MicroPET and NIR Fluorescence Imaging Tumor Angiogenesis

描述（由申请人提供）：我们的长期目标是开发和验证新的成像标记和技术，以识别癌前细胞或癌细胞的血管生成特性，从而预测临床过程和对干预的反应。最近已经确定肿瘤的生长依赖于血管生成，并且在癌症的血管密度和它们的转移潜能之间存在特定的相关性。旨在阻断肿瘤中新血管生长的抗血管生成疗法引起了极大的兴趣，因为它们可能为长期控制癌症提供一种实用的手段。成像在抗血管生成治疗的临床前开发和临床应用中发挥着重要作用。整合素α β 3在静止血管中不易检测到，但在血管生成血管和各种恶性人类肿瘤中高表达，是影响肿瘤生长、局部侵袭和转移潜能的重要粘附受体。肿瘤血管生成可以通过含有Arg-Gly-Asp （RGD）氨基酸序列的小肽拮抗α - β 3整合素在体内阻断。由于其高度受限的表达和在血管生成中的重要作用，α β 3整合素是抗癌治疗的一个有吸引力的候选者。能够量化alphavbeta3在肿瘤及其他血管生成相关疾病中的表达水平，对于制定alphavbeta3靶向治疗的治疗方案至关重要。系统优化分子探针对肿瘤靶向疗效的评价以及体内药代动力学和药效学，也将使药物快速筛选和新药发现成为可能。在本项目中，我们建议开发一系列基于环状RGD肽的新型探针，用于不同实体瘤模型中肿瘤血管生成的显微pet和光学成像。目的1：标记环状RGD肽，用于胶质母细胞瘤模型的微pet成像和近红外荧光成像。目的2：利用具有最佳肿瘤靶向效果和体内药代动力学的放射性示踪剂和NIRF探针对不同实体肿瘤模型进行成像。我们预计，利用microPET和NIRF成像技术对alphavbeta3的表达和功能活性进行无创系列研究，将成为评估alphavbeta3整合素在肿瘤进展和转移中的作用的重要工具。在此获得的所有结果将用于将来申请R01类拨款。

DESCRIPTION (provided by applicant): Our long-term objective is to develop and validate new imaging markers and techniques that identify the angiogenic properties of precancerous or cancerous cells that will predict clinical course and response to intervention. It has been recently established that tumor growth is angiogenesis dependent, and there is a specific correlation between blood vessel density in cancers and their metastatic potential. Anti-angiogenic therapy aimed at blocking new blood vessel growth in tumors is of great interest, since they may provide a practical means for long-term control of cancer. Imaging can play a major role in the pre-clinical development and clinical application of anti-angiogenic therapy. Integrin alphavbeta3, which is not readily detectable in quiescent vessels but becomes highly expressed in angiogenic vessels and various malignant human tumors, is an important adhesion receptor affecting tumor growth, local invasiveness, and metastatic potential. Tumor angiogenesis can be blocked in vivo by antagonizing the alphavbeta3 integrin with small peptides containing the Arg-Gly-Asp (RGD) amino acid sequence. Because of its highly restricted expression and its vital role in angiogenesis, the alphavbeta3 integrin is an attractive candidate in anticancer therapy. The ability to quantify the alphavbeta3 expression level in tumors and other angiogenesis related diseases is of vital importance for therapeutic planning of alphavbeta3 targeted therapy. Systemic optimization of molecular probes for evaluation of tumor targeting efficacy as well as in vivo pharmacokinetics and pharmacodynamics will also enable rapid drug screening and new drug discovery. In this project we propose to develop a series of new cyclic RGD peptide based probes for microPET and optical imaging of tumor angiogenesis in different solid tumor models. Aim 1: label cyclic RGD peptides for microPET imaging and near-infrared fluorescence (NIRF) imaging of glioblastoma model. Aim 2: Apply the radiotracers and NIRF probes with optimal tumor targeting efficacy and in vivo pharmacokinetics to image different solid tumor models. We anticipate that noninvasive serial studies of alphavbeta3 expression and functional activity using microPET and NIRF imaging will become important tools complementary each other to evaluate the role of alphavbeta3 integrin during tumor progression and metastasis. All the results obtained here will be used for future application of a R01 type grant.