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，最终导致血清和肿瘤细胞表面的特征性“签名”。强大 蛋白质组学的努力是确定一套生物标志物，是肿瘤的先天生物学特征， 对于预测和监测对治疗的反应将是重要的。由于癌症的发展是一个 复杂的过程需要突变和改变多个基因的表达， 肿瘤的生物学状态和治疗敏感性将需要评估多种生物标志物， vivo.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， 可以产生具有限定的发射波长的光谱，用于产生多路检测器， 生物标志物。在目的1中，制备了对前列腺癌和前列腺癌中充分表征的生物标志物具有特异性的抗体。 淋巴瘤，将被工程化并耦合到项目5中开发的近红外量子点。生物物理学， 这些肿瘤特异性量子点的生物化学和生物学性质。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志物来扩展平台， 重组靶点，并通过噬菌体展示选择新的抗体，用于偶联到用于多重成像的Qdot 多重标记目标3将集中于用于靶向α-v-β 3整合素的量子点的生物修饰 表达的肿瘤和肿瘤新生血管，使用Arg-Gly-Asp肽，特异性结合这个 蛋白最后，在目标4中，用于扩增Qdot信号的策略将利用与肽的偶联，所述肽将 增强细胞摄取，当它们的活性被肿瘤特异性蛋白酶揭开时。在整个 项目期间，将提供肿瘤靶向量子点用于小鼠治疗中的体内成像 人类癌症模型，以验证其效用。肿瘤特异性量子点将成为细胞免疫学中非常宝贵的试剂 生物学和临床前模型，用于体内、真实的时间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型的药物的体内递送。 纳米颗粒用于替代检测模式或用于治疗。对 生物体中肿瘤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。