A Molecular Scaffold for Colonic Drug Delivery

A molecule which passes through the gastrointestinal tract was successfully synthesized and tested for GI MRI imaging in mice. A molecular scaffold bearing eight terminal alkyne groups was synthesized from sucrose, and copies of an azide-terminated Gd-DOTA complex were attached via copper(I)-catalyzed azide-alkyne cycloaddition. This contrast agent was administered by gavage to C3H mice. Passage of the CA through the gastrointestinal tract was followed by T1-weighted magnetic resonance imaging (MRI) over a period of 48 hours. Thus, a new, orally administered, GI-specific contrast agent for MRI has been developed and successfully demonstrated.

Background:
Gastrointestinal (GI) radiography using barium contrast media has been widely used as a first-choice diagnostic imaging modality for detection of GI pathologies. Colonoscopy is the standard of care for colorectal cancer screening. However, colonoscopy is an invasive procedure that requires intravenous sedation and suffers from patient noncompliance. CT colonography has high sensitivity to identify large polyps, but sensitivity decreases with polyp size and radiation dosage is a concern. MRI colonography uses non-ionizing radiation and provides lesion detection with high specificity, yet modest sensitivity. MRI colonography has been indicated in cases of incomplete colonoscopy, due to obstruction, and is increasingly being applied as a non-invasive screening tool without the need for sedation.

Advantages: 

• Targeted contrast agents for molecular imaging of GI lesions or pathologies may circumvent these many limitations of current MR-C
• CAs that have multiple Gd-chelates per molecule may exhibit increased molar relaxivities (r1), making the contrast agent detectable at lower concentrations than previously developed MRI colonography agents
• The advantages of such an agent leverage the benefits of strongly enhanced tumors in T1-weighted images, resulting in a significantly lower limit of detectability without the need to use bright or dark lumen methods
• If such an agent were targeted to a cell-surface marker that is specifically expressed in GI lesions or pathologies, but not in surrounding GI tissue, it would provide the benefits of lesion specificity and enhanced sensitivity after unbound agent has cleared from the GI tract

Applications: 

• GI-specific MRI contrast agent