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

Case Western Reserve University, Cleveland OH

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Abstract

? 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.