Abstract Vascular injury with disruption of the endothelial barrier is an inevitable consequence of the pathological processes contributing to the development of pulmonary hypertension (PH). Despite earlier diagnosis and recent improvements in its clinical management, pediatric PH remains ultimately fatal, with poor treatment outcomes and dismal prognosis. Centered on developing an effective and safe therapy for PH in children, these studies will evaluate cleavable multimeric prodrugs taking advantage of the increased vascular permeability associated with this pathology to enhance uptake and provide a lasting therapeutic effect of the drug cargo on the pulmonary vasculature, while minimizing off-target distribution and systemic toxicity. This delivery strategy will be evaluated with non-prostanoid prostacyclin mimetics exhibiting pleiotropic effects against PH. As small-molecule drugs, they have shown promise in clinical trials, however their clinical utility is limited by rapid clearance and significant systemic adverse effects. Guided by our prior work on the design of prodrugs for target- specific delivery and the results of our proof-of-principle studies toward this project, we hypothesize that multimeric prodrugs designed as reversibly assembled, covalent [polymer- drug] complexes will achieve sustained presence of the prostacyclin analogs at therapeutically adequate levels in the lung tissue, resulting in a strong and lasting suppression of the PH development in a clinically relevant model recapitulating key features of the disease. This hypothesis will be tested and the overall objective of this project will be attained by pursuing the following specific aims: Aim 1 studies will focus on in vitro evaluation of the prodrugs by comparatively determining their effects on cAMP accumulation, platelet activation, and growth kinetics of proliferative smooth muscle cells; Aim 2 studies will comparatively examine pulmonary uptake and biodistribution of a model macromolecular construct (Subaim 2a), and evaluate therapeutic efficacy and toxicity of the multimeric prodrugs in a preclinical model of PH (Subaim 2b). These studies are expected to have a lasting impact on the field by demonstrating feasibility of using multimeric prodrugs with a cleavable chemical design to improve safety and effectiveness of drug therapy while mitigating the risk for delayed adverse effects due to accumulation of the carrier, and by implementing prodrug-based delivery to enhance selectivity and extend the duration of the pharmacological activity of synthetic non- prostanoid prostacyclin mimetics as an experimental new treatment for pediatric pulmonary hypertension - a severe, ultimately fatal disease lacking curative treatment options.