Nanoparticles targeting extra domain B of fibronectin-specific to the atherosclerotic lesion types III, IV, and V-enhance plaque detection and cargo delivery.

Extra domain B of fibronectin (FN-EDB) is upregulated in the extracellular matrix during tissue remodeling and has been postulated as a potential biomarker for atherosclerosis, yet no systematic test for FN-EDB in plaques has been reported. We hypothesized that FN-EDB expression would intensify in advanced plaques. Furthermore, engineering of FN-EDB-targeted nanoparticles (NPs) could enable imaging/diagnosis and local delivery of payloads to plaques. Methods: The amount of FN-EDB in human atherosclerotic and normal arteries (ages: 40 to 85 years) was assessed by histological staining and quantification using an FN-EDB-specific aptide (APT _FN-EDB ). FN-EDB-specific NPs that could serve as MRI beacons were constructed by immobilizing APT _FN-EDB on the NP surface containing DTPA[Gd]. MRI visualized APT _FN-EDB -[Gd]NPs administered to atherosclerotic apolipoprotein E-deficient mice in the brachiocephalic arteries. Analysis of the ascending-to-descending thoracic aortas and the aortic roots of the mice permitted quantitation of Gd, FN-EDB, and APT _FN-EDB -[Gd]NPs. Cyanine, a model small molecule drug, was used to study the biodistribution and pharmacokinetics of APT _FN-EDB -NPs to evaluate their utility for drug delivery. Results: Atherosclerotic tissues had significantly greater FN-EDB-positive areas than normal arteries ( P < 0.001). This signal pertained particularly to Type III ( P < 0.01), IV ( P < 0.01), and V lesions ( P < 0.001) rather than Type I and II lesions (AHA classification). FN-EDB expression was positively correlated with macrophage accumulation and neoangiogenesis. Quantitative analysis of T1-weighted images of atherosclerotic mice revealed substantial APT _FN-EDB -[Gd]NPs accumulation in plaques compared to control NPs, conventional MRI contrast agent (Gd-DTPA) or accumulation in wild-type C57BL/6J mice. Additionally, the APT _FN-EDB -NPs significantly prolonged the blood-circulation time (t _1/2 : ~ 6 h) of a model drug and increased its accumulation in plaques (6.9-fold higher accumulation vs. free drug). Conclusions: Our findings demonstrate augmented FN-EDB expression in Type III, IV, and V atheromata and that APT _FN-EDB -NPs could serve as a platform for identifying and/or delivering agents locally to a subset of atherosclerotic plaques.
Competing Interests: Competing Interests: O.C.F. declares financial interests in Selecta Biosciences, Tarveda Therapeutics, Placon Therapeutics, and Seer Biosciences.