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<p>Matrix metalloproteinase-14 (MMP-14) and Cathepsin-B (Cat-B) are overexpressed in glioblastoma (GBM) and not normal brain, making them promising targets for prodrug activation. We investigated a novel combination therapy using two tumor-enzyme activatable theranostic nanoprobes (TNP): TNP-MMP-14, which disrupts the blood tumor barrier via MMP-14 activation, and TNP-Cat-B, which selectively targets GBM cells through Cat-B activation. We hypothesized that combining TNP-MMP-14 and TNP-Cat-B would enhance TNP tumor accumulation and therapeutic efficacy compared to TNP-Cat-B monotherapy. Thirty NSG mice with luciferase-expressing GBM39 tumors received either TNP-MMP-14 plus TNP-Cat-B, TNP-Cat-B only, or saline. Magnetic resonance imaging (MRI) was conducted pre- and post-treatment, with T2* relaxation times analyzed using a generalized linear model. Histopathological differences were assessed using Kruskal–Wallis and Mann–Whitney tests. A Bonferroni correction was applied to account for multiple comparisons. Combination therapy significantly reduced tumor T2* relaxation times (12.98 ± 4.20&#xa0;ms) compared to TNP-Cat-B monotherapy (22.49 ± 3.95&#xa0;ms, p &lt; 0.001). The apoptotic marker caspase-3 was also significantly higher in the combination group (64.46 ± 23.43 vs. 15.93 ± 5.81, p &lt; 0.001). These findings demonstrate the potential of dual-enzyme activatable nanoparticles to enhance GBM treatment by overcoming drug delivery barriers and improving therapeutic efficacy over monotherapy.</p>

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Dual-enzyme activated theranostic nanoparticles for image-guided glioblastoma therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月19日

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  • Zahra Shokri Varniab,
  • Edwin Chang,
  • Jie Wang,
  • Ramesh Duwa,
  • Vidyani Suryadevara,
  • Wei Wu,
  • Manoj Kumar,
  • Tie Liang,
  • Zubeda Khatoon,
  • Goreti Ribeiro Morais,
  • Robert Falconer,
  • Yifeng Shi,
  • Grigory Tikhomirov,
  • Kerem Nernekli,
  • Laura Jean Pisani,
  • Heike Elisabeth Daldrup-Link

摘要

Matrix metalloproteinase-14 (MMP-14) and Cathepsin-B (Cat-B) are overexpressed in glioblastoma (GBM) and not normal brain, making them promising targets for prodrug activation. We investigated a novel combination therapy using two tumor-enzyme activatable theranostic nanoprobes (TNP): TNP-MMP-14, which disrupts the blood tumor barrier via MMP-14 activation, and TNP-Cat-B, which selectively targets GBM cells through Cat-B activation. We hypothesized that combining TNP-MMP-14 and TNP-Cat-B would enhance TNP tumor accumulation and therapeutic efficacy compared to TNP-Cat-B monotherapy. Thirty NSG mice with luciferase-expressing GBM39 tumors received either TNP-MMP-14 plus TNP-Cat-B, TNP-Cat-B only, or saline. Magnetic resonance imaging (MRI) was conducted pre- and post-treatment, with T2* relaxation times analyzed using a generalized linear model. Histopathological differences were assessed using Kruskal–Wallis and Mann–Whitney tests. A Bonferroni correction was applied to account for multiple comparisons. Combination therapy significantly reduced tumor T2* relaxation times (12.98 ± 4.20 ms) compared to TNP-Cat-B monotherapy (22.49 ± 3.95 ms, p < 0.001). The apoptotic marker caspase-3 was also significantly higher in the combination group (64.46 ± 23.43 vs. 15.93 ± 5.81, p < 0.001). These findings demonstrate the potential of dual-enzyme activatable nanoparticles to enhance GBM treatment by overcoming drug delivery barriers and improving therapeutic efficacy over monotherapy.