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

摘要

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 degrees 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.