Enhancement of oral bioavailability of salmon calcitonin through chitosan-modified, dual drug-loaded nanoparticles

Because numerous challenges limit the effective oral delivery of protein and peptide drugs, we developed promising chitosan (CS)-modified, dual drug-loaded nanoparticles (NPs) simultaneously containing salmon calcitonin (sCT) and puerarin (PR) (CS-sCT/PR-NPs), and to explore the potential of PR as a protease inhibitor. This oral delivery system showed efficient encapsulation of sCT (75.7%) and PR (50.9%), protection of encapsulated sCT and PR from premature release in simulated gastric fluid (SGJ, pH 1.2), and sustained-release behavior in phosphate buffer saline (PBS, pH 7.4). CS-sCT/PR-NPs were capable of sequential drug-release in which PR was partially released prior to sCT, allowing PR to play a role of enzyme inhibitor before sCT release. Compared with CS-sCT-NPs, CS-sCT/PR-NPs were more stable in simulated intestinal fluid containing pancreatinum. The internalization of fluorescein isothiocyanate-labeled sCT (FITC-sCT) by Caco-2 cells increased when incorporated into NPs compared with free sCT. In vivo, the oral absolute bioavailability of sCT in CS-sCT/PR-NPs was 12.52 ± 1.83%, approximately 1.74-fold higher than that of the NPs not co-loaded with PR. In conclusion, the CS-based NPs and introduction of PR as a protease inhibitor improved the oral bioavailability of sCT and had potential to be developed as an oral delivery system of peptide drug.