Pulmonary delivery and tissue distribution of aerosolized antisense 2'-O-Methyl RNA containing nanoplexes in the isolated perfused and ventilated rat lung.

Pulmonary delivery of drugs, particularly in the treatment of lung cancer, is an attractive strategy for future targeted therapy. In this context, inhalation of nanoplexes might offer a new mode for drug delivery in gene therapy. However, limited data are currently available demonstrating pulmonary delivery, cellular uptake as well as local tolerability in lung tissue. The aim of this study was to elucidate the pulmonary delivery, tissue distribution and local tolerability of aerosolized chitosan-coated poly(lactide-co-glycolide) based nanoplexes containing antisense 2'-O-Methyl RNA (OMR). Therefore, an aerosol of OMR-nanoplexes or OMR alone was administered intra-tracheally using the model of the isolated perfused and ventilated rat lung. Localization of OMR in rat lung tissue was examined by immunohistochemistry. Administration of the OMR-nanoplex formulation resulted in significantly higher cellular OMR uptake of the respiratory epithelium in contrast to the administration of OMR alone, indicating that drug administration via aerosolized nanoplexes is able to target lung tissue. No prominent changes in lung physiology parameters were observed following inhalation, suggesting good local tolerability of OMR-nanoplex formulation.

Effects of opioid antagonists and morphine in a hippocampal hypoxia/hypoglycemia model.

The influence of opioid antagonists and of morphine on rat hippocampal slices in a model of reversible hypoxia/hypoglycemia was investigated by assessment of evoked field potentials (population spike amplitude). In control slices, a brief hypoxia/hypoglycemia led to a loss of field potentials followed by an impaired recovery (40-50% of baseline) during reperfusion. In contrast, restoration was significantly improved when the opioid receptor antagonists funaltrexamine (mu) or naltrindole (delta) were administered prior to and during hypoxia/hypoglycemia. In addition, recovery was improved in brain slices derived from mu-opioid receptor-deficient mice as compared to wild-type mice, indicating a deleterious role of endogenous opioids in hypoxia/hypoglycemia. Exogenous opiate exposure with morphine (0.1, 1.0, 10 microM) prior to hypoxia/hypoglycemia caused a slight concentration dependent increase of evoked field potentials. When morphine exposure was terminated after 1h and immediately followed by hypoxia/hypoglycemia, an impaired recovery of population spike amplitude was obtained, dependent on morphine concentration during preincubation. These results demonstrate that morphine aggravates neurotoxic effects of hypoxia/hypoglycemia. Conversely, when onset of hypoxia/hypoglycemia was delayed for 3h after morphine termination, a significantly improved recovery was observed. Similarly, in vivo administration of morphine 12h prior to slice preparation resulted in a dose dependent improved recovery of field potentials after hypoxia/hypoglycemia. These results provide evidence that preconditioning with morphine is able to induce neuroprotective effects.