A Phosphorus-Based Dendrimer Targets Inflammation and Osteoclastogenesis in Experimental Arthritis

Abstract

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.

Article retiré – Utilisation de dendrimères pour une nanomédecine innovatrice

“…Nous avons très récemment découvert une autre propriété extrêmement intéressante (activation de monocytes via une voie anti-inflammatoire) permettant d'envisager de nouvelles stratégies thérapeutiques pour le traitement de la polyarthrite rhumatoïde ou de maladies inflammatoires auto-immunes (collaboration Poupot, Davignon) (Hayder et al, 2011).…”

Bifunctional Phosphorus Dendrimers and Their Properties

“…The analogous compound with a maleimide group instead of the julolidine group was also synthesized [38]. These compounds were synthesized among a large library of dendrimers ended by azabisphosphonic salts [39], which have numerous properties, for the multiplication of human natural killer (NK) cells [40], and for the potential treatment of rheumatoid arthritis [41] and multiple sclerosis [42]. In general, multicharged dendrimers, which are soluble in water, have many biological properties [43].…”

Dendrimers as anti-inflammatory agents

“…They treated dendrimers capped with anionic azabisphophonate (ABP) end groups, dendrimer azamonophosphate (AMP) and polypropyleneimine (PPI), at a dose of 10 mg/kg four times weekly ( figure 2A,B,C). Only ABP significantly inhibited the proinflammatory cytokines secretion and osteoclastogenesis process (Hayder et al, 2011) (Figure 2D). …”

“…These osteoclasts are responsible for bone resorption, a typical bone erosion mechanism involved in RA (Takayanagi, 2007). Recently, Hayder et al (2011) explored the potential of dendrimers in arthritic mice models. They treated dendrimers capped with anionic azabisphophonate (ABP) end groups, dendrimer azamonophosphate (AMP) and polypropyleneimine (PPI), at a dose of 10 mg/kg four times weekly ( figure 2A,B,C).…”