Abstract Rationale Neonatal lung injury and Pediatric Acute Respiratory Distress Syndrome (PARDS) are urgent public health concerns given the high mortality rate and severe long-term morbidity. These disorders develop due to damage to developing lung endothelium and vasculature leading to long-term respiratory complications. Pediatric ARDS is more severe than adult ARDS due ongoing development and early maturational stage of lungs. Due to lack of data, current PARDS cases are managed based on the investigations done in adult ARDS cases. These treatment strategies may not consider the long-term respiratory issues due to early-stage damage to lungs. Advanced target-specific therapeutic interventions to protect lung vasculature in PARDS are in dire need. FOXF1 is a transcription factor expressed in endothelial cells and critical for neonatal lung angiogenesis and vascular repair after injury. However, whether FOXF1 is a useful pharmacological target for PARDS is unknown. Methods In this study, we developed nanoparticle-based Lung Endothelial Drug Delivery (LEDD) system and tested its efficacy to deliver a novel FOXF1-activating small molecule compound, TanFeF, in mouse model of PARDS. Further, therapeutic efficacy of nano-TanFeF was evaluated in preclinical mouse model of PARDS using histological, biochemical, and survival studies . Results Single-cell RNA sequencing data indicate that expression of FOXF1 and its target genes is decreased in endothelial cells (ECs) after LPS-induced lung injury. Intravenous delivery of LEDD nanoparticle system delivered multiple compounds specifically to lung endothelium with 90% efficiency and minimal effects on other cells in mice lungs, or other organs tested. Nano-TanFeF treatment increased FOXF1 expression in lung ECs in vitro and in vivo. Toxicity profile in blood and plasma samples indicate nano-TanFeF treatment was non-toxic and well-tolerated. The treatment strategy improved survival in mice exposed to higher dose of LPS. Finally, the treatment caused a significant improvement in the pathophysiological parameters in preclinical mouse model of PARDS including endothelial permeability, lung inflammation, lung angiogenesis and alveolarization after neonatal LPS injury. Conclusions Nanoparticle drug delivery precisely to lung ECs has promise for human PARDS. This abstract is funded by: NIH
Mohammed et al. (Fri,) studied this question.