Exploring the intrinsic micro−/nanoparticle size on their in vivo fate after lung delivery

Micro-/nanocarriers due to their significant advantages are widely investigated in pulmonary drug delivery. However, different size carriers have varied drug release rate, concealing the effect of particle size on the fate of drugs in vivo. Therefore, by keeping drug release rate comparable, the objective of this study is to elucidate the influence of particle size itself on drug in vivo fate after intratracheal instillation to mice. Here, using paclitaxel (PTX) as a drug model, 100 nm, 300 nm, 800 nm, and 2500 nm poly(lactide-co-glycolide) (PLGA) particles with the same release rate were prepared. It was demonstrated that the in vivo fate of particles after lung delivery was size-dependent. Consistent with most reports of model particles with neglected release kinetics, the mucus penetration capacity in airtifical mucus decreased with increasing particle size and there is no significant difference between 800 nm and 2500 nm particles. The in vivo airway distribution experiments confirmed the results of the in vitro mucus penetration study, that is, the smaller the particles, the more distributed in the airway. Both in vitro and in vivo macrophage uptake results confirmed that the larger particles were more readily taken up by macrophages. In contrast, the uptake of smaller particles in A549 cells was higher than that of larger particles. Some new findings were disclosed in lung retention, lung absorption and lung targeting. Different from previous reports, this study demonstrated that particles with smaller size had longer lung retention, AUC(0-t) in bronchoalveolar lavage fluid (BALF) of 100 nm particles was 1.6, 1.9, 2.5 times higher than that of 300 nm, 800 nm, and 2500 nm particles and 11.7 times of the PTX solution group. The same trend was observed in lung tissue absorption, the AUC(0-t) in the lavaged lung of 100 nm particles was 1.8, 2.2, 2.8, 8.6 times higher than that of 300 nm, 800 nm, 2500 nm particles and PTX solution groups, respectively. The lung targeting efficiency was particles size independent. In conclusion, the in vivo fate of particles with the same release kinetics after intratracheal instillation is size-dependent, smaller size particles are conducive for lung retention and lung absorption. Overall, our study provided scientific guidance for the rational design of particle based pulmonary drug delivery system.