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: 9094573
• 负责人: Nicole Franziska Steinmetz
• 金额: $ 23.03万
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9094573
• 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; Health; 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 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; scaffold; scale up; self assembly; small molecule; soft tissue; success; surface coating; targeted agent; 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.



项目成果

Viral nanoparticles decorated with novel EGFL7 ligands enable intravital imaging of tumor neovasculature.

• DOI: 10.1039/c7nr02558k
• 发表时间: 2017-08-24
• 期刊: Nanoscale
• 影响因子: 6.7
• 作者: Cho CF;Yu L;Nsiama TK;Kadam AN;Raturi A;Shukla S;Amadei GA;Steinmetz NF;Luyt LG;Lewis JD
• 通讯作者: Lewis JD

Optical and Magnetic Resonance Imaging Using Fluorous Colloidal Nanoparticles.

• DOI: 10.1021/acs.biomac.6b01389
• 发表时间: 2017-01-09
• 期刊: Biomacromolecules
• 影响因子: 6.2
• 作者: Wallat JD;Czapar AE;Wang C;Wen AM;Wek KS;Yu X;Steinmetz NF;Pokorski JK
• 通讯作者: Pokorski JK