uPAR-targeted senolytic delivery to enhance cancer therapy

Purpose: The urokinase-type plasminogen activator receptor (uPAR) protein is a potential biomarker for cellular senescence. This study aimed to develop a targeted nano-system for delivering the senolytic agent, dasatinib to target uPAR-overexpressing senescent cells induced by cancer therapies. Methods: Senescence was induced in HCT-116 and MDA-MB-231 cells using low-dose irinotecan and palbociclib, respectively, and assessed for senescent phenotypes and uPAR overexpression. A design of experiment approach optimized key attributes of uPAR-targeted nanoparticles, and designed to deliver dasatinib to uPAR-overexpressing carcinomas. In vitro studies evaluated cellular uptake and senescent cell clearance, whereas in vivo experiments evaluated the formulation’s anti-tumor and anti-metastasis effects. Results: uPAR-targeted nanoparticles (L-DAS@AE-105) were successfully optimized with a suitable size (117.9 ± 0.9 nm), zeta potential (−14.0 ± 1.6 mV), spherical shape, and stability in serum-rich condition for 72 h. In vitro, irinotecan- and palbociclib-induced senescent cells efficiently internalized L-DAS@AE105, enhancing toxicity. In vivo, nanoparticles accumulated in tumors following pro-senescence treatments that upregulated membranous uPAR in tumor cells. The combination of irinotecan and uPAR-targeted nanoparticles significantly inhibited tumor growth in colorectal xenograft models. In addition, sequential treatment with palbociclib and L-DAS@AE105 exhibited strong antimetastatic effects in an orthotopic triple-negative breast cancer model. Conclusion: uPAR-targeted nanoparticles enhanced dasatinib’s senolytic effects, improving tumor suppression when combined with irinotecan in colon cancer and palbociclib in triple-negative breast cancer models.