Evaluation of drug release from polymeric nanoparticles in simulated saliva and gastric media by asymmetric flow field–flow fractionation (AF4)†

Nanocarriers for oral drug delivery will encounter various biochemical environments throughout the digestive tract, which could induce different drug release behaviors. Conventional drug release assays can provide total drug release rates but have limited capability to identify drug release mechanisms in complex samples. The objective of this study is to compare the rates and mechanisms for release of an antibiotic, enrofloxacin, from poly(lactic-co-glycolic acid) (PLGA) nanoparticles in simulated saliva and simulated gastric fluid (SGF) by combining drug release profiling using asymmetric flow field–flow fractionation (AF4) with physical release models and density functional theory (DFT) analyses. At 30 °C, similar release profiles were observed in media with near-neutral pH, represented by saliva and phosphate buffered saline (PBS) as a comparative medium, whereas antibiotic release was accelerated in SGF. However, negligible drug release was observed in SGF at room temperature (below the glass transition temperature of the nanoparticles). Enzymatic proteins in the media did not significantly influence the release rates. The advanced AF4 analyses of the drug distribution and release profiles affirmed negligible drug–protein interactions in the media and provided evidence that accelerated release in SGF was attributed to enhanced radial diffusion rates of entrapped drug through the nanoparticles, rather than particle erosion or shrinking. DFT modeling further demonstrated that changes in the charge state of the enrofloxacin and carboxylated PLGA result in diminished drug–polymer interactions upon SGF intrusion into the nanoparticles. Altogether, this study demonstrates the benefits of integrated experimental and modeling analyses to understand drug release mechanisms.