Coating of PLA-nanoparticles with cyclic, arginine-rich cell penetrating peptides enables oral delivery of liraglutide.

Until today, the oral delivery of peptide drugs is hampered due to their instability in the gastrointestinal tract and low mucosal penetration. To overcome these hurdles, PLA (polylactide acid)-nanoparticles were coated with a cyclic, polyarginine-rich, cell penetrating peptide (cyclic R9-CPP). These surface-modified nanoparticles showed a size and polydispersity index comparable to standard PLA-nanoparticles. The zeta potential showed a significant increase indicating successful CPP-coupling to the surface of the nanoparticles. Cryo-EM micrographs confirmed the appropriate size and morphology of the modified nanoparticles. A high encapsulation efficiency of liraglutide could be achieved. In vitro tests using Caco-2 cells showed high viability indicating the tolerability of this novel formulation. A strongly enhanced mucosal binding and penetration was demonstrated by a Caco-2 binding and uptake assay. In Wistar rats, the novel nanoparticles showed a substantial, 4.5-fold increase in the oral bioavailability of liraglutide revealing great potential for the oral delivery of peptide drugs.

In vivo monitoring of cystic fibrosis-like lung disease in mice by volumetric computed tomography.

The onset and spontaneous development of cystic fibrosis (CF) lung disease remain poorly understood. In the present study, we used volumetric computed tomography (VCT) as a new method for longitudinal in vivo monitoring of early lesions and disease progression in CF-like lung disease in ß-epithelial Na(+) channel (ENaC)-transgenic (TG) mice. Using a VCT scanner prototype (80 kV, 50 mA·s, scan time 19 s and spatial resolution 200 µm), ßENaC-TG mice and wild-type (WT) littermates were examined longitudinally at 10 time-points from neonatal to adult ages, and VCT images were assessed by qualitative and quantitative morphological parameters. We demonstrate that VCT detected early-onset airway mucus obstruction, diffuse infiltrates, atelectasis and air trapping as characteristic abnormalities in ßENaC-TG mice. Furthermore, we show that early tracheal mucus obstruction predicted mortality in ßENaC-TG mice and that the density of lung parenchyma was significantly reduced at all time-points in ßENaC-TG compared with WT mice (median ± sem -558 ± 8 HU in WT versus -686 ± 16 HU in ßENaC-TG at 6 weeks of age; p < 0.005). Our study demonstrates that VCT is a sensitive, noninvasive technique for early detection and longitudinal monitoring of morphological abnormalities of CF-like lung disease in mice, and may thus provide a useful tool for pre-clinical in vivo evaluation of novel treatment strategies for CF.