Enhancing pharmacokinetic properties of Chikusetsusaponin IVa via modification of polyethylenimine/poly(lactic-co-glycolic acid) nanoparticles for sustained drug delivery

Distinguishing pharmacokinetic enhancements of novel drug delivery systems from conventional formulations is critical for optimizing therapeutic outcomes of poorly soluble drugs like Chikusetsusaponin IVa (CHIVA), which suffers from low aqueous solubility and limited oral bioavailability. We optimized polyethyleneimine (PEI)-modified poly(lactic-co-glycolic acid) (PLGA) polymeric nanoparticles for CHIVA delivery using response surface methodology (RSM) and the double emulsion-solvent evaporation method, varying PEI (0.25-0.75%), PLGA (1.5-4.5%), and CHIVA (2-4 mg/mL) concentrations. Optimized nanoparticles (0.5% PEI, 3% PLGA, 3 mg/mL CHIVA) achieved an encapsulation efficiency of 86 ± 1.3%, drug loading of 2.201 ± 0.201%, particle size of 222 ± 11 nm, and zeta potential of 3.9 ± 0.6 mV, with sustained CHIVA release over 132 h fitting a first-order kinetic model (R² > 0.95), supported by in vitro-in vivo correlation (IVIVC) confirming release profile consistency with in vivo absorption. In rat models, oral administration (20 mg/kg) yielded a 1.45-fold higher peak serum concentration (309 ± 30 ng/mL vs. 213 ± 23 ng/mL), nearly twofold greater area under the curve (AUC) (5487 ± 416 h·ng/mL vs. 2811 ± 264 h·ng/mL), and prolonged mean residence time (15.1 ± 1.3 h vs. 12.6 ± 1.6 h) compared to free CHIVA, indicating enhanced bioavailability. This multiproxy approach provides a framework for tunable nanoparticle systems in similar therapeutics.