Journal Article

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

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

2025

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/67 / 692/308 / Animals / Apoptosis / Brain Neoplasms - diagnostic imaging / Brain Neoplasms - drug therapy / Brain Neoplasms - pathology / Caspase-3 / Cathepsin B - metabolism / Cell activation / Cell Line, Tumor / Combination therapy / Drug delivery / Enzymes / Ferumoxytol / Generalized linear models / Glioblastoma / Glioblastoma - diagnostic imaging / Glioblastoma - drug therapy / Glioblastoma - pathology / Glioblastoma - therapy / Glioma / Humanities and Social Sciences / Humans / Magnetic Resonance Imaging / Matrix metalloproteinase / Matrix Metalloproteinase 14 - metabolism / Metalloproteinase / Mice / MRI / multidisciplinary / Nanoparticles / Nanoparticles - administration & dosage / Nanoparticles - chemistry / Neuroimaging / Prodrugs / Science / Science (multidisciplinary) / Theranostic / Theranostic Nanomedicine - methods / Tumors / Xenograft Model Antitumor Assays