No abstract

Background: The Fibronection extradomain B (FN-EDB) is upregulated during tissue remodeling and has been postulated as a potential biomarker for atherosclerosis, yet a systematic investigation for the presence of FN-EDB in plaque has not been reported. We hypothesized that the FN-EDB expression would intensify in advanced plaques; furthermore the engineering of FN-EDB-targeted nanoparticles (FN-EDB-NPs) could enable the imaging/diagnosis and local delivery of therapeutic payloads to plaques. Methods: The amount of FN-EDB in atherosclerotic ( n =143) and normal arteries ( n =43) of human tissue specimen (ages: 40 to 85 years) was histologically stained and quantified using FN-EDB specific bi-podal peptide (APT FN-EDB ). Next, FN-EDB-NPs were developed by immobilization of APT FN-EDB on nanoparticles surface containing Gd-DTPA for MRI imaging. These NPs were administered to apolipoprotein E-deficient mice fed a western diet and the brachiocephalic arteries were visualized with MRI. The mice were sacrificed and the ascending to the descending thoracic aortas and the aortic roots of the mice were studied for Gd, FN-EDB, and FN-EDB-NPs quantification. The utility of FN-EDB-NPs for drug delivery was evaluated using Cyanine, as a model small molecule drug, and NPs biodistribution and pharmacokinetics were studied. Results: The FN-EDB positive area was significantly greater in the atherosclerotic tissues than in the normal arteries ( P <0.001). It was particularly specific to the Type III ( P <0.01), IV ( P <0.01) and V lesions ( P <0.001) compared to the Type I and II lesions. The FN-EDB expression indicated a positive correlation with macrophage infiltration and neoangiogenesis. T1-weighted images of the atherosclerosis mouse models ( n =86) revealed substantial FN-EDB-NPs accumulation in plaques compared to the control NPs, Magnevist® or wild type C57BL/6J mice ( n =21). Additionally, FN-EDB-NPs significantly enhanced the blood circulation time (t 1/2 : ~ 6 h) and plaque accumulation (up to 72 h) of a model drug. Conclusions: Our findings offer the first evidence that FN-EDB expression is specific to the Type III, IV and V lesions and suggest that the FN-EDB-NPs could be a promising platform for targeted imaging/diagnosis and therapy of atherosclerosis.

No abstract