Repeated intravenous injections in non-human primates demonstrate preclinical safety of an anti-inflammatory phosphorus-based dendrimer

Abstract

Dendrimers are nanosized hyperbranched polymers synthesized through an iterative step-by-step process; their size and structure are perfectly controlled, and they are widely used for biomedical purposes. Previously, we showed that a phosphorous-based dendrimer capped with anionic AzaBisPhosphonate groups (so-called ABP dendrimer) has immunomodulatory and anti-inflammatory properties toward the human immune system. It dramatically inhibits the onset and development of experimental arthritis in a mouse model relevant for human rheumatoid arthritis, a chronic inflammatory disease of auto-immune origin. In this article, we demonstrate in an unprecedented study that cynomolgus macaques repeatedly injected with the ABP dendrimer displayed no adverse response. Indeed, biochemical, haematological, clotting and immunological parameters remained with a normal physiological range during the study. Moreover, quantification of serum cytokines and histopathological analyses failed to reveal any noticeable lesion or noteworthy non-physiological occurrence. These results strengthen the potential of the ABP dendrimer as an innovative drug-candidate for the treatment of inflammatory diseases and favor the regulatory preclinical development of the molecule.

• Nanomedicine
• nanotoxicology
• non-human primates
• phosphorus-based dendrimers
• systemic administration

Acknowledgements

We thank Dr. Geanncarlo Lugo-Villarino for critical review of the article; Jérémy Le Dall and Dr. Muriel Blanzat for the measurements of zeta potential and Dr. Talal Al Saati for anatomo-pathology review. The authors would like to dedicate this paper to Dr Charlotte Behr-Tisné, in memoriam.

Declaration of interest

We thank the university Paul Sabatier, INSERM and CNRS for institutional funding. This work was funded by the French National Research Agency (ANR), program “Recherche Partenariale et Innovation Biomédicale”, contract No. ANR-2011-RPIB-005.

Supplementary material available online

Supplementary Figures S1–S3 and Supplementary Tables S1–S4.