Detection of lethal prostate cancer with macromolecule-based, EGFL-7 targeted MR imaging approach

使用基于大分子的 EGFL-7 靶向 MR 成像方法检测致命性前列腺癌

• 批准号: 8954282
• 负责人: Nicole Franziska Steinmetz
• 金额: $ 20.29万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8954282
• 关键词: Accounting; Affinity; American; Angiogenic Factor; Animal Model; Applications Grants; Architecture; Area; Benign; Binding; Biodistribution; Biological Markers; Blood; CD47 gene; Cancer Patient; Cell Adhesion; Cells; Cessation of life; Chemistry; Clinical; Contrast Media; Detection; Diagnosis; Diagnostic; Discipline of Nuclear Medicine; Disease; Disease Progression; Dose; Drug Kinetics; Early Diagnosis; Endothelial Cells; Engineering; Epidermal Growth Factor; Equilibrium; Exhibits; Extracellular Matrix; Gadolinium; Goals; Histology; Human; Image; Imagery; Immune; In Vitro; Indolent; Ionizing radiation; Length; Ligand Binding; Ligands; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Medicine; Molecular; Molecular Profiling; Molecular Target; Mononuclear; Morbidity - disease rate; Mus; Nanotubes; Optics; Patients; Peptides; Phagocytes; Preparation; Proteins; Protocols documentation; Resolution; Screening for Prostate Cancer; Shapes; Signal Transduction; Specificity; Stratification; Surface; System; Technology; Tissues; Tobacco Mosaic Virus; Toxic effect; Vascular Endothelium; angiogenesis; base; biomaterial compatibility; cancer diagnosis; cancer therapy; cohort; fluorescence imaging; follow-up; gadolinium 1,4,7,10-tetraazacyclododecane-N,N' ,N' ' ,N' ' ' -tetraacetate; gadolinium oxide; high risk; imaging probe; immune clearance; in vivo; in vivo imaging; macromolecule; men; minimally invasive; molecular imaging; mortality; nanoparticle; outcome forecast; particle; pre-clinical; programs; public health relevance; scaffold; scale up; self assembly; small molecule; soft tissue; success; surface coating; tool; translational study; tumor

 DESCRIPTION (provided by applicant): Imaging approaches have made a transformative impact in medicine, allowing the detection of disease before clinical manifestation, and facilitating diagnosis, prognosis, and the longitudinal follow-up of disease progression and treatment success. Magnetic resonance imaging (MRI) provides high spatial resolution and soft tissue contrast without exposing the patient to ionizing radiation. However, diagnosis can be difficult in areas where diseased and healthy tissues produce similar signal intensities. We propose macromolecular contrast-enhancement agents that are targeted to molecular signatures and that deliver a large payload of magnetic resonance contrast Gd(DOTA) agents. We will evaluate the proposed MRI contrast agents in the setting of prostate cancer. The balance between early diagnosis and the potential for overtreatment in prostate cancer remains a clinical dilemma. To distinguish between aggressive and indolent disease, we propose a minimally-invasive molecular imaging approach targeting epidermal growth factor-like 7 (EGFL7). This is a pro-angiogenic factor whose expression is restricted to actively-remodeling vascular endothelium and correlates with poor prognosis. We have isolated peptide ligands that bind EGFL7 (HMYFLLGH) with high selectively and affinity (KD 7.2 nM). For effective MRI, carriers are required to deliver a sufficient payload of contrast enhancement agents; we have developed a supramolecular MRI contrast agent carrying large payloads of chelated gadolinium (Gd(DOTA)) which exhibits a T1 relaxivity of ~35,000 mM-1 s-1. This is four orders of magnitude higher than small-molecule agents, allowing the visualization of molecular signatures in vivo at sub-micromolar doses of Gd(DOTA). The contrast agent is self-assembled using hollow protein nanotubes formed by tobacco mosaic virus (TMV), which shows excellent blood and tissue biocompatibility, including rapid tissue clearance to avoid long-term toxicity. The elongated shape of the nanotube allows it to evade the mononuclear phagocyte system (MPS) and enhances molecular targeting. Building on these exciting results, we propose to develop this technology as a diagnostic tool for prostate cancer stratification. Toward this long-term goal, thi proposal sets out to optimize the shape and surface chemistry of the contrast agent to achieve high sensitivity and spatial resolution of the angiogenic signatures. A bottom-up self-assembly protocol will be used to produce nanotubes of various length and surface coatings including stealth and camouflage will be applied to avoid immune clearance and enhance molecular targeting. The probes will be evaluated in animal models of prostate cancer. MRI results will be validated by fluorescence imaging and histology. We hypothesize that the macromolecular MRI probe will outperform contemporary small-molecule, peptide-based agents by increasing sensitivity by at least three orders of magnitude. This will be achieved by delivering larger payloads and by optimized molecular targeting (surface chemistry and carrier shape). This technology could make a broad impact in MR imaging approaches aiding diagnosis and prognosis across malignancies.

 描述（由适用提供）：成像方法对医学产生了变革性的影响，允许在临床表现前检测疾病，并支持诊断，预后以及疾病进展和治疗成功的纵向随访。磁共振成像（MRI）提供了高空间分辨率和软组织对比度，而无需暴露患者电离辐射。但是，在患病和健康组织产生相似信号强度的地区可能很困难。我们提出了针对分子特征的大分子对比增强剂，并提供大量的有效磁共振对比度GD（DOTA）剂。我们将在前列腺癌的情况下评估所提出的MRI对比剂。早期诊断与前列腺癌过度治疗的潜力之间的平衡仍然是临床困境。为了区分侵略性和惰性疾病，我们提出了一种靶向表皮生长因子样7（EGFL7）的最小侵入性分子成像方法。这是一个促血管生成因子，其表达仅限于主动重塑血管内皮，并且与预后不良相关。我们具有与高度选择性和亲和力（KD 7.2 nm）结合EGFL7（HMYFLLGH）的分离肽配体。对于有效的MRI，要求运营商提供足够的对比度增强剂的有效载荷；我们已经开发了一种超分子MRI对比剂，该对比剂具有大量的化学处理gadolinium（GD（DOTA）），其T1松弛度约为35,000 mm-1 S-1。这是四个比小分子剂高四个数量级，从而可以在GD亚微摩尔剂量（dota）的体内可视化分子特征。对比剂是使用由烟草病毒（TMV）形成的空心蛋白纳米管进行自组装的，该纳米管（TMV）显示出极好的血液和组织生物相容性，包括快速的组织清除率，以避免长期毒性。纳米管的细长形状使其能够逃避单核吞噬细胞系统（MPS）并增强分子靶向。在这些令人兴奋的结果的基础上，我们建议开发这项技术作为前列腺癌分层的诊断工具。为了实现这一长期目标，THI提议着手优化对比剂的形状和表面化学，以实现血管生成特征的高灵敏度和空间分辨率。自下而上的自组装方案将用于生产各种长度和表面涂层在内的纳米管，包括隐形和伪装，以避免免疫清除率并增强分子靶向。这些问题将在前列腺癌的动物模型中进行评估。 MRI结果将通过荧光成像和组织学来验证。我们假设大分子MRI探针将通过至少提高敏感性至少三个数量级来优于当代小分子的基于肽的剂。这将通过提供较大的有效载荷和优化的分子靶向（表面化学和载体形状）来实现。这项技术可能会在MR成像方法中产生广泛的影响，从而帮助诊断和跨恶性肿瘤的预后。