Hydroxypropyl trimethyl ammonium chloride chitosan (HACC)-modified protein nanoparticles enhance docetaxel oral delivery and exhibit potent in vitro anti-tumor and macrophage-activating effects.

The antitumor drug docetaxel (DTX) has limited oral bioavailability. This study aimed to develop novel oral nanoparticles to enhance DTX's absorption and bioactivities. The nanoparticles (H-N-D) were prepared by inducing the self-assembly of a Coptis protein through heating, followed by modification using hydroxypropyl trimethyl ammonium chloride chitosan (HACC). H-N-D was characterized, its effects on DTX's pharmacokinetics and bioactivities were evaluated, and related mechanisms were explored. H-N-D exhibited a spherical morphology, a size of 174.9 ± 1.53 nm, a zeta potential of 19.81 ± 0.79 mV, and good stability in gastric and intestinal fluids. DTX had an encapsulation efficiency of 99.17 ± 0.57 % and a drug loading of 2.95 ± 0.40 %. DTX, originally a crystal, existed as an amorphous form in H-N-D and produces hydrogen bond interactions. H-N-D significantly enhanced DTX's solubility (4.6 times, p < 0.01), release (p < 0.01), metabolic stability (p < 0.05 or p < 0.01), uptake in Caco-2 cells (p < 0.01), and absorption in mouse gut sacs (p < 0.01). Pharmacokinetic studies in mice revealed a 235.2-fold increase in blood AUC0-12 h and enhanced colon, liver, and lung distribution (4.8, 277.4, and 66.8-fold, respectively). H-N-D demonstrated superior cytotoxicity against HepG2 (IC50 reduction, p < 0.01) and MCF-7 cells (IC50 reduction, p < 0.01) compared to free DTX. Additionally, H-N-D induced tumor necrosis factor-α and nitric oxide release in macrophages and exhibited antioxidant activity in concentration-dependent manners. In conclusion, H-N-D significantly improved DTX's oral bioavailability and bioactivities, offering a promising strategy for oral DTX delivery.