Aims: Particle size-lung retention time correlation is a vital guiding principle in developing pulmonary nanoparticle drug delivery systems (PNDDS). Fluorescence probes with accurate water-quenching attributes, which are emissive under PNDDS encapsulation while quenched after release in psysiological environments, reflex fluorescence signals of intact PNDDS and thus unambigously clarify the lung retention profile of PNDDS. Herein, water-quenching probe P2 was used to investigate the particle size-lung retention time correlation.

Methods: P2 was donated by Prof. Wei Wu (Fudan University). P2-loaded PNDDS, viz. solid lipid nanoparticles (SLN) with different sizes, were prepared by high-pressure homogenization, encoded as P2-SLN1~P2-SLN4. Particle sizes of P2-SLN1~P2-SLN4 were measured, and then endotracheally aerosolized to male BALB/c mice (22~26 g), and P2 fluorescence signals were detected by living imaging. Half-life (T_1/2) and mean retention time (MRT_0-∞) were computed by WinNonlin to describe lung retention time. T_1/2 or MRT_0-∞ was plotted versus particle size, and linear regression was performed.

Results: P2-SLN1~P2-SLN4 possessed average sizes of circa 120, 240, 360 and 480 nm, respectively, with good size distribution homogeneity. After inhalation, P2 fluorescence intensity continuously decreased in the pulmonary region. Noticeably, T_1/2 or MRT_0-∞ were positively correlated to particle size, with great model-fitness (R² > 0.99, p < 0.05). Therefore, larger particle size (within the range of 120~480 nm) caused longer retention time.

Conclusion: A positive particle size-lung retention time correlation in SLN was demonstrated. For the development of PNDDS, appropriately increase the particle size would enhance lung retention, vice versa.