TY - JOUR
T1 - Hyaluronan Nanoparticles Selectively Target Plaque-Associated Macrophages and Improve Plaque Stability in Atherosclerosis
AU - Beldman, Thijs J.
AU - Senders, Max L.
AU - Alaarg, Amr
AU - Pérez-Medina, Carlos
AU - Tang, Jun
AU - Zhao, Yiming
AU - Fay, Francois
AU - Deichmöller, Jacqueline
AU - Born, Benjamin
AU - Desclos, Emilie
AU - van der Wel, Nicole N.
AU - Hoebe, Ron A.
AU - Kohen, Fortune
AU - Kartvelishvily, Elena
AU - Neeman, Michal
AU - Reiner, Thomas
AU - Calcagno, Claudia
AU - Fayad, Zahi A.
AU - de Winther, Menno P. J.
AU - Lutgens, Esther
AU - Mulder, Willem J. M.
AU - Kluza, Ewelina
PY - 2017
Y1 - 2017
N2 - 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
AB - 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
U2 - https://doi.org/10.1021/acsnano.7b01385
DO - https://doi.org/10.1021/acsnano.7b01385
M3 - Article
C2 - 28463501
SN - 1936-0851
VL - 11
SP - 5785
EP - 5799
JO - ACS nano
JF - ACS nano
IS - 6
ER -