Journal
THERANOSTICS
Volume 8, Issue 21, Pages 6008-6024Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.24365
Keywords
atherosclerosis; aptides; extra domain B of fibronectin; magnetic resonance imaging; nanoparticles
Categories
Funding
- NHLBI Program of Excellence in Nanotechnology (PEN) from the National Heart, Lung, and Blood Institute [HHSN268201000045C]
- National Institute of Health (NIH) [HL127464]
- Global Research Laboratory (GRL) through the National Research Foundation of Korea (NRF) - Ministry of Science and ICT [NRF-2012K1A1A2045436]
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science and ICT [NRF-2018R1A3B1052661]
- David Koch-Prostate Cancer Foundation Award in Nanotherapeutics
- American Heart Association (AHA) [18CSA34080399]
- Heart, Lung, and Blood Institute [HL080472]
- RRM Charitable Fund
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL127464, R01HL080472] Funding Source: NIH RePORTER
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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): similar to 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.
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