Pulmonary drug delivery is a common route of administration for the treatment of respiratory diseases, including pulmonary infections, asthma and chronic obstructive pulmonary diseases, by providing several advantages over other routes of administration including rapid onset of action, high local drug concentration and low systemic exposure.

Among different carriers, liposome is one of the most promising one for pulmonary drug delivery attributed to its biocompatibility, biodegradability, avoidance of local irritation, sustained release, and intracellular targeting. A liposome based product, ARIKAYCE® (amikacin liposome inhalation suspension) has already been approved by the FDA for the treatment of Mycobacterium avium complex lung disease. In general, based on their size and microstructure, liposomes are categorized into small unilamellar liposomes (20–100 nm), large unilamellar liposomes (100–1000 nm), multilamellar liposomes (1–5 μm), and multivesicular liposomes (5–100 μm) [1], [2]. And most of the liposomes employed for inhalation are nanosized unilamellar liposomes [3], [4]. Due to the small size and single lipid bilayer, these unilamellar liposomes usually have some limitations in terms of drug loading capacity as well as controlled drug release, which is not favorable for maintaining effective drug concentration in the lung for prolonged period of time. In contrast, the micron-sized liposomes are able to overcome these shortcomings to a certain extent. For example, multivesicular liposome (MVL) is a microscopic spheroid with non-concentric network of lipid membrane. The non-concentric architecture and large diameter provide the MVL with high drug loading capacity, structural stability, and a better controlled drug release over hours to weeks after local injection [5], [6]. Also, multilamellar liposomes (MLL), another micron-sized liposomes with the structure of concentric multiple lipid layers, can entrap greater amounts drugs and prolong their therapeutic effects [7]. Moreover, due to the micron-sized geometric diameter, the micron-sized liposomes are more likely to be engulfed by macrophages, which could be an ideal drug delivery vector in the treatment of diseases such as mycobacterium tuberculosis infection whereas the alveolar macrophages are the host [8]. Accordingly, micron-sized liposomes might also serve as promising drug delivery vehicles for pulmonary administration, but to the best of our knowledge, no related study is available so far.

Moreover, the type of phospholipid selected for liposomes preparation is also of special importance. Previous studies have shown that the liposomes prepared with different kinds of phospholipids behaved differently in terms of cellular uptake and interaction with the tissues [9], which reveal that phospholipid type could also influence the in vivo fate, and thus therapeutic efficiency of micron-sized liposomes.

Thus, the purpose of this study is to investigate the influence of microstructure and phospholipid type of liposomes on their interaction with the lung to widen their applications in the area of inhalation delivery. Using different types of phospholipids (including soya phosphatidylcholine (SPC), egg yolk phosphatidylcholine (EPC), and dipalmitoyl phosphatidylcholine (DPPC)), both MLL and MVL liposomes were prepared. The geometric diameter of all the liposomes were controlled at around 5 µm to achieve both good lung deposition as well as evasion of alveolar macrophages phagocytosis [10], [11]. After characterizing physicochemical properties of the micron-sized liposomes including particle size and size distribution, stability, structure and fluidity, the effect of liposomes’ microstructure and phospholipid type on their interaction with the lung biological barriers was studied systemically, including in vitro pulmonary cellular uptake, in vivo lung retention and organ distribution. This study could provide a theoretical basis for designing inhaled micron-sized liposomes.