Multi-Layered Valency: A Novel Design of Peptidic Imaging Agents for ??v??6

多层化合价：??v??6 肽显像剂的新颖设计

基本信息

批准号：
8507549
负责人：
Kathlynn C Brown
金额：
$ 33.74万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8507549
关键词：
Affinity Animal Model Animals Antibodies Attention Bacteriophages Binding Biodistribution Biological Markers Biopsy Blood Cell surface Cells Chelating Agents Chemicals Detection Development Diagnosis Diagnostic Imaging Disease Disease Progression Epithelial Evaluation Fibrosis Filtration Floods Foundations Generations Goals Half-Life Hamman-Rich syndrome Image Immunoglobulin Fragments In Vitro Integrins Kidney Laboratories Lesion Life Ligand Binding Ligands Lung Malignant Neoplasms Malignant neoplasm of lung Medicine Modeling Modification Molecular Molecular Profiling Non-Small-Cell Lung Carcinoma Organism PET/CT scan Patients Peptide Phage Display Library Peptides Phage Display Phase I Clinical Trials Plasma Positron-Emission Tomography Property Radiation therapy Radioisotopes Reading Reporting Series Solid Neoplasm Specificity Therapeutic Translating Work cell type clinical application design driving force imaging probe improved in vivo innovation molecular imaging novel particle peptide structure pre-clinical research study scaffold screening synthetic peptide tumor

项目摘要

DESCRIPTION (provided by applicant): Recent efforts in diagnostic imaging have focused not only on improving anatomical imaging but designing approaches to detect molecular changes within a living system. Pioneering work in immuno-PET demonstrates the power of molecular imaging. However, the number of ligands that bind disease specific cell surface biomarkers must be expanded to fully realize the power of molecular imaging. Synthetic peptides have attracted attention as targeting molecules to deliver radioisotopes to in vivo targets for imaging. This has been stimulated in part by advances in screening phage-displayed peptide libraries to identify peptidic ligands that target different cell types. Yet, a flood of peptide guided imaging agents has not occurred. This is partially due to the difficulty in retaining the affinity and actiity of peptides outside of the context of the phage particle. Moreover, peptides typically have short half-lives in the blood because of degradation and rapid renal filtration, which limits their accumulation in their targets. Multimerization can improve affinity, enhance stability, and extend in vivo half-life of peptides. None-the-less, most current multimeric peptide constructs are not systematically designed. We propose to create multivalent peptidic PET imaging agents in which the valency can be layered using a novel bifunctional chelator scaffold (BFCS) and a unique multimeric peptide scaffold for displaying cell-targeting peptides. First, we will take advantage of a multivalent BFCS for multimeric peptide presentation. Second, we will generate a series of multimeric peptides that can be conjugated to a monovalent BFCS. Finally, we will combine the multivalent BFC scaffolds with the multivalent peptides to create higher order peptide structures that can be used for PET imaging. The valency will vary from 1-8 peptide branches per molecule. To develop this probe design, we will use a peptide isolated in our laboratory which binds with high affinity and specificity to the restrictively expressed integrin ?v?6. This integrin is a biomarker for a number of epithelial derived cancers and lung fibrosis, diseases in which molecular imaging probes would have wide clinical applicability. Aim 1 will identify the optimal valency while aim 2 focuses on chemically modifying the peptide to achieve optimal biodistribution. In aim 3, we will utilize the optimized probe to image ?v?6 in other cancers as well as in a model of idiopathic pulmonary fibrosis. The imaging agent is anticipated to have a wide impact on molecular imaging of ?v?6 in solid tumors and fibrotic diseases. These experiments will lay the foundation for moving into preclinical and Phase I clinical trials.

描述（由申请人提供）：最近在诊断成像方面的努力不仅集中于改进解剖成像，还集中于设计检测生命系统内分子变化的方法。免疫 PET 领域的开创性工作展示了分子成像的力量。然而，必须扩大结合疾病特异性细胞表面生物标志物的配体数量，才能充分发挥分子成像的威力。合成肽作为将放射性同位素传递到体内靶点进行成像的靶向分子而引起了人们的关注。这在一定程度上是由于筛选噬菌体展示肽库以识别针对不同细胞类型的肽配体的进展所刺激的。然而，肽引导成像剂的大量涌现尚未出现。这部分是由于在噬菌体颗粒的环境之外难以保留肽的亲和力和活性。此外，由于降解和快速肾过滤，肽在血液中的半衰期通常很短，这限制了它们在目标中的积累。多聚化可以提高肽的亲和力、增强稳定性并延长体内半衰期。尽管如此，大多数当前的多聚肽构建体都不是系统设计的。我们建议创建多价肽 PET 成像剂，其中可以使用新型双功能螯合剂支架 (BFCS) 和用于展示细胞靶向肽的独特多聚肽支架对价进行分层。首先，我们将利用多价 BFCS 进行多聚肽呈递。其次，我们将生成一系列可以与单价 BFCS 缀合的多聚肽。最后，我们将多价 BFC 支架与多价肽结合起来，创建可用于 PET 成像的更高阶肽结构。每个分子的化合价从 1-8 个肽分支不等。为了开发这种探针设计，我们将使用在我们实验室分离的肽，该肽以高亲和力和特异性与限制性表达的整联蛋白αvβ6结合。这种整合素是许多上皮来源的癌症和肺纤维化的生物标志物，分子成像探针在这些疾病中具有广泛的临床适用性。目标 1 将确定最佳化合价，而目标 2 侧重于对肽进行化学修饰以实现最佳生物分布。在目标 3 中，我们将利用优化的探针对其他癌症以及特发性肺纤维化模型中的 ?v?6 进行成像。预计该显像剂将对实体瘤和纤维化疾病中αvβ6的分子成像产生广泛影响。这些实验将为进入临床前和一期临床试验奠定基础。