Probing Tumor Microenvironment Using Nanotechnology

描述(申请人提供)：该生物工程研究伙伴关系(BRP)将利用半导体纳米晶体生物医学成像方面的新进展，以探测肿瘤微环境，并开发治疗和诊断策略。为了实现这一目标，我们在麻省总医院(MGH)和麻省理工学院(MIT)组建了一支由科学家和工程师组成的多学科团队，他们在基础和翻译研究方面有着成功的记录。在过去的十年里，这个团队对肿瘤中运输障碍的性质提供了前所未有的洞察力(《自然评论癌症》，2002年)。这些令人兴奋的科学发现源于体内成像的创新(自然医学，1997、2001、2003、2004)、分子工具和量子点技术的开发(自然医学，2005)，以及独特的体外、体内和数学模型的发展(PNAS，1998，JCO，2006)。到目前为止，我们的发现已经导致了改进对肿瘤的药物输送的新策略(《科学》，2005)。由M.Bawendi(量子点的早期先驱)和D.Nocera在麻省理工学院领导的开发核心是这一BRP的基石。他们将开发新的纳米晶体(量子点)结构、生物传感器和免疫结合物，这些不仅对本BRP的所有三个项目至关重要，而且通过创建化学和形态环境的“智能”纳米晶体探针，为基于纳米晶体的生物成像提供了一个新的方向。在由D.Fukumura和L.Munn领导的项目1中，我们的目标是开发纳米粒子的“设计规则”，并应用这些规则来制造“智能”纳米粒子，通过改变它们的大小和电荷，可以绕过肿瘤屏障。在由R.K.Jain领导的项目2中，我们试图用新型纳米晶体生物传感器绘制肿瘤的代谢微环境图，并改进对pH敏感的化疗和对氧敏感的放射治疗。在由D.Duda和Y.Boucher领导的项目3中，我们利用纳米晶体免疫结合探针和生物传感器的多重能力来开发体内多细胞分子和功能表型技术，并建立基于肿瘤间质细胞靶向的新治疗策略。三个项目、两个开发核心和四个科学核心之间高度的科学互动是战略规划的一大优势--正如项目和核心领导人的联合出版物所记录的那样。每个项目都将依赖于由Core A提供的多光子显微镜、数学建模和统计支持；由Core B提供的尖端分子、细胞和组织学专业知识；由Core C提供的卓越外科和动物支持；以及由Core D提供的行政支持。我们还拥有资源和临床合作者，可以随时将我们的科学发现应用于临床试验(《自然医学》，2004，《癌症细胞》，2007)。

DESCRIPTION (provided by applicant): This Bioengineering Research Partnership (BRP) will exploit emerging advances in semiconductor nanocrystal-based biomedical imaging to probe the tumor microenvironment and to develop therapeutic and diagnostic strategies. To accomplish this, we have assembled a multidisciplinary team of scientists and engineers at the Massachusetts General Hospital (MGH) and Massachusetts Institute of Technology (MIT) with a successful track record of basic and translational research. Over the past decade, this team has provided unprecedented insight into the nature of transport barriers in tumors (Nature Reviews Cancer, 2002). These exciting scientific findings resulted from innovations in intravital imaging (Nature Medicine, 1997, 2001, 2003, 2004), from exploiting molecular tools and quantum dot technology (Nature Medicine, 2005), and from the development of unique in vitro, in vivo, and mathematical models (PNAS, 1998, JCO, 2006). Our discoveries to date have led to novel strategies for improving drug delivery to tumors (Science, 2005). Development Cores led by M. Bawendi (an early pioneer of quantum dots) and D. Nocera at MIT are the corner stone of this BRP. They will develop novel nanocrystal (quantum dot) constructs, biosensors, and immunoconjugates which are not only essential for all three projects in this BRP but also provide a new direction in nanocrystal based bio-imaging by creating "smart" nanocrystal probes of chemical and morphological environment. In Project 1, led by D. Fukumura and L. Munn, we aim to develop "design rules" for nanoparticles and apply these rules to make "smart" nanoparticles that, by changing their size and charge, can circumvent tumor barriers. In Project 2, led by R.K.Jain, we seek to map metabolic microenvironment of tumors with novel nanocrystal based biosensors and improve pH-sensitive chemotherapy and oxygen-sensitive radiation therapy. In Project 3, led by D. Duda and Y. Boucher, we harness the multiplexing capabilities of nanocrystal immunoconjugate probes and biosensors to develop in vivo multi-cell molecular and functional phenotyping techniques and establish a novel treatment strategy based on targeting stromal cells in tumors. A high level of scientific interaction among the three Projects, two Development Cores and four scientific Cores is a major strength of the BRP - as documented in joint publications by Project and Core leaders. Each Project will rely on multi-photon microscopy, mathematical modeling, and statistical support provided by Core A; cutting-edge molecular, cellular and histological expertise provided by Core B; superb surgical and animal support provided by Core C; and administrative support provided by Core D. We also have the resources and the clinical collaborators in place to readily take our scientific findings to clinical trials (Nature Medicine, 2004, Cancer Cell, 2007).