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Beldman, Thijs J.; Senders, Max L.; Alaarg, Amr; Perez-Medina, Carlos; Tang, Jun; Zhao, Yiming; Fay, Francois; Deichmöller, Jacqueline; Born, Benjamin; Desclos, Emilie; Wel, Nicole N. van der; Höbe, Ron A.; Kohen, Fortune; Kartvelishvily, Elena; Neeman, Michal; Reiner, Thomas; Calcagno, Claudia; Fayad, Zahi A.; Winther, Menno P. J. de; Lutgens, Esther; Mulder, Willem J. M. and Kluza, Ewelina (2017): Hyaluronan Nanoparticles Selectively Target Plaque-Associated Macrophages and Improve Plaque Stability in Atherosclerosis. In: Acs Nano, Vol. 11, No. 6: pp. 5785-5799

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Hyaluronan is a biologically active polymer, which can be formulated into nanoparticles. In our study, we aimed to probe atherosclerosis-associated inflammation by using hyaluronan nanoparticles and to determine whether they can ameliorate atherosclerosis. Hyaluronan nanoparticles (HA-NPs) were prepared by reacting amine-functionalized oligomeric hyaluronan (HA) with cholanic ester and labeled with a fluorescent or radioactive label. HA-NPs were characterized in vitro by several advanced microscopy methods. The targeting properties and biodistribution of HA-NPs were studied in apoe(-/-) mice, which received either fluorescent or radiolabeled HA-NPs and were examined ex vivo by flow cytometry or nuclear techniques. Furthermore, three atherosclerotic rabbits received Zr-89-HA-NPs and were imaged by PET/MRI. The therapeutic effects of HA-NPs were studied in apoe(-/-) mice, which received weekly doses of 50 mg/kg HA-NPs during a 12-week high-fat diet feeding period. Hydrated HA-NPs were ca. 90 nm in diameter and displayed very stable morphology under hydrolysis conditions. Flow cytometry revealed a 6- to 40-fold higher uptake of Cy7-HA-NPs by aortic macrophages compared to normal tissue macrophages. Interestingly, both local and systemic HA-NP immune cell interactions significantly decreased over the disease progression. Zr-89-HA-NPs-induced radioactivity in atherosclerotic aortas was 30% higher than in wild-type controls. PET imaging of rabbits revealed 6-fold higher standardized uptake values compared to the muscle. The plaques of HA-NP-treated mice contained 30% fewer macrophages compared to control and free HA-treated group. In conclusion, we show favorable targeting properties of HA-NPs, which can be exploited for PET imaging of atherosclerosis-associated inflammation. Furthermore, we demonstrate the anti-inflammatory effects of HA-NPs in atherosclerosis.

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