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 P001 conjugated via a cathepsin B-cleavable linker (Val-Ala-PAB-MAC) to create the albumin-binding prodrug, PI3K-001. Leveraging albumin's natural lung-targeting properties, PI3K-001 achieves site-specific drug delivery and controlled release. In vivo 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.