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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Developmental Therapeutics Study Section (DT)
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Forry, Suzanne L
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University of Oklahoma Health Sciences Center
Schools of Medicine
Oklahoma City
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