A novel theranostic strategy for MMP-14 expressing glioblastomas impacts survival
Menée in vitro et à l'aide de xénogreffes de glioblastome exprimant la métalloprotéase matricielle MMP-14, cette étude met en évidence l'intérêt d'une stratégie thérapeutique combinant témozolomide et nanoparticules d'oxyde de fer conjuguées à un perturbateur vasculaire activable par l'enzyme MMP-14 dans les vaisseaux tumoraux
Glioblastoma (GBM) has a dismal prognosis. Evidence from preclinical tumor models and human trials indicates the role of GBM initiating cells (GIC) in GBM drug resistance. Here, we propose a new treatment option with tumor enzyme-activatable, combined therapeutic and diagnostic (theranostic) nanoparticles, which caused specific toxicity against GBM tumor cells and GICs. The theranostic cross-linked iron oxide nanoparticles (CLIO) were conjugated to a highly potent vascular disrupting agent (ICT) and secured with a matrix-metalloproteinase (MMP-14) cleavable peptide. Treatment with CLIO-ICT disrupted tumor vasculature of MMP-14 expressing GBM, induced GIC apoptosis and significantly impaired tumor growth. In addition, the iron core of CLIO-ICT enabled in vivo drug tracking with MR imaging. Treatment with CLIO-ICT plus temozolomide achieved tumor remission and significantly increased survival of human GBM bearing mice by more than 2 fold compared to treatment with temozolomide alone. Thus, we present a novel therapeutic strategy with significant impact on survival and great potential for clinical translation.
http://mct.aacrjournals.org/content/early/2017/06/21/1535-7163.MCT-17-0022.abstract