。我们可以将aunp作为一种抗血管生成剂直接注入腹腔，也可以通过静脉注射的方式给药用于晚期卵巢癌的常规抗癌药物。这种给药方式不仅会阻断血管生成，而且由于肿瘤血管的正常化，使肿瘤细胞对化疗敏感。公共卫生相关性：血管生成在许多病理性疾病如类风湿关节炎、黄斑变性和癌症中起着核心作用，这是公认的。我们最近证明，“裸”金纳米颗粒（AuNPs）通过肝素结合域与肝素结合生长因子如血管通透性因子/血管内皮生长因子165 （VPF/VEGF165）、碱性成纤维细胞生长因子（bFGF）和胎盘生长因子（PlGF）结合并抑制其活性。它还能减少小鼠卵巢肿瘤（MOT）小鼠腹水积聚，提高存活率。然而，这种活性的分子机制尚不清楚。因此，在本课题中，我们将阐明AuNPs抑制肝素结合促血管生成生长因子功能的机制，测定其血浆蛋白结合特性、药代动力学、毒性和代谢，最终将其作为抗血管生成分子在体内抑制肿瘤发生。这项研究将提供无机纳米颗粒作为抑制肿瘤血管生成的治疗剂的第一个例子。这项多学科研究将整合纳米科学和基础科学的专业知识，可能会产生治疗血管生成依赖性疾病的新策略。