Ultrasound and Microbubbles for Targeted Drug Delivery to the Lung Endothelium in ARDS: Cellular Mechanisms and Therapeutic Opportunities

Abstract

Acute respiratory distress syndrome (ARDS) is characterized by increased permeability of the alveolar–capillary membrane, a thin barrier composed of adjacent monolayers of alveolar epithelial and lung microvascular endothelial cells. This results in pulmonary edema and severe hypoxemia and is a common cause of death after both viral (e.g., SARS-CoV-2) and bacterial pneumonia. The involvement of the lung in ARDS is notoriously heterogeneous, with consolidated and edematous lung abutting aerated, less injured regions. This makes treatment difficult, as most therapeutic approaches preferentially affect the normal lung regions or are distributed indiscriminately to other organs. In this review, we describe the use of thoracic ultrasound and microbubbles (USMB) to deliver therapeutic cargo (drugs, genes) preferentially to severely injured areas of the lung and in particular to the lung endothelium. While USMB has been explored in other organs, it has been under-appreciated in the treatment of lung injury since ultrasound energy is scattered by air. However, this limitation can be harnessed to direct therapy specifically to severely injured lungs. We explore the cellular mechanisms governing USMB and describe various permutations of cargo administration. Lastly, we discuss both the challenges and potential opportunities presented by USMB in the lung as a tool for both therapy and research.

Controlled Shrinkage of Microfluidically Generated Microbubbles by Tuning Lipid Concentration

“…As a result, MBs have higher echogenic response to ultrasound compared to blood and surrounding tissues . The higher echogenicity of MBs, combined with their nonlinear response to ultrasound waves, increases the intensity of the scattered ultrasound signal and produces higher-quality ultrasound images. − In drug delivery applications, when MBs are exposed to an ultrasound field, the MBs oscillate and generate fluid flow (i.e., acoustic micro-streaming) that causes targeted uptake of drugs by nearby cells. ,− This process may also increase vascular permeability by widening the gap between cell–cell junctions, facilitating the migration of drugs across cells into specific areas of interest. ,, This efficient technique enables noninvasive targeted drug delivery and could be utilized in different therapeutic applications, including tumor treatment. ,, In in vivo biomedical applications, the diameter of the MBs should be smaller than 10 μm to prevent the MBs from being trapped in micro vessels while passing through capillary beds. , Additionally, small, sub-10 μm diameter MBs are better matched to clinical ultrasound transducers. − …”

Low-frequency ultrasound for pulmonary hypertension therapy

“…Such improved absorption of drugs into cells is due to the increased permeability of the membrane under the influence of ultrasound [ 28 ]. The results of therapeutic drugs delivery using thoracic ultrasound and microbubbles, primarily to damaged areas of the lung, especially to the endothelium, have been described in a study [ 29 ]. Using our proposed low-frequency ultrasound transducer, it is possible to select an excitation frequency that coincides with the resonant frequency of the microbubbles, which results in their disruption, thereby accelerating drug delivery.…”

Ultrasound-guided transfection of claudin-5 improves lung endothelial barrier function in lung injury without impairing innate immunity

“…Sufficient tissue penetration of ultrasound may also be an issue in larger animals, although endobronchial ultrasound could in principle permit access to deeper areas of the injured lung. Optimization of USMB for its use in humans and delineation of its potential additional applications is now underway ( 24 ).…”