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

描述(申请人提供)：这项研究计划的目的是开发一种新型的荧光纳米颗粒，用于体内肿瘤微环境的高灵敏度和多色成像，以了解和改善纳米颗粒的药物传递。我们将重点介绍半导体量子点，这是一种纳米晶体，具有明亮的荧光和独特的光学和电学性质。我们最近设计了一种新的量子点，称为合金量子井，它可以使广泛的颜色范围内的荧光亮度相等。这种新的性质是有机染料、荧光蛋白或传统量子点所不具备的，它将使对纳米药物输送到实体肿瘤的定量研究成为可能。其基本思想是，我们可以改变这些多色探针上的尺寸、表面化学或靶向配体来模拟纳米药物配方，然后可以定量比较它们在实体肿瘤中的摄取和渗透。由于这些颗粒在单分子水平上非常明亮，实体肿瘤的活体显微镜将允许以多色方式单分子、机械地理解药物输送的限速步骤。这种同时的多色方法对于在不同的肿瘤微环境中进行比较是至关重要的，传统的光学探针是不可能的。在这项计划中，我们将对这些纳米粒子进行光学工程，开发用于致密尺寸和血液循环时间较长的惰性表面涂层，并基于自组装原理开发新的高精度生物偶联策略。我们将使用这些新的探针来成像靶向递送到肿瘤的微观过程，集中在小窝介导的跨细胞作用，这是一种最近被证明有效地将纳米颗粒从肿瘤血管泵入间质组织的主动转运过程。这些研究将实施高度相关的人类乳腺癌原位模型，以确保研究结果的临床意义。在该奖项的指导阶段，候选人将由埃默里大学的Nhuming Nie博士和系统医学蛋白质基因组研究所的Jan Schnitzer博士共同指导，并将接受使用人类癌症原位模型、活体显微技术和基于抗体的肿瘤靶向策略的培训。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，这将使专业知识得以汇聚，以指导这一跨学科研究项目，并促进候选人从受指导的博士后研究员转变为学术环境中的独立研究员。 公共卫生相关性：基于纳米颗粒的药物是一种很有前途的癌症治疗方法，然而，我们合理和优化设计这些颗粒的能力目前受到对它们在肿瘤中的行为缺乏了解的限制。在这项计划中，我们将开发一类新的荧光纳米颗粒探测器，使高灵敏度、定量、单分子成像和跟踪癌症组织中的纳米颗粒成为可能。我们将使用这些探针来了解靶向肿瘤的纳米颗粒传递的机制，以提供将增强肿瘤摄取和治疗效果的设计参数。

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.