Lung-specific delivery of paclitaxel by chitosan-modified PLGA nanoparticles via transient formation of microaggregates

Chitosan-modified paclitaxel-loaded poly lactic-co-glycolic acid (PLGA) nanoparticles with a mean diameter of 200-300 nm in distilled water were prepared by a solvent evaporation method. The mean diameter increased dramatically in contact with the mouse (CDF1) plasma, as a function of chitosan concentration in the modification solution (e.g., 2670.5 nm for 0.7% chitosan-modified nanoparticles, NP₃), but reverted to almost its original size (i.e., 350.7 nm for NP₃) following 5 min of gentle agitation. The zeta potential of PLGA nanoparticles was changed to positive by the chitosan modification. The in vitro uptake into, and cytotoxicity of the nanoparticles against, a lung cancer cell line (A549) were significantly increased by the modification. Most importantly, a lung-specific increase in the distribution index of paclitaxel (i.e., AUC_lung/AUC _plasma) was observed for chitosan-modified nanoparticles (e.g., 99.9 for NP₃ vs. 5.4 for Taxol^TM) when nanoparticles were administered to lung-metastasized mice via the tail vein at a paclitaxel dose of 10 mg/kg. Transient formation of aggregates in the blood stream followed by enhanced trapping in the lung capillaries, and electrical interaction-mediated enhanced uptake across the endothelial cells of the lung tumor capillary appear to be responsible for the lung-tumor-specific distribution of the chitosan modified nanoparticles.