Nitric Oxide Releasing Polyamide Dendrimer with Anti-inflammatory Activity

Abstract

Inflammatory processes are related to a wide variety of diseases with high global impact. Nitric oxide (NO) is an excellent candidate for the treatment of such diseases due to its important anti-inflammatory role in living systems, which is related to its concentration in the cellular medium that in turn depends directly on its release rate from NO releasing compounds. In this work, we synthesized a nitrate-terminated dendrimer and evaluated its anti-inflammatory properties. Remarkably, dendrimer bearing 18 NO-releasing groups was nontoxic, and exhibited antiinflammatory activity (13.7−27.9% of IL-8 inhibition) throughout the tested concentrations (6.50 × 10 −2 to 4.17 × 10 3 nM of dendrimer; (1.17−7.50) × 10 4 nM of NO-moiety). On the other hand, the NO-releasing monomer was pro-inflammatory at concentrations higher than 62.5 nM. Investigation of the NO-releasing profiles from monomer and dendrimer using real-time NO analyzer NOA confirmed the slow release of NO from the dendrimer. Our results suggest that the NO release from the dendrimer occurs in a controlled fashion, keeping the anti-inflammatory effect of NO even at high concentrations.

Well-Defined Bifunctional Dendrimer Bearing 54 Nitric Oxide-Releasing Moieties and 54 Ursodeoxycholic Acid Groups Presenting High Anti-Inflammatory Activity

“…Moreover, in Dendri-(NO) 18 , the polyamide dendrimer backbone promotes a slower, controlled, and safer NO-releasing rate. 49 Herein, we demonstrate that Dendri-(NO/UDCA) 18 14 and Dendri-(NO/UDCA) 54 20 confirm these behaviors, suggesting that this advantage is incremented at higher generation. This is a clear positive dendritic effect.…”

“…In Vitro. Our previous works evaluated the inhibition of LPS-induced IL-8 secretion for the compounds UDCA, 50 3-NPAN 8, 49 and the homofunctionalized G2-polyamide dendrimers Dendri-(NO) 18 49 and Dendri-(UDCA) 18 . 50 These dendrimers presented promising results compared to their precursors.…”

“…Our results suggested that the dendritic structure promoted the NO release in a controlled and sustained manner. 49 We have also synthesized a dendrimer bearing 18 UDCA groups (Dendri-(UDCA) 18 ) and evaluated its anti-inflammatory activity. 50 Dendri-(UDCA) 18 was more than 6000 times more potent than the free UDCA when comparing with the number of UDCA molecules per dendrimer, and more than 100,000 times more potent when comparing one UDCA molecule with one dendrimer molecule.…”

“…We have recently attached 3-nitroxypropylammonium nitrate (3-NPAN) to a polyamide dendrimer yielding a dendrimer with 18 NO-releasing termini (Dendri-(NO) 18 ) . Dendri-(NO) 18 showed IL-8 inhibition activity in a wide range of concentrations, while the monomeric 3-NPAN was proinflammatory even at lower concentrations than those tested for Dendri-(NO) 18 .…”

“…Dendri-(NO) 18 showed IL-8 inhibition activity in a wide range of concentrations, while the monomeric 3-NPAN was proinflammatory even at lower concentrations than those tested for Dendri-(NO) 18 . Our results suggested that the dendritic structure promoted the NO release in a controlled and sustained manner . We have also synthesized a dendrimer bearing 18 UDCA groups (Dendri-(UDCA) 18 ) and evaluated its anti-inflammatory activity .…”