Cathepsin B-Responsive Phosphatidylinositol 3-Kinase (PI3K) Prodrug for the Treatment of Pulmonary Fibrosis

PI3K inhibitors are effective therapeutic agents for pulmonary fibrosis, but they are plagued by systemic toxicity and a narrow therapeutic window. To overcome this limitation, we developed a novel enzyme-responsive prodrug delivery system designed for targeted lung delivery. This system is based on the PI3K inhibitor <b>P001</b> conjugated via a cathepsin B-cleavable linker (Val-Ala-PAB-MAC) to create the albumin-binding prodrug, <b>PI3K-001</b>. Leveraging albumin's natural lung-targeting properties, <b>PI3K-001</b> achieves site-specific drug delivery and controlled release. <i>In vivo</i> studies demonstrated that the prodrug provides optimized pharmacokinetics, sustained drug release in lung tissue, significantly enhanced antifibrotic efficacy, and reduced systemic toxicity. Our findings validate this targeted, controlled-release strategy as an effective means to harness the therapeutic potential of PI3K inhibitors while mitigating their toxicity for the treatment of pulmonary fibrosis.