MicroPET and NIR Fluorescence Imaging Tumor Angiogenesis

描述(申请人提供)：我们的长期目标是开发和验证新的成像标记物和技术，以识别癌症前期或癌症细胞的血管生成特性，从而预测临床过程和干预反应。最近发现，肿瘤的生长依赖于血管生成，肿瘤的血管密度与其转移潜能之间存在着特定的相关性。以阻断肿瘤新生血管生长为目标的抗血管生成治疗引起了人们的极大兴趣，因为它们可能为癌症的长期控制提供一种实用的手段。影像可以在抗血管生成治疗的临床前发展和临床应用中发挥重要作用。整合素αvbeta3是影响肿瘤生长、局部侵袭和转移潜能的重要黏附受体，在静止的血管中不易检测到，但在血管新生血管和多种人类恶性肿瘤中高表达。通过用含有Arg-Gly-Asp(RGD)氨基酸序列的小肽拮抗αvbeta3整合素，可以在体内阻断肿瘤血管的生成。由于其高度限制性的表达和在血管生成中的重要作用，αvbeta3整合素是一种有吸引力的抗癌治疗候选基因。能够量化αvbeta3在肿瘤和其他血管生成相关疾病中的表达水平对于alphavbeta3靶向治疗的治疗计划至关重要。用于评估肿瘤靶向效果的分子探针的系统优化以及体内药代动力学和药效学也将使快速药物筛选和新药发现成为可能。在这个项目中，我们计划开发一系列新的基于环状RGD肽的探针，用于microPET和光学成像不同实体肿瘤模型中的肿瘤血管生成。目的1：标记环RGD多肽，用于胶质母细胞瘤模型的microPET和近红外荧光(NIRF)成像。目的：应用肿瘤靶向性和体内药代动力学最佳的放射性示踪剂和NIRF探针对不同实体瘤模型进行成像。我们预计，使用microPET和NIRF成像对αvbeta3表达和功能活性的无创系列研究将成为相互补充的重要工具，以评估αvbeta3整合素在肿瘤进展和转移中的作用。所得结果将用于将来申请R01型奖助金。

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.