Journal
MOLECULAR THERAPY
Volume 31, Issue 3, Pages 875-889Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2023.01.003
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Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions characterized by excessive lung inflammation. This study developed a peptide-based strategy using a targeting peptide called CRV to deliver glucocorticoids for ALI treatment. The CRV peptide selectively targeted the inflamed lung tissue, reducing side effects in healthy organs. The conjugation of prednisolone (PSL) and CRV using a reactive oxygen species (ROS)-responsive linker allowed for the release of PSL specifically in the inflamed lung tissue, leading to reduced lung injury.
Acute lung injury (ALI) and acute respiratory distress syn-drome (ARDS) are life-threatening conditions with excessive inflammation in the lung. Glucocorticoids had been widely used for ALI/ARDS, but their clinical benefit remains unclear. Here, we tackled the problem by conjugating prednisolone (PSL) with a targeting peptide termed CRV. Systemically administered CRV selectively homes to the inflamed lung of a murine ALI model, but not healthy organs or the lung of healthy mice. The expression of the CRV receptor, retinoid X receptor b, was elevated in the lung of ALI mice and patients with interstitial lung diseases, which may be the basis of CRV targeting. We then covalently conjugated PSL and CRV with a reactive oxygen species (ROS)-responsive linker in the mid-dle. While being intact in blood, the ROS linker was cleaved intracellularly to release PSL for action. In vitro, CRV-PSL showed an anti-inflammatory effect similar to that of PSL. In vivo, CRV conjugation increased the amount of PSL in the inflamed lung but reduced its accumulation in healthy organs. Accordingly, CRV-PSL significantly reduced lung injury and immune-related side effects elsewhere. Taken together, our peptide-based strategy for targeted delivery of glucocorticoids for ALI may have great potential for clinical translation.
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