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

项目摘要 这项研究计划的目的是开发一类新的荧光纳米颗粒，用于高灵敏度的 和肿瘤微环境的生物成像，以了解和改善 纳米颗粒药物递送。我们将关注半导体量子点（QD），这是纳米晶体， 显示出明亮的荧光和独特的光学和电学性质。我们最近设计了一个新的 这类量子点被称为“合金量子威尔斯”，其在整个量子点上具有均衡的荧光亮度。 颜色的光谱。这种新颖的性质是有机染料、荧光蛋白或 传统的量子点，并将使定量研究纳米颗粒药物输送到实体肿瘤。 基本的想法是，我们可以改变这些纳米颗粒的大小、表面化学性质或靶向配体， 探针来模拟纳米颗粒药物制剂，然后可以定量地比较纳米颗粒药物制剂的摄取和 在实体瘤中的渗透。因为这些粒子在单分子水平上非常明亮， 实体瘤的活体显微镜检查将允许对肿瘤的限速机制进行单分子的、机械的理解。 以一种快速的方式给药的步骤。这种同时进行的方法对于比较至关重要 在异质性肿瘤微环境中，这是常规光学探针无法实现的。在这 我们将对这些纳米粒子进行光学工程设计，开发紧凑尺寸的惰性表面涂层， 在血液中循环时间长，并开发新的高精度生物结合策略， 组装原则。我们将使用这些新的探针来成像靶向递送的微观过程， 肿瘤，集中在小窝介导的转胞吞，一个积极的运输过程，最近已被 显示出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 调查结果在此奖项的指导阶段，候选人将由聂树明博士共同指导 和系统医学蛋白基因组研究所的Jan Schnitzer博士， 将接受使用人类癌症原位模型、活体显微镜技术和抗体- 基于肿瘤靶向策略。这两位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，以指导这一跨学科的 研究项目和设施的候选人从一个指导博士后研究员过渡到一个 学术环境中的独立调查员。

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.