144 - Exosomes as Drug Delivery Vehicles for Dexamethasone: Findings from an In Vivo Model of Bronchopulmonary Dysplasia

To investigate the effects of exosomes loaded with dex on lung inflammation in a rat model of BPD

Design/Methods:

Exosomes were extracted from adult rat lungs by density gradient centrifugation, loaded with dex by sonication, washed, and resuspended in sterile saline.  In a series of experiments, rat pups were exposed to hyperoxia (85% to 95% O₂) from day 0 to 7.  On days 0 and 4, pups were intraperitoneally injected with 25µg dex-loaded exosomes (n=7), unloaded exosomes (n=5), or saline (n=7). Controls were reared in normoxia and received either no treatment, the treatments listed above, or free dex (tapering doses days 0-3). On day 7, the lungs were extracted, weighed, homogenized, and 12 inflammatory cytokines were measured using the Luminex platform. Animal weight, length, and brain weight were also measured.

Results:

Eight of the 12 cytokines were significantly elevated in the lung homogenates of the hyperoxia/saline group compared to controls. In pups treated with dex-loaded exosomes, IL-1β, MCP-1 and MCP-3 were significantly lower compared to the saline-treated group; there was a trend toward reduction of MIP-1-α, MIP-2-α and TNF-α. There were no differences between the unloaded exosome group and the saline group. Exposure to free dex was associated with decreased weight, length, and brain weight. In the dex-loaded exosome group, length and brain weight were comparable to saline-treated controls; weight was significantly decreased in 2 of 3 experiments.

Conclusion(s):

In this study, we demonstrate that exosomes loaded with dex protect against lung injury caused by sustained hyperoxia. The observed anti-inflammatory effects are attributable to dex, rather than the exosome vehicle. Furthermore, loading dex into exosomes may effectively target drug delivery to the lungs, while decreasing adverse systemic side effects associated with free dex. Future studies will evaluate the effects of dex-loaded exosomes on histologic markers of BPD and investigate tropism of exosomes for the lungs versus the brain, with the overarching aim of finding safer and more effective therapies for BPD.