Dendrimers are highly branched “tree-like” polymers that have demonstrated therapeutic potential in drug delivery, medical imaging, and tissue engineering in recent years. In addition, we have shown that an azabisphosphonate (ABP)–capped dendrimer selectively targets monocytes and directs them toward anti-inflammatory activation. We explored this property to assess the therapeutic potential of dendrimer ABP in the treatment of an inflammatory disease, rheumatoid arthritis. Intravenous injections of dendrimer ABP inhibited the development of inflammatory arthritis in two animal models: IL-1ra^−/− mice and mice undergoing K/BxN serum transfer. Suppression of disease was characterized by normal synovial membranes, reduced levels of inflammatory cytokines, and the absence of cartilage destruction and bone erosion. Dendrimer ABP also exhibited anti-osteoclastic activity on mouse and human cells, mediated by c-FMS (cellular-feline McDonough strain sarcoma virus oncogene homolog) inhibition. These preclinical demonstrations suggest the potential use of dendrimer ABP as a nanotherapeutic for rheumatoid arthritis.

Dendrimers are well-defined macromolecules whose highly branched structure is reminiscent of many natural structures, such as trees, dendritic cells, neurons or the networks of kidneys and lungs. Nature has privileged such branched structures for increasing the efficiency of exchanges with the external medium; thus, the whole structure is of pivotal importance for these natural networks. On the contrary, it is generally believed that the properties of dendrimers are essentially related to their terminal groups, and that the internal structure plays the minor role of an ‘innocent’ scaffold. Here we show that such an assertion is misleading, using convergent information from biological data (human monocytes activation) and all-atom molecular dynamics simulations on seven families of dendrimers (13 compounds) that we have synthesized, possessing identical terminal groups, but different internal structures. This work demonstrates that the scaffold of nanodrugs strongly influences their properties, somewhat reminiscent of the backbone of proteins.

The monocyte-macrophage (MΦ) lineage can undergo different pathways of activation. The classical priming by IFN-γ, then triggering by LPS, conducts MΦ toward proinflammatory responses, whereas the alternative activation by IL-4, IL-10, IL-13, or glucocorticoids directs them toward an anti-inflammatory, immunosuppressive phenotype. Recently, we have shown that synthetic phosphorus-containing dendrimers activate human monocytes. Here, we analyzed the gene expression of monocytes activated by an acid azabisphosphonic-capped, phosphorus-containing dendrimer by comparison with untreated monocytes. We found that 78 genes were up-regulated, whereas 62 genes were down-regulated. Analysis of these genes directed the hypothesis of an alternative-like, anti-inflammatory activation of human monocytes. This was confirmed by quantitative RT-PCR and analysis of the surface expression of specific markers by flow cytometry. Functional experiments of inhibition of CD4+ T-lymphocyte proliferation in MLR indicated that dendrimer-activated monocytes (da-monocytes) have an immune-suppressive phenotype similar to the one induced by IL-4. Moreover, da-monocytes preferentially enhanced amplification of CD4+ T cells, producing IL-10, an immunosuppressive cytokine. Therefore, phosphorus-containing dendrimers appear as new nanobiotools promoting an anti-inflammatory and immunosuppressive activation of human monocytes and thus, prove to be good candidates for innovative, anti-inflammatory immunotherapies.

The physiological functions of human TCRVγ9Vδ2⁺ γδ lymphocytes reactive to non‐peptide phosphoantigens contribute to cancer immunosurveillance and immunotherapy. However, their regulation by mesenchymal stem cells (MSC), multipotent and immunomodulatory progenitor cells able to infiltrate tumors, has not been investigated so far. By analyzing freshly isolated TCRVγ9Vδ2⁺ lymphocytes and primary cell lines stimulated with synthetic phosphoantigen or B‐cell lymphoma cell lines in the presence of MSC, we demonstrated that MSC were potent suppressors of γδ‐cell proliferation, cytokine production and cytolytic responses in vitro. This inhibition was mediated by the COX‐2‐dependent production of prostaglandin E2 (PGE₂) and by MSC through EP2 and EP4 inhibitory receptors expressed by Vγ9Vδ2 T lymphocytes. COX‐2 expression and PGE₂ production by MSC were not constitutive, but were induced by IFN‐γ and TNF‐α secreted by activated Vγ9Vδ2 T cells. This regulatory cross‐talk between MSC and Vγ9Vδ2 T lymphocytes involving PGE₂ could be of importance for the antitumor and antimicrobial activities of γδ T cells.

Adoptive cell therapy with allogenic NK cells constitutes a promising approach for the treatment of certain malignancies. Such strategies are currently limited by the requirement of an efficient protocol for NK cell expansion. We have developed a method using synthetic nanosized phosphonate-capped dendrimers allowing such expansion. We are showing here that this is due to a specific inhibitory activity towards CD4+ T cell which could lead to further medical applications of this dendrimer.

Specific interaction and internalization of an azabisphosphonate-capped polyphosphorhydrazone dendrimer lead to anti-inflammatory activation of human monocytes.