Although the application of nanotechnology to
drug therapy has been widely investigated, very few nanomedicine-based treatments for traumatic
hemorrhage have been reported so far. The aim of this work was to develop nanostructured
lipid carriers (NLCs) loaded with
phosphodiesterase 4 (
PDE4) inhibitors to treat acute
inflammation in peripheral organs. The pharmacokinetics and biodistribution of
DSM-RX78 and EFB-1, two novel
PDE4 inhibitors, were examined using rats as an animal model. Entrapment by NLCs resulted in sustained drug release. The plasma concentrations of
DSM-RX78 and EFB-1 in NLCs were lower, and their half-lives were much shorter in the NLC condition than in the control condition.
PDE4 inhibitors delivered in NLCs accumulated with high abundance in many organs, especially the brain and lungs.
Polyethylene glycol (PEG) coating on the particulate surface (P-NLCs) significantly reduced brain delivery of the drugs. P-NLCs enhanced drug distribution to the lungs by 5-fold compared to free control. In vivo real-time imaging confirmed rapid escape of nanoparticles from the blood circulation. Histological examination and
aminotransferase measurement revealed that P-NLCs containing EFB-1 improved
hemorrhagic shock-induced
injuries in the lungs, intestines, and liver. P-NLCs even reversed acute
lung inflammation to the level observed in an uninjured condition. Our results indicate that NLC-based delivery of
PDE4 inhibitors is a candidate treatment for traumatic
hemorrhage.