The potential of lipid-polymer nanoparticles as epigenetic and ROS control approaches for COPD.

Chronic obstructive pulmonary disease (COPD) is a lung disease caused by an inflammatory response to various inhaled toxins, especially cigarette smoke. Reactive oxygen species (ROS) and epigenetic abnormality are intimately related to the pathology of COPD, and the overproduction of ROS results in a decrease of histone deacetylase 2 (HDAC2), leading to glucocorticoid resistance. Therefore, a novel treatment that simultaneously reduces ROS level and glucocorticoid resistance is urgently needed. In this study, we developed a codelivery system using core-shell type lipid-polymer nanoparticles (LPNs) composed of a poly(lactic acid) (PLA) core encapsulating a potent antioxidant Mn-porphyrin dimer (MnPD) and a cationic lipid (DOTAP) shell that binds HDAC2-encoding plasmid DNA (pHDAC2), as a new therapeutic approach toward COPD. The transfection of pHDAC2 combined with the elimination of ROS by MnPD exhibited a significant enhancement of intracellular HDAC2 expression levels, suggesting that the multi-antioxidative activity of MnPD plays a crucial role in the expression of HDAC2. Moreover, treatment with LPNs efficiently ameliorated the steroid resistance in COPD models in vitro as evidenced by the lowered expression levels of IL-8. Recovery from mitochondrial dysfunction may be the mechanism underlying the action of LPNs. The PLA-MnPD/DOTAP/pHDAC2 system proposed offers a new therapeutic approach for COPD based on the synergism of ROS elimination and HDAC2 expression.

New class of artificial enzyme composed of Mn-porphyrin, imidazole, and cucurbit[10]uril toward use as a therapeutic antioxidant.

In this study, we investigated a new class of artificial enzymes composed of Mn-porphyrin, imidazole, and cucurbit[10]uril (CB[10]) toward therapeutic antioxidants. Structural characterization by means of NMR indicated that the inclusion mode of metalloporphyrin in CB[10] was sensitive to the chemical structure of metalloporphyrin and that the structure of the artificial enzyme had a similarly to that of native heme catalase. Kinetic analysis for catalytic antioxidative activities demonstrated that the artificial enzyme exhibited highly efficient activity for H2O2 disproportionation (catalase activity) in water. The activity was classified as top-performing among the water-soluble artificial catalases. The artificial enzyme was constructed by simply mixing the components in water. We consider that this is a great advantage over previously reported artificial catalases, which require a multi-step synthesis or that lack water solubility. The pro-oxidative peroxidase activity was remarkably suppressed due to inclusion in CB[10]. Furthermore, a preliminary in vitro study suggested that the artificial enzyme catalytically eliminated reactive oxygen species, including H2O2, in human cell lines. It was presumed that CB[10] contributed to the bioavailability of the artificial enzyme. Overall, the artificial enzyme was shown to have high potential as a therapeutic antioxidant. We consider that the results in this study could lead to a new conceptual advance toward therapeutic antioxidants that could simultaneously improve the catalytic and biological properties of Mn-porphyrins.