Biological Modification of Quantum Dots for in vivo Imaging

用于体内成像的量子点的生物修饰

• 批准号: 8073609
• 负责人: Anna M Wu
• 金额: $ 50.73万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073609
• 关键词: Address; Amines; Antibodies; Antigens; B-Cell Lymphomas; Binding; Biochemical; Biological; Biological Markers; Biology; Blood Vessels; Cancer Detection; Cancer cell line; Cell Adhesion Molecules; Cell Culture Techniques; Cell Line; Cell Surface Proteins; Cell surface; Cellular biology; Characteristics; Chemistry; Color; Complex; Coupled; Coupling; Cyclic Peptides; Detection; Development; Disease; Endothelial Cells; Engineering; Enzymes; Fingerprint; Fluorescent Dyes; Gelatinase A; Generations; Genes; Growth; Growth Factor Receptors; Head; Human; Image; Immunoglobulin Fragments; In Vitro; Integrin beta3; Integrins; Label; Life; Ligands; Ligation; Lymphoma; MS4A1 gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Masks; Matrilysin; Matrix Metalloproteinases; Mediating; Modeling; Modification; Molecular; Monitor; Mus; Mutation; Normal tissue morphology; Optics; Organism; Pattern; Peptide Hydrolases; Peptides; Phage Display; Phosphotransferases; Photobleaching; Play; Positron-Emission Tomography; Pre-Clinical Model; Predisposition; Process; Property; Prostate; Proteins; Proteomics; Quantum Dots; RGD (sequence); Radioactive; Radioisotopes; Reagent; Recombinants; Research Personnel; Research Project Grants; Role; Semiconductors; Serum; Signal Transduction; Sulfhydryl Compounds; Surface; Tail; Testing; Therapeutic; Time; Tissues; Tumor Cell Line; Tumor Specific Peptide; Tumor Tissue; Work; antibody conjugate; antibody engineering; base; biomaterial compatibility; cancer cell; cancer imaging; cellular imaging; detector; dimer; effective therapy; extracellular; fluorescence imaging; improved; in vivo; nanocrystal; nanoparticle; neoplastic cell; neovascularization; neovasculature; novel; novel strategies; overexpression; prostate stem cell antigen; protein aminoacid sequence; protein expression; receptor; response; retinal rods; single photon emission computed tomography; sortase; tumor; uptake

Cancer originates in fundamental genetic alterations in tumor cells, leading to changes in protein expression and function, finally resulting in characteristic "signatures" in the serum and on tumor cell surfaces. Powerful proteomics efforts are identifying sets of biomarkers that are characteristic of a tumor's innate biology, which will be important for prediction and monitoring of response to therapy. Since cancer development is a complex process requiring mutation and altered expression of multiple genes, full determination of the biological state and treatment susceptibility of a tumor will require assessment of numerous biomarkers in vivo. To address this issue, we turn to quantum dots (Qdots), which are tiny fluorescent nanocrystals that can be produced with a spectrum of defined emission wavelengths, for generation of multiplex detectors for biomarkers. In Aim 1, antibodies specific for well characterized biomarkers in prostate cancer and lymphoma, will be engineered and coupled to near-infrared Qdots developed in Project 5. Biophysical, biochemical, and biological properties of these tumor-specific Qdots. In Aim 2, we will extend the platform by using cell-surface markers in prostate cancer identified by Project 4, to produce recombinant targets and select novel antibodies by phage display for coupling to Qdots for multiplex imaging of multiple markers. Aim 3 will focus on biological modification of Qdots for targeting the alpha-v-beta3 integrin expressed on tumors and tumor neovasculature, using Arg-Gly-Asp peptides that bind specifically to this protein. Finally, in Aim 4 a strategy for amplifying Qdot signals will utilize coupling to peptides that will enhance cellular uptake, when their activity is unmasked by tumor-specific proteases. Throughout the project period, tumor-targeting Qdots will be provided for in vivo imaging in mouse therapy models of human cancer, to validate their utility. Tumor-specific Qdots will be invaluable reagents in cell biology and preclinical models, for in vivo, real time monitoring of tumor cell activity and function. Furthermore, the targeting strategies developed here can be extended to in vivo delivery of other classes of nanoparticles for alternative modes of detection or for therapy. A sophisticated understanding of the differences between tumor and normal tissues in living organisms will advance our understanding of how to detect and treat cancer.

癌症起源于肿瘤细胞的基本遗传改变，导致蛋白质表达的变化 和功能，最终导致血清和肿瘤细胞表面的特征“特征”。强大的 蛋白质组学的努力正在确定一组肿瘤先天生物学特征的生物标志物 对于预测和监测对治疗的反应至关重要。由于癌症的发展是 需要突变和改变多个基因表达的复杂过程，完全确定 肿瘤的生物状态和治疗敏感性将需要评估众多生物标志物 体内。为了解决这个问题，我们转向量子点（QDOTS），这是微小的荧光纳米晶体 可以用一系列定义的发射波长产生，以生成用于的多路复用检测器 生物标志物。在AIM 1中，针对前列腺癌和 淋巴瘤将进行设计并耦合到项目5中开发的近红外QDOT。生物物理， 这些肿瘤特异性QDOTS的生化和生物学特性。在AIM 2中，我们将 通过在项目4鉴定的前列腺癌中使用细胞表面标记来扩展平台，以生产 重组靶标，并通过噬菌体显示出新的抗体，以耦合与QDOTS进行多重成像 多个标记。 AIM 3将重点介绍用于靶向alpha-V-Beta3整合素的QDOT的生物学修饰 使用与此特异性结合的arg-gly-asp肽在肿瘤和肿瘤新生腔的表达 蛋白质。最后，在目标4中 当其活性被肿瘤特异性蛋白酶揭开时，可以增强细胞摄取。整个 项目期，将提供小鼠治疗中的体内成像的肿瘤QDOT 人类癌症的模型，以验证其效用。肿瘤特异性QDOTS将是细胞中的宝贵试剂 生物学和临床前模型，用于体内，实时监测肿瘤细胞活性和功能。 此外，这里制定的目标策略可以扩展到其他类别的其他类别 用于替代检测模式或治疗的纳米颗粒。对 肿瘤和正常组织在生物体中的差异将促进我们对如何的理解 检测和治疗癌症。