Eric Tanifum PhD, Presenter: Stockholder, Alzeca Biosciences LLC

Ketan B. Ghaghada PhD, Abstract Co-Author: Research Grant, Marval Biosciences Inc Consultant, Marval Biosciences Inc Shareholder, Marval Biosciences Inc

Zbigniew Starosolski PhD, Abstract Co-Author: Stockholder, Alzeca Biosciences, LLC

Ananth Annapragada PhD, Abstract Co-Author: Stockholder, Marval Pharma Ltd Stockholder, Alzeca Biosciences LLC Stockholder, Sensulin LLC Stockholder, Abbott Laboratories Stockholder, Johnson & Johnson

A hyper-relaxive Gd containing liposome targeted to amyloid plaques by a novel targeting ligand was fabricated. We tested (a) the ability of this particle to label amyloid plaques, and (b) detection of the labeling by T1-weighted MRI. If sufficiently sensitive and specific, such particles could be alternatives to PET based molecular imaging agents.

 Liposomes targeted to amyloid plaques by a novel amyloid binding ligand, surface-coated with Gd-DOTA and containing  ICG (10µM) for near-Infrared detection, were fabricated. They were injected into 9-month old Tg2576 mice via the tail vein at a dose of 8µL/gram body weight. Imaging pre-contrast and at daily intervals up to 5 days post-contrast was conducted using a 1T permanent magnet based system, and a T1 weighted spin-echo sequence with TE=30ms, TR=700ms, FA=90°, NEX=4.  The animals were sacrificed, brains perfused with saline, fixed with formaldehyde, and immersed in 10% sucrose. 20µ frozen alternating sections were stained with 4G8 antibody and visualized with a Cy3 labeled secondary antibody to confirm amyloid burden. The other alternate sections were visualized unstained in both in bright field, and for ICG. 

Amyloid positive animals (n=6) treated with the targeted liposomes showed clear T1 signal in the hippocampus and cerebral cortex, while both amyloid positive animals treated with a control untargeted formulation (n=6), and amyloid negative animals treated with the targeted formulation (n=6) showed no such signal. Histologically, the presence of amyloid plaques only in the brains of the positive animals was confirmed, as was the presence of the fluorescent ligand and the ICG only in the positive animals treated with the targeted formulation. 

The MRI data are clearly consistent with avid labeling of amyloid plaques in this animal model by the targeted liposomes, with sufficient sensitivity for T1 weighted imaging using 1T field strength. The histological data confirmed the presence of amyloid plaques in the positive animals as well as the presence of targeted particles in the brains of the amyloid positive animals treated with them. 

The high sensitivity and specificity suggest this agent could be highly successful in imaging amyloid plaques, and could be worthy of development an alternative to currently available PET ligands.

Tanifum, E, Ghaghada, K, Starosolski, Z, Annapragada, A, Targeted Gd Nanoparticle for T1-MR Molecular Imaging of Amyloid Plaques.  Radiological Society of North America 2014 Scientific Assembly and Annual Meeting, - ,Chicago IL. http://archive.rsna.org/2014/14013307.html