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: 7067899
• 负责人: Anna M Wu
• 金额: $ 30.41万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7067899
• 关键词: antineoplastics; bioimaging /biomedical imaging; biomarker; cell surface receptors; clinical research; cooperative study; electron crystallography; immunomagnetic separation; microarray technology; microprocessor /microchip; nanotechnology; neoplasm /cancer diagnosis; neoplasm /cancer therapy; neoplastic process; prognosis; protein binding; protein quantitation /detection; proteomics; quantum chemistry; technology /technique development

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，最终在血清和肿瘤细胞表面产生特征“特征”。强大的 蛋白质组学工作正在识别一组生物标志物，这些标志物是肿瘤先天生物学的特征， 对于预测和监测治疗反应非常重要。由于癌症的发展是 复杂的过程需要突变和改变多个基因的表达，全面确定 肿瘤的生物学状态和治疗敏感性需要评估许多生物标志物 体内。为了解决这个问题，我们转向量子点（Qdots），这是一种微小的荧光纳米晶体， 可以产生具有定义的发射波长的光谱，用于生成多重检测器 生物标志物。在目标 1 中，针对前列腺癌和 淋巴瘤，将被设计并与项目 5 中开发的近红外 Qdot 耦合。生物物理， 这些肿瘤特异性 Qdot 的生化和生物学特性。在目标 2 中，我们将 通过使用项目 4 确定的前列腺癌细胞表面标记来扩展平台，以产生 重组靶标并通过噬菌体展示选择新型抗体，以耦合到 Qdot 进行多重成像 的多个标记。目标 3 将重点关注 Qdot 的生物修饰，以靶向 α-V-β3 整合素 使用与此特异性结合的 Arg-Gly-Asp 肽在肿瘤和肿瘤新血管系统上表达 蛋白质。最后，在目标 4 中，放大 Qdot 信号的策略将利用与肽的偶联，该肽将 当肿瘤特异性蛋白酶揭示其活性时，增强细胞摄取。整个 项目期间，将提供肿瘤靶向Qdots用于小鼠治疗的体内成像 人类癌症模型，以验证其实用性。肿瘤特异性Qdots将成为细胞中无价的试剂 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，这里开发的靶向策略可以扩展到其他类别的体内递送 纳米颗粒用于替代检测或治疗模式。对事物的深刻理解 生物体中肿瘤组织和正常组织之间的差异将促进我们对如何 检测和治疗癌症。