An Azabisphosphonate-Capped Poly(phosphorhydrazone) Dendrimer for the Treatment of Endotoxin-Induced Uveitis

Abstract

Over the last decade, different types of dendrimers have shown anti-inflammatory properties in their own right. In particular, we have shown that poly(phosphorhydrazone) (PPH) dendrimers are able to foster an efficient anti-inflammatory response in human monocytes and can resolve the main physiopathological features of chronic arthritis in mice at 1 mg/kg. Here we afford new insights into the therapeutic potential of an azabisphosphonate-capped dendrimer (dendrimer ABP). We have challenged its anti-inflammatory and immuno-modulatory properties in a robust rat model of acute uveitis induced by lipopolysaccharide (LPS). We show that dendrimer ABP at 2 µg/eye is as efficient as the "gold standard" dexamethasone at 20 µg/eye. We have demonstrated that the effect of dendrimer ABP is mediated at least through an increase of the production of the anti-inflammatory Interleukin(IL)-10 cytokine.

Theoretical and experimental characterization of amino‐PEG‐phosphonate‐terminated Polyphosphorhydrazone dendrimers: Influence of size and PEG capping on cytotoxicity profiles

“…Similar observations have been made with a PPH dendrimer functionalized with terminal amino‐ bis (methylene phosphonate) groups . The same molecule has unprecedented anti‐inflammatory and immunomodulatory properties towards human immune cells and in clinically relevant rodent models of rheumatoid arthritis and of uveitis . Therefore, some of these PPH dendrimers having phosphonic acids or phosphonates on their surface could undoubtedly stand as exciting candidates for the development of innovative therapeutic strategies for the treatment of chronic inflammatory diseases by targeting human monocytes .…”

Fluorescent Phosphorus Dendrimer as a Spectral Nanosensor for Macrophage Polarization and Fate Tracking in Spinal Cord Injury

“…Several papers dating back to as early as 1990s report the beneficial role of macrophages as a cell therapy tool for SCI . Therapeutic use of pre‐activated macrophages in combination with phosphorus dendrimer modifications possessing proven anti‐inflammatory properties, or loaded with therapeutic cargo, may elicit synergistic regenerative effects in a variety of neurologic conditions.…”

“…Dendrimers are also being tested in preclinical research for cancer treatment, anti‐inflammation, and targeted delivery . Certain modifications of phosphorus dendrimers were shown to inhibit alpha‐synuclein fibrillation (related to Parkinson's disease), interfere with the Aβ 1 −28 fragment and MAP‐Tau protein aggregation processes (related to the onset and development of Alzheimer's disease), and to modulate activation of monocytes; these dendrimer species possess remarkable anti‐inflammatory properties, as demonstrated in rodent models of uveitis and experimental arthritis . We have previously reported the properties of phosphorus dendrimers as gene and siRNA transfection reagents in stem cells and other cell types .…”

Phosphorhydrazones as Useful Building Blocks for Special Architectures: Macrocycles and Dendrimers

“…ABP was either injected (ip) or given orally ( per os ) with an almost analogous efficiency . In view of these very promising results, the dendrimer ABP was also tested in model of several inflammatory diseases, such as induced uveitis, and neuro‐inflammation, in mice suffering from a model disease of multiple sclerosis . In order to assess the preclinical safety of dendrimer ABP, it was injected repetitively to monkeys, and no adverse effect was observed …”