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: 8009750
• 负责人: Andrew Michael Smith
• 金额: $ 8.67万
• 依托单位: EMORY UNIVERSITY
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8009750
• 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; efficacy research; improved; in vivo; interstitial; intravital microscopy; macromolecule; malignant breast neoplasm; molecular/cellular imaging; nanocrystal; nanoparticle; next generation; novel; particle; protein aminoacid sequence; public health relevance; quantum; research study; self assembly; single molecule; surface coating; targeted delivery; transcytosis; tumor; uptake

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Nanoparticle-based drugs are a promising therapeutic approach for cancer, however our ability to rationally and optimally design these particles is currently limited by a poor understanding of their behavior in tumors. In this proposal, we will develop a new class of fluorescent nanoparticle probes that will enable highly sensitive, quantitative, single-molecule imaging and tracking of nanoparticles in cancer tissue. We will use these probes to understand the mechanisms of targeted nanoparticle delivery to tumors to inform design parameters that will enhance tumor uptake and therapeutic efficacy.

描述（由申请人提供）：该研究建议的目的是开发一类新的荧光纳米颗粒，用于体内肿瘤微环境的高度敏感和多色成像，以理解和改善纳米粒子药物的递送。我们将专注于半导体量子点（QD），纳米晶体表现出明亮的荧光和独特的光学和电子特性。我们最近设计了一种新的量子点，称为“合金量子井”，它们在各种颜色上都均衡了荧光亮度。这种新型特性不可能从有机染料，荧光蛋白或常规量子点中获得，并且可以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探针上的大小，表面化学或靶向配体，以模拟纳米粒子药物制剂，然后可以定量比较实体瘤中的摄取和渗透。由于这些颗粒在单分子水平上非常明亮，因此实体瘤的浸润显微镜将允许以多色方式对药物递送的速率限制步骤产生单分子的理解。这种同时的多色方法对于在异质肿瘤微环境中进行比较至关重要，并且在常规光学探针中不可能。在此提案中，我们将光学地设计这些纳米颗粒，开发出惰性的表面涂层，以使血液中的大小和长期循环时间在血液中开发，并根据自组装原理制定新的高精度生物缀合策略。我们将使用这些新探针来对肿瘤的靶向分娩的显微镜过程进行成像，并集中在小窝介导的转胞膜上，这是一种活跃的转运过程，最近已证明可以有效地从肿瘤血管中泵送纳米颗粒进入间隙组织。这些研究将实施高度相关的人类乳腺癌的原位模型，以确保发现结果的临床意义。在该奖项的指导阶段，候选人将由埃默里大学的Shuming Nie博士和蛋白质组学系统医学研究所的Jan Schnitzer博士进行，并将接受培训的人类癌症，玻璃体显微镜技术的原始模型，基于抗体的肿瘤靶向策略。这两位导师都是各自纳米技术和癌症生物学领域的领导者，这将使专业知识能够指导这项跨学科研究项目，并设施将候选人从学术环境中的一名受过指导的博士后研究员转变为独立研究者。 公共卫生相关性：基于纳米颗粒的药物是癌症的一种有希望的治疗方法，但是我们在理性和最佳设计上设计这些颗粒的能力目前受到对它们在肿瘤中行为的不良了解的限制。在此提案中，我们将开发一类新的荧光纳米粒子探针，该探针将实现高度敏感，定量，单分子成像和癌组织中纳米颗粒的跟踪。我们将使用这些探针来了解靶向纳米颗粒向肿瘤的递送的机制，以告知设计参数，以增强肿瘤摄取和治疗功效。