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

Abstract

Nitric oxide (NO) and ursodeoxycholic acid (UDCA) are endogenous molecules involved in physiological processes associated with inflammation. Since inflammatory processes are present in the mechanisms of many diseases, these molecules are important for the development of new drugs. Herein, we describe the synthesis of a well-defined bifunctional dendrimer with 108 termini bearing 54 NO-releasing groups and 54 UDCA units (Dendri-(NO/UDCA)54). For comparison, a lower-generation dendrimer bearing 18 NO-releasing groups and 18 UDCA units (Dendri-(NO/UDCA)18) was also synthesized. The anti-inflammatory activity of these dendrimers was evaluated, showing that the bifunctional dendrimers have an inverse correlation between concentration and anti-inflammatory activity, with an effect dramatically pronounced for Dendri-(NO/UDCA)54 20, which at just 0.25 nM inhibited 76.1% of IL-8 secretion. Data suggest that nanomolar concentrations of these dendrimers aid in releasing NO in a safe and controlled way. This bifunctional dendrimer has great potential as a drug against multifactorial diseases associated with inflammatory processes.

Nitric Oxide: Physiological Functions, Delivery, and Biomedical Applications

“…[ 171 ] Their multifaceted functionality, due to their dynamic multivalency, make dendrimers a suitable macromolecule for drug delivery. [ 172 ] Since regulating the branching of dendrimers based on their synthesis procedure and generation is unfavorable, the surface functionalization of dendrimers along with the desired number of NO groups can be achieved via chemical conjugations. Hence, the dendrimers‐based system provides high NO storage and disseminates substantial amounts of NO, thereby providing evidence of its ability to act as a potential platform for donating NO.…”

“…The NO and UDCA‐releasing bifunctional dendritic structure exhibited substantial inhibition of IL‐8 production demonstrating their synergistic anti‐inflammatory activity. [ 176 ]…”