Interaction studies reveal specific recognition of an anti-inflammatory polyphosphorhydrazone dendrimer by human monocytes.
Dendrimers are nano-materials with perfectly defined structure and size, and multivalency properties that confer substantial advantages for biomedical applications. Previous work has shown that phosphorus-based polyphosphorhydrazone (PPH) dendrimers capped with azabisphosphonate (ABP) end groups have immuno-modulatory and anti-inflammatory properties leading to efficient therapeutic control of inflammatory diseases in animal models. These properties are mainly prompted through activation of monocytes. Here, we disclose new insights into the molecular mechanisms underlying the anti-inflammatory activation of human monocytes by ABP-capped PPH dendrimers. Following an interdisciplinary approach, we have characterized the physicochemical and biological behavior of the lead ABP dendrimer with model and cell membranes, and compared this experimental set of data to predictive computational modelling studies. The behavior of the ABP dendrimer was compared to the one of an isosteric analog dendrimer capped with twelve azabiscarboxylate (ABC) end groups instead of twelve ABP end groups. The ABC dendrimer displayed no biological activity on human monocytes, therefore it was considered as a negative control. In detail, we show that the ABP dendrimer can bind both non-specifically and specifically to the membrane of human monocytes. The specific binding leads to the internalization of the ABP dendrimer by human monocytes. On the contrary, the ABC dendrimer only interacts non-specifically with human monocytes and is not internalized. These data indicate that the bioactive ABP dendrimer is recognized by specific receptor(s) at the surface of human monocytes.
INSERM, UMR1043, CNRS, U5282, Université de Toulouse, UPS, Center of Physiopathology of Toulouse-Purpan, CHU Purpan, BP 3028, Toulouse F-31300, France. remy.poupot@inserm.fr and CNRS, UPR 8241, Université de Toulouse, UPS, INPT, Laboratoire de Chimie de Coordination, 205 route de Narbonne, BP 44099, Toulouse F-31077, France. cedric-olivier.turrin@lcc-toulouse.fr.
Jérémy
J
Ledall
INSERM, UMR1043, CNRS, U5282, Université de Toulouse, UPS, Center of Physiopathology of Toulouse-Purpan, CHU Purpan, BP 3028, Toulouse F-31300, France. remy.poupot@inserm.fr and CNRS, UPR 8241, Université de Toulouse, UPS, INPT, Laboratoire de Chimie de Coordination, 205 route de Narbonne, BP 44099, Toulouse F-31077, France. cedric-olivier.turrin@lcc-toulouse.fr.
Séverine
S
Fruchon
Department of Innovative Technologies, University of Applied Sciences and Arts of Southern Switzerland, Galleria 2, Manno 6928, Switzerland.
Matteo
M
Garzoni
Department of Innovative Technologies, University of Applied Sciences and Arts of Southern Switzerland, Galleria 2, Manno 6928, Switzerland.
Giovanni M
GM
Pavan
CNRS, UPR 8241, Université de Toulouse, UPS, INPT, Laboratoire de Chimie de Coordination, 205 route de Narbonne, BP 44099, Toulouse F-31077, France. cedric-olivier.turrin@lcc-toulouse.fr.
Anne-Marie
AM
Caminade
CNRS, UPR 8241, Université de Toulouse, UPS, INPT, Laboratoire de Chimie de Coordination, 205 route de Narbonne, BP 44099, Toulouse F-31077, France. cedric-olivier.turrin@lcc-toulouse.fr.
Cédric-Olivier
CO
Turrin
Laboratoire IMRCP, CNRS UMR 5623, Université de Toulouse, UPS, 118 route de Narbonne, Toulouse F-31062, France. blanzat@chimie.ups-tlse.fr.
Muriel
M
Blanzat
INSERM, UMR1043, CNRS, U5282, Université de Toulouse, UPS, Center of Physiopathology of Toulouse-Purpan, CHU Purpan, BP 3028, Toulouse F-31300, France. remy.poupot@inserm.fr.
Rémy
R
Poupot
D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000378:metabolism; D002152:Calorimetry, Differential Scanning; D002478:Cells, Cultured; D050091:Dendrimers / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D018613:Microscopy, Confocal; D056004:Molecular Dynamics Simulation; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000737:chemistry; D010758:Phosphorus / Q000737:chemistry
D000893:Anti-Inflammatory Agents; D050091:Dendrimers; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D010758:Phosphorus; C028694:1-palmitoyl-2-oleoylphosphatidylcholine