N,N Dimethylacetamide a drug excipient that acts as bromodomain ligand for osteoporosis treatment

Abstract

N,N-Dimethylacetamide (DMA) is a water-miscible solvent, FDA approved as excipient and therefore widely used as drug-delivery vehicle. As such, DMA should be devoid of any bioactivity. Here we report that DMA is epigenetically active since it binds bromodomains and inhibits osteoclastogenesis and inflammation. Moreover, DMA enhances bone regeneration in vivo. Therefore, our in vivo and in vitro data reveal DMA’s potential as an anti-osteoporotic agent via the inhibition of osteoclast mediated bone resorption and enhanced bone regeneration. Our results highlight the potential therapeutic benefits of DMA and the need for reconsideration of previous reports where DMA was used as an ‘inactive’ drug-delivery vehicle.

The Release of the Bromodomain Ligand N,N-Dimethylacetamide Adds Bioactivity to a Resorbable Guided Bone Regeneration Membrane in a Rabbit Calvarial Defect Model

“…More recently, we have identified the underlying mechanism for all these diverse and beneficial activities. DMA binds bromodomains, based on the low affinity of DMA for this acetyl-residue-binding site [22]. Since bromodomains are an important element to assemble the machinery for NF-kappa-B transcription [25], DMA significantly attenuates lipopolysaccharide-and tumor necrosis factor-induced proinflammatory responses [26].…”

“…Since bromodomains are an important element to assemble the machinery for NF-kappa-B transcription [25], DMA significantly attenuates lipopolysaccharide-and tumor necrosis factor-induced proinflammatory responses [26]. In conjunction with guided bone regeneration, a reduction in inflammation could be beneficial, and so would the enhancement of the activity of bone morphogenetic protein signaling, and the inhibition of osteoclast differentiation and activity [22]. This notion proved true in our in vivo experiments, where the DMA-loaded membrane performed significantly better in terms of bony bridging than the control ( Figure 5).…”

“…The major problem utilizing DMA as a drug is achieving a sustained delivery of dosages in the millimolar range, since its affinity to bromodomains is in this range [22]. Therefore, we tried the vapor deposition methodology, which we have used before to load membranes with N-methyl pyrrolidone (NMP) [27], another FDA-approved excipient.…”

“…To estimate the expected effective concentration of DMA released from the DMA-loaded membranes into the calvaria defect rabbit model, the size of the applied membranes was set to 2 × 38 mm 2 and the volume enclosed by the two membranes was set to 100 µL. Based on these estimations, the calculated concentrations for all but the vapor 10% membranes exceeded 10 mM, which is toxic for cells [22]. Therefore, only the membrane vapor 10% was chosen for the in vivo experiment.…”

“…We showed that DMA binds bromodomains, and is thus epigenetically active in bone regeneration, bone degradation, and osteoporosis [22]. In conjunction with guided bone-regeneration procedures, its ability to enhance bone regeneration and to inhibit bone destruction by osteoclasts [22] could be beneficial.…”