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Design of phosphorylated dendritic architectures to promote human monocyte activation

Mary Poupot^*,1, Laurent Griffe^,1, Patrice Marchand, Alexandrine Maraval, Olivier Rolland, Ludovic Martinet^*, Fatima-Ezzahra L’Faqihi-Olive^*, Cédric-Olivier Turrin, Anne-Marie Caminade^,2, Jean-Jacques Fournié^*, Jean-Pierre Majoral^,2 and Rémy Poupot^*,2

^* INSERM, U.563, Centre de Physiopathologie de Toulouse-Purpan, Toulouse, F-31300 France; Université Paul-Sabatier, Toulouse, F-31400 France; and

Laboratoire de Chimie de Coordination du CNRS, Toulouse cedex, France

²Correspondence: INSERM 563, Centre de Physiopathologie de Toulouse-Purpan, Hôpital Purpan, BP3028, 31024 Toulouse cedex 03, France. E-mail: remy.poupot{at}toulouse.inserm.fr; Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse cedex 04, France. E-mail: majoral{at}lcc-toulouse.fr; Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse cedex 04, France. E-mail: caminade{at}lcc-toulouse.fr

As first defensive line, monocytes are a pivotal cell population of innate immunity. Monocyte activation can be relevant to a range of immune conditions and responses. Here we present new insights into the activation of monocytes by a series of phosphonic acid-terminated, phosphorus-containing dendrimers. Various dendritic or subdendritic structures were synthesized and tested, revealing the basic structural requirements for monocyte activation. We showed that multivalent character and phosphonic acid capping of dendrimers are crucial for monocyte targeting and activation. Confocal videomicroscopy showed that a fluorescein-tagged dendrimer binds to isolated monocytes and gets internalized within a few seconds. We also found that dendrimers follow the phagolysosomial route during internalization by monocytes. Finally, we performed fluorescence resonance energy transfer (FRET) experiments between a specifically designed fluorescent dendrimer and phycoerythrin-coupled antibodies. We showed that the typical innate Toll-like receptor (TLR)-2 is clearly involved, but not alone, in the sensing of dendrimers by monocytes. In conclusion, phosphorus-containing dendrimers appear as precisely tunable nanobiotools able to target and activate human innate immunity and thus prove to be good candidates to develop new drugs for immunotherapies.—Poupot, M., Griffe, L., Marchand, P., Maraval, A., Rolland, O., Martinet, L., L’Faqihi-Olive, F.-E., Turrin, C.-O., Caminade, A.-M., Fournié, J.-J., Majoral, J.-P., Poupot, R. Design of phosphorylated dendritic architectures to promote human monocyte activation.

Key Words: cellular immunotherapy • targeting • phosphorus dendrimers