Oral bioavailability and evaluation of docetaxel–nicotinamide complex loaded chitosan nanoparticles

Abstract

Although docetaxel (DTX) is an efficient chemotherapeutic drug, its low and variable oral bioavailability restricts its oral applications. In this study, docetaxel–nicotinamide (DTX–NA) complex was prepared using crystallization technology. The DTX–NA complex loaded chitosan nanoparticles (DTX–NA/NPs) were obtained through modified ionic gelation method. Results showed that the saturated solubility of DTX–NA complex increased five-fold compared to DTX in water at 37 °C. The particle size of DTX–NA/NPs was 197.8 ± 16.9 nm. The cumulative drug release of DTX–NA/NPs was 1.88 times higher than that of DTX suspension. DTX–NA/NPs with a zeta potential of +28.12 ± 4.07 mV enhanced cell uptake by 3.85 times and showed a significant cytotoxicity with IC₅₀ decreased from 63.37 ± 6.20 ng mL⁻¹ to 22.06 ± 11.32 ng mL⁻¹. Further analysis indicated that DTX–NA/NPs could down-regulate survivin, caspase-9 and caspase-3 expression, arrest cell cycle at the G2 stage, and induce apoptosis. The oral relative bioavailability of DTX–NA/NPs increased, and was 30.26 times higher than that of free DTX, which was consistent with in vitro permeation results. This study proved that the synergism of the DTX–NA complex and positively charged chitosan NPs could prolong drug residence, facilitate drug absorption, and restrain drug excretion. This novel DTX–NA/NPs drug delivery system exhibits potential for oral, instead of intravenous, administration of DTX.