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Purpose <p>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.</p> Methods <p>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.</p> Results <p>uPAR-targeted nanoparticles (L-DAS@AE-105) were successfully optimized with a suitable size (117.9 ± 0.9&#xa0;nm), zeta potential (−14.0 ± 1.6&#xa0;mV), spherical shape, and stability in serum-rich condition for 72&#xa0;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.</p> Conclusion <p>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.</p>

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uPAR-targeted senolytic delivery to enhance cancer therapy

  • 期刊论文

  • 发表日期：

    2025年7月15日

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  • Thi Oanh Oanh Nguyen,
  • Bao Loc Nguyen,
  • Basavaraj R. Patil,
  • Ngoc Duy Le,
  • Beomsu Kim,
  • Sung Giu Jin,
  • Han-Gon Choi,
  • Sae Kwang Ku,
  • Huy Xuan Luong,
  • Jeonghwan Kim,
  • So-Young Park,
  • Jong Oh Kim

摘要

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.