Larger Particle Size Results in Longer Lung Retention Time of Inhaled Solid Lipid Nanoparticles ^†

Aims: The 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 upon release into physiological environments, reflect the fluorescence signals of intact PNDDS, and thus, unambiguously clarify the lung retention profile of PNDDS. Herein, the 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, Shanghai, China). P2-loaded PNDDS, viz. solid lipid nanoparticles (SLN) of different sizes, were prepared via high-pressure homogenization, and encoded as P2-SLN1~P2-SLN4. The particle sizes of P2-SLN1~P2-SLN4 were measured, and then, endotracheally aerosolized in male BALB/c mice (22~26 g), and the P2 fluorescence signals were detected via live imaging. Half-life (T_1/2) and mean retention time (MRT_0–∞) were computed using WinNonlin to describe lung retention time. T_1/2 or MRT_0–∞ was plotted against 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 and MRT_0–∞ were positively correlated with 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. Conclusions: A positive particle size–lung retention time correlation in SLN was demonstrated. For the development of PNDDS, appropriately increasing the particle size enhances lung retention, and vice versa.