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（由申请人提供）：成像方法对医学产生了变革性影响，允许在临床表现之前检测疾病，并促进诊断、预后以及疾病进展和治疗成功的纵向随访。 ）提供高空间分辨率和软组织对比度，而无需使患者暴露于电离辐射，但是，在患病组织和健康组织产生相似信号强度的区域中，诊断可能会很困难。我们将评估所提出的 MRI 造影剂在前列腺癌中的作用。前列腺癌的早期诊断和过度治疗的可能性之间的平衡仍然是一个临床困境。为了区分侵袭性和惰性疾病，我们提出了一种针对表皮生长因子样 7 (EGFL7) 的微创分子成像方法。这是一种促血管生成因子，其表达仅限于主动重塑的血管内皮和血管内皮细胞。我们已经分离出以高选择性和亲和力 (KD 7.2 nM) 结合的肽配体，需要载体提供足够的造影剂增强负载；携带大量螯合钆 (Gd(DOTA)) 的造影剂，其 T1 弛豫率约为 35,000 mM-1 s-1。这比小分子试剂高四个数量级，可以在亚微摩尔剂量的 Gd(DOTA) 下实现体内分子特征的可视化，该造影剂是使用烟草形成的中空蛋白质纳米管进行自组装的。花叶病毒（TMV），表现出优异的血液和组织生物相容性，包括快速组织清除以避免长期毒性。纳米管的细长形状使其能够逃避单核吞噬细胞系统（MPS）和基于这些令人兴奋的结果，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，该提案着手优化造影剂的形状和表面化学以实现高水平。将使用自下而上的自组装方案来生产各种长度的纳米管，并应用包括隐形和伪装在内的表面涂层来避免免疫清除和分子增强靶向。在前列腺癌的动物模型中进行评估，我们将通过荧光成像和组织学来验证大分子 MRI 探针的灵敏度，从而将其性能提高至少三个数量级。通过提供更大的有效载荷和优化分子靶向（表面化学和载体形状）来实现该技术可以对有助于恶性肿瘤诊断和预后的 MR 成像方法产生广泛影响。