Nano‐in‐Microparticles for Aerosol Delivery of Antibiotic‐Loaded, Fucose‐Derivatized, and Macrophage‐Targeted Liposomes to Combat Mycobacterial Infections: In Vitro Deposition, Pulmonary Barrier Interactions, and Targeted Delivery

Abstract

Nontuberculous mycobacterial infections rapidly emerge and demand potent medications to cope with resistance. In this context, targeted loco‐regional delivery of aerosol medicines to the lungs is an advantage. However, sufficient antibiotic delivery requires engineered aerosols for optimized deposition. Here, the effect of bedaquiline‐encapsulating fucosylated versus nonfucosylated liposomes on cellular uptake and delivery is investigated. Notably, this comparison includes critical parameters for pulmonary delivery, i.e., aerosol deposition and the noncellular barriers of pulmonary surfactant (PS) and mucus. Targeting increases liposomal uptake into THP‐1 cells as well as peripheral blood monocyte‐ and lung‐tissue derived macrophages. Aerosol deposition in the presence of PS, however, masks the effect of active targeting. PS alters antibiotic release that depends on the drug's hydrophobicity, while mucus reduces the mobility of nontargeted more than fucosylated liposomes. Dry‐powder microparticles of spray‐dried bedaquiline‐loaded liposomes display a high fine particle fraction of >70%, as well as preserved liposomal integrity and targeting function. The antibiotic effect is maintained when deposited as powder aerosol on cultured Mycobacterium abscessus. When treating M. abscessus infected THP‐1 cells, the fucosylated variant enabled enhanced bacterial killing, thus opening up a clear perspective for the improved treatment of nontuberculous mycobacterial infections.

Targeting Intracellular Bacteria with Dual Drug-loaded Lactoferrin Nanoparticles

“…Interestingly, the proportion of Lf-NPs taken up by dTHP-1 cells decreased when free lactoferrin was included in the culture medium at increasing concentrations, which indicates specific uptake of lactoferrin nanoparticles. The current observation is similar to recent studies that utilized fucose as a targeting ligand on liposomal drug carriers. , Confocal laser scanning microscopic analysis further confirmed the internalization of fluorescent Lf-NPs in the endosomal compartments. Although free lactoferrin (which is also present in the lung lining and other body fluids) reduced the uptake of Lf-NPs and given the high basal phagocytic activity of macrophages, it appears possible to administer decent quantities of Lf-NPs through the pulmonary route because high concentrations of Lf-NPs would be necessary for a competitive uptake of exogenous lactoferrin to achieve desired effects.…”

“…aureus at a multiplicity of infection of 1:5 and 1:1, respectively. After 3 h, infected cells were washed carefully 3–4 times with sterile prewarmed PBS to remove extracellular bacteria . The cells were then treated with medium containing free drugs (at MIC), drug combinations (at MIC of combination), and Lf-NPs (final concentration of ca.…”

Nanomedicines for targeted pulmonary delivery: receptor-mediated strategy and alternatives

“…Besides tuberculosis, nontuberculous mycobacterial infections also manifest as intracellular infections. Huck et al prepared a fucose-derivatized liposome for the treatment of nontuberculous mycobacterial infections by targeting CLR overexpressed on AM 52 (Fig. 3).…”

Minimum Information for Conducting and Reporting In Vitro Intracellular Infection Assays

“…For example, intracellular infections are often found within the deep tissues of the lungs in the cases of cystic fibrosis and tuberculosis. Pulmonary administration of nanoantibiotic will improve the concentration of antibiotics delivered to the lungs while avoiding stability and side effects resulting from oral therapy . However, this presents a unique set of challenges and considerations in which formulation strategies to enable pulmonary delivery (i.e., nebulization or dry powder inhalers), their ability to reach the site of infection upon administration, ability to bypass the thick mucus layer, and interaction with the local immune system need to be investigated.…”