Hyaluronan Nanoparticles Selectively Target Plaque-Associated Macrophages and Improve Plaque Stability in Atherosclerosis

Thijs J. Beldman, Max L. Senders, Amr Alaarg, Carlos Pérez-Medina, Jun Tang, Yiming Zhao, Francois Fay, Jacqueline Deichmöller, Benjamin Born, Emilie Desclos, Nicole N. Van Der Wel, Ron A. Hoebe, Fortune Kohen, Elena Kartvelishvily, Michal Neeman, Thomas Reiner, Claudia Calcagno, Zahi A. Fayad, Menno P.J. De Winther, Esther LutgensWillem J.M. Mulder, Ewelina Kluza

Research output: Contribution to journalArticlepeer-review

136 Scopus citations


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 89Zr-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. 89Zr-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.

Original languageEnglish
Pages (from-to)5785-5799
Number of pages15
JournalACS Nano
Issue number6
StatePublished - 27 Jun 2017


  • PET imaging
  • anti-inflammatory effects
  • antiatherogenic therapy
  • atherosclerosis
  • hyaluronan nanoparticles
  • inflammation


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