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

描述（由申请人提供）：本研究计划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灵敏度和多色成像，以了解和改善纳米颗粒给药。我们将专注于半导体量子点（QDs），这是一种纳米晶体，具有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叫做“合金量子阱”的新型量子点，它可以在广泛的颜色光谱中均匀地显示荧光亮度。这种新特性是有机染料、荧光蛋白或传统量子点无法提供的，它将使纳米颗粒药物递送到实体肿瘤的定量研究成为可能。基本的想法是，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来模拟纳米颗粒药物配方，然后可以定量地比较它们在实体肿瘤中的吸收和渗透。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对药物递送的限速步骤进行单分子的机械理解。这种同时的多色方法对于异质肿瘤微环境的比较至关重要，而传统的光学探针是不可能的。在本研究中，我们将对这些纳米颗粒进行光学工程设计，开发具有紧凑尺寸和长血液循环时间的惰性表面涂层，并基于自组装原理开发新的高精度生物偶联策略。我们将使用这些新探针来成像靶向递送到肿瘤的微观过程，重点关注小囊泡介导的胞吞作用，这是一种主动运输过程，最近被证明可以有效地将纳米颗粒从肿瘤血管泵入间质组织。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Shuming 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，并将接受人类癌症原位模型、活体显微镜技术和基于抗体的肿瘤靶向策略的使用培训。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，这将使专业知识的融合能够指导这个跨学科的研究项目，并促进候选人从受指导的博士后到学术环境中的独立研究者的过渡。

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.