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

• 批准号: 8956924
• 负责人: Kathlynn C Brown
• 金额: $ 34.7万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 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/8956924
• 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

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在改进解剖成像上，而且还集中在设计检测生命系统内分子变化的方法上。免疫PET的开创性工作证明了分子成像的力量。然而，结合疾病特异性细胞表面生物标志物的配体的数量必须扩大以充分实现分子成像的能力。合成肽作为靶向分子将放射性同位素递送到体内靶点用于成像已经引起了关注。 这在一定程度上受到了筛选噬菌体展示肽库以鉴定靶向不同细胞类型的肽配体的进展的刺激。然而，肽引导的成像剂的洪水还没有发生。这部分是由于在噬菌体颗粒的环境之外难以保持肽的亲和力和活性。此外，由于降解和快速肾过滤，肽通常在血液中具有短的半衰期，这限制了它们在其靶标中的积累。多聚化可以提高亲和力，增强稳定性，并延长肽的体内半衰期。尽管如此，大多数当前的多聚体肽构建体不是系统设计的。我们建议创建多价肽PET成像剂，其中化合价可以使用新型双功能螯合剂支架（BFCS）和独特的多聚体肽支架进行分层，用于显示细胞靶向肽。首先，我们将利用多价BFCS进行多聚体肽呈递。第二，我们将产生一系列可以与单价BFCS缀合的多聚体肽。最后，我们将联合收割机结合多价BFC支架与多价肽，以创建可用于PET成像的更高级肽结构。化合价将从每分子1-8个肽分支变化。为了开发这种探针设计，我们将使用在我们的实验室中分离的肽，其以高亲和力和特异性结合到限制性表达的整合素？v？6.这种整联蛋白是许多上皮来源的癌症和肺纤维化的生物标志物，其中分子成像探针将具有广泛的临床应用性。目标1将确定最佳的化合价，而目标2侧重于化学修饰肽，以实现最佳的生物分布。在目标3中，我们将利用优化的探针图像？v？6在其他癌症中以及在特发性肺纤维化模型中。该显像剂预计将有广泛的影响，分子成像？v？6例实体瘤和纤维化疾病。这些实验将为进入临床前和I期临床试验奠定基础。