Department of Radiology, Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California.
Institute of Cancer Therapeutics, Faculty of Life Sciences, University of Bradford, Bradford, United Kingdom.
Mol Cancer Ther. 2017 Sep;16(9):1909-1921. doi: 10.1158/1535-7163.MCT-17-0022. Epub 2017 Jun 28.
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 -expressing GBM, induced GIC apoptosis, and significantly impaired tumor growth. In addition, the iron core of CLIO-ICT enabled 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 with treatment with temozolomide alone. Thus, we present a novel therapeutic strategy with significant impact on survival and great potential for clinical translation. .
胶质母细胞瘤（GBM）预后不良。临床前肿瘤模型和人体试验的证据表明，胶质母细胞瘤起始细胞（GIC）在 GBM 耐药中起作用。在这里，我们提出了一种新的治疗选择，使用肿瘤酶激活的联合治疗和诊断（治疗诊断）纳米颗粒，该纳米颗粒对 GBM 肿瘤细胞和 GIC 具有特异性毒性。治疗诊断交联氧化铁纳米颗粒（CLIO）与一种高效的血管破坏剂（ICT）连接，并与基质金属蛋白酶（MMP-14）可切割肽结合。CLIO-ICT 的治疗破坏了表达 - 的 GBM 的肿瘤血管，诱导 GIC 凋亡，并显著抑制肿瘤生长。此外，CLIO-ICT 的铁核能够通过磁共振成像进行药物追踪。与单独使用替莫唑胺相比，CLIO-ICT 联合替莫唑胺治疗可实现肿瘤消退，并使携带人类 GBM 的小鼠的存活率显著提高 2 倍以上。因此，我们提出了一种具有生存显著影响和临床转化巨大潜力的新治疗策略。
