Next-Generation Quantum Dots for Molecular and Cellular Imaging of Cancer

用于癌症分子和细胞成像的下一代量子点

• 批准号: 8466012
• 负责人: Andrew Michael Smith
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-03 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466012
• 关键词: Active Biological Transport; Adsorption; Alloys; Antibodies; Artificial nanoparticles; Award; Behavior; Binding; Biological; Biotin; Blood; Blood Circulation; Cancer Biology; Caveolae; Cells; Chemicals; Chemistry; Color; Complex; Crowding; Data; Development; Diffusion; Drug Delivery Systems; Drug Formulations; Electronics; Engineering; Ensure; Environment; Exhibits; Fluorescence; Fluorescent Dyes; Fluorescent Probes; Generations; Goals; Histidine; Human; Image; Interdisciplinary Study; Lead; Length; Ligands; Malignant Neoplasms; Mechanics; Mediating; Medicine; Mentors; Metals; Microscopic; Microscopy; Modeling; Nanotechnology; Neoplasms in Vascular Tissue; Optics; Penetration; Peptides; Pharmaceutical Preparations; Pharmacotherapy; Phase; Postdoctoral Fellow; Process; Property; Proteins; Pump; Quantum Dots; Recombinant Proteins; Research; Research Institute; Research Personnel; Research Project Grants; Research Proposals; Resistance; Semiconductors; Series; Serum Proteins; Site; Solid Neoplasm; Streptavidin; Surface; Surface Properties; System; Techniques; Technology; Therapeutic; Time; Tissues; Training; Transport Process; Treatment Efficacy; Universities; Work; aerobic respiration control protein; base; cancer imaging; clinical application; clinically significant; design; improved; in vivo; interstitial; intravital microscopy; macromolecule; malignant breast neoplasm; molecular/cellular imaging; nanocrystal; nanoparticle; next generation; novel; particle; protein aminoacid sequence; quantum; research study; self assembly; single molecule; surface coating; targeted delivery; transcytosis; tumor; uptake

Project Summary The aim of this research proposal is to develop a new class of fluorescent nanoparticles for highly sensitive and multicolor imaging of the tumor microenvironment in vivo toward understanding and improving nanoparticle drug delivery. We will focus on semiconductor quantum dots (QDs), which are nanocrystals that exhibit bright fluorescence and unique optical and electronic properties. We have recently designed a new class of quantum dots called 'alloyed quantum wells,' which have equalized fluorescence brightness across a broad spectrum of colors. This novel property is not available from organic dyes, fluorescent proteins, or conventional quantum dots, and will enable quantitative studies of nanoparticle drug delivery to solid tumors. The basic idea is that we can modify the size, surface chemistry, or targeting ligands on these multicolor probes to model nanoparticle drug formulations, which can then be quantitatively compared for uptake and penetration in solid tumors. Because these particles are immensely bright on the single molecule level, intravital microscopy of solid tumors will allow a single-molecule, mechanistic understanding of the rate-limiting steps of drug delivery in a multicolor fashion. This simultaneous multicolor approach is critical for comparisons in the heterogeneous tumor microenvironment, and is not possible with conventional optical probes. In this proposal, we will optically engineer these nanoparticles, develop inert surface coatings for compact sizes and long circulation times in blood, and develop new high-precision bioconjugation strategies based on self- assembly principles. We will use these new probes to image the microscopic processes of targeted-delivery to tumors, concentrating on caveolae-mediated transcytosis, an active transport process that has recently been shown to efficiently pump nanoparticles from the tumor blood vessels into the interstitial tissue. These studies will implement highly relevant orthotopic models of human breast cancer that will ensure clinical significance of the findings. During the mentored phase of this award, the candidate will be co-mentored by Dr. Shuming Nie of Emory University and Dr. Jan Schnitzer of the Proteogenomic Research Institute for Systems Medicine, and will be trained in the use of orthotopic models of human cancer, intravital microscopy techniques, and antibody- based tumor targeting strategies. Both of these mentors are leaders in their respective fields of nanotechnology and cancer biology, which will enable a convergence of expertise to guide this interdisciplinary research project and to facility the transition of the candidate from a mentored postdoctoral fellow to an independent investigator in an academic setting.

项目摘要 该研究建议的目的是开发一种新的荧光纳米颗粒，以高度敏感 以及体内肿瘤微环境的多色成像，用于理解和改善 纳米粒子药物输送。我们将专注于半导体量子点（QD），这是纳米晶体 具有明亮的荧光以及独特的光学和电子特性。我们最近设计了一个新的 一类称为“合金量子井”的量子点，它们在横跨A的荧光亮度均衡 广泛的颜色。这种新型特性不可能从有机染料，荧光蛋白或 常规量子点，并将对纳米颗粒药物递送到实体瘤进行定量研究。 基本思想是，我们可以修改这些多色上的大小，表面化学或靶向配体 探针对纳米粒子药物制剂进行建模，然后可以定量比较摄取和 在实体瘤中渗透。因为这些颗粒在单分子水平上非常明亮，所以 实体瘤的弹力显微镜将允许对速率限制的单分子理解 以多色的方式输送药物的步骤。这种同时多色方法对于比较至关重要 在异质肿瘤微环境中，常规光学探针不可能。在这个 提案，我们将光学地设计这些纳米颗粒，为紧凑尺寸和 血液中的长时间流通时间，并基于自我制定新的高精度生物缀合策略 组装原则。我们将使用这些新探针对目标交付的显微镜过程成像 肿瘤，集中于小窝介导的转胞病，这是一种活跃的运输过程，最近一直是 显示可有效地从肿瘤血管中泵入纳米颗粒进入间质组织。这些研究 将实施人类乳腺癌高度相关的原位模型，以确保 发现。在该奖项的指导阶段，候选人将由Shuming Nie博士授予 埃默里大学（Emory University）和蛋白质组学研究所医学研究所的Jan Schnitzer博士， 将在使用人类癌，插入显微镜技术和抗体的原位模型的使用中接受训练。 基于肿瘤的靶向策略。这两个导师都是各自领域的领导者 纳米技术和癌症生物学，这将使专业知识的融合能够指导这一跨学科 研究项目和设施使候选人从受过指导的博士后研究员过渡到 在学术环境中的独立调查员。