Curing inflammatory diseases using phosphorous dendrimers

Abstract

Different types of water-soluble phosphorous dendrimers have been synthesized and display many different biological properties. It has been shown in particular that phosphorous dendrimers of first generation functionalized with azabisphosphonate terminal functions are able to stimulate the human immune system ex vivo. These dendrimers are internalized by monocytes within a few seconds, and induce their anti-inflammatory activation. The presence of the dendrimers induces also the inhibition of the differentiation of monocytes into osteoclasts, the maturation of dendritic cells, and inhibits the proliferation of the proinflammatory CD4 + T lymphocytes. Finally, after 2-3 weeks of culture of peripheral blood mononuclear cells, amplifications by several tens of natural killer cells is observed. In view of all these properties, the influence of these azabisphosphonate-dendrimers has been tested in vivo with several animal models, against different chronic or acute inflammatory diseases, such as multiple sclerosis, rheumatoid arthritis, uveitis, and psoriasis, but also against myeloid leukemia, a hematological cancer. The hematological safety has been demonstrated in mice, as there is no platelet aggregation, no hemolysis, and no disturbance in the hematological formula. The safety of the azabisphosphonate-dendrimer has been assessed also with non-human primates (cynomolgus monkeys) which received repeated injections, as a derisking pre-clinical test. Biochemical, hematological, and all immunological parameters in peripheral blood remained within a normal physiological range throughout the study, and all survived well. Other phosphorous dendrimers also display anti-inflammatory properties in vivo, in particular dendrimers functionalized with mannose derivatives, which prevent acute lung diseases when given orally (per os) to mice.

Dendrimers, an Emerging Opportunity in Personalized Medicine?

“…The hope of expanding the number of dendrimers actually used in human health lies in the phase 1 clinical trials carried out recently and on others that are planned. One can cite in particular ongoing and future assays against influenza A and B virus; against COVID-19 [ 26 ]; against neurology, ophthalmology, inflammatory diseases, and neuro-oncology [ 49 ]; and to modulate the activity of the immune system to treat chronic inflammatory diseases [ 62 , 63 ]. The field of theranostic (diagnosis and therapy with the same “object”) could be developed with multifunctional dendrimers (see for instance 18F-OP-801).…”

Phosphorus-carrying cascade molecules: inner architecture to biomedical applications

“…The 3rd generation dendrimers capped with trimannosides showed the highest binding avidity. The compound significantly reduced acute lung inflammation in a mouse model when administered per se [ 97 ].…”

Useful synthetic pathways to original, stable tunable neutral and anionic phosphorus dendrimers: new opportunities to expand dendrimer space

“…Their antimicrobial activities 16 as well those concerning the interaction between phosphorus dendrimers and peptides involved in Alzheimer diseases 17 can be mentioned while the use and anti-inflammatory properties of an anionic phosphorus dendrimer generation 1 were reported recently in details with emphasis concerning its role against several diseases as rheumatoid arthritis, psoriasis, uveitis. 18 Anti-inflammatory properties of phosphorus dendrimers of higher generation 19,20 as well as the anti-inflammatory and antioxidative therapy of acute lung injury using phosphorus dendron micelles were also reported. 21 All of these dendrimers were designed from a building block namely the methylhydrazino dichlorophosphine sulfide H 2 NN-(CH 3 )P(S)Cl 2 22 which allows via the reiteration of a sequence of two reactions to obtain neutral phosphorus dendrimers up to generation 12 23 as well as other multifunctionalized phosphorus dendrimers.…”

“…Their antimicrobial activities 16 as well those concerning the interaction between phosphorus dendrimers and peptides involved in Alzheimer diseases 17 can be mentioned while the use and anti-inflammatory properties of an anionic phosphorus dendrimer generation 1 were reported recently in details with emphasis concerning its role against several diseases as rheumatoid arthritis, psoriasis, uveitis. 18 Anti-inflammatory properties of phosphorus dendrimers of higher generation 19,20 as well as the anti-inflammatory and antioxidative therapy of acute lung injury using phosphorus dendron micelles were also reported. 21…”