Chen Yinhsuan Michely, Chambon Julien, Moquin Alexandre, Hashimoto Masakazu, Perrino Stephanie, Leibovitch Matthew, Benslimane Yasmine, Haçariz Orçun, Yang Qin, Nakano Ichiro, Meehan Brian, Rak Janusz, Gagné Stéphane, Brodt Pnina
Department of Medicine, Division of Experimental Medicine, McGill University.
The Research Institute of the McGill University Health Center, Montreal, QC, Canada H4A 3J1.
Neuro Oncol. 2025 Jun 21;27(5):1227-1240. doi: 10.1093/neuonc/noaf011.
Glioblastoma is an aggressive brain cancer with a 5-year survival rate of 5-10%. Current therapeutic options are limited, due in part to drug exclusion by the blood-brain barrier, restricting access of targeted drugs to the tumor. The receptor for the type 1 insulin-like growth factor (IGF-1R) was identified as a therapeutic target in glioblastoma. We previously reported that the intracerebral growth of glioma cells with reduced IGF-1R levels was inhibited. The objectives of this study were to evaluate the sensitivity of glioma cells to a novel IGF-axis inhibitor, the IGF-Trap, and optimize its delivery to the brain.
We tested the effect of the IGF-Trap on the growth of the human glioma stem cells MES-1123 and U87 MG cells, and of murine GL261 cells in vivo, using subcutaneous and orthotopic implantation.
We show that the growth of glioma cells implanted subcutaneously or orthotopically in the brain was inhibited by systemic and direct intracerebral administration of IGF-Trap, respectively, resulting in increased survival. To increase the efficiency of systemic delivery to the brain, we encapsulated the IGF-Trap in trimethyl chitosan (TRIOZAN™) nanoparticles prior to intravenous injection. We found that nanoparticle encapsulation increased the uptake and retention of the IGF-Trap in the brain and resulted in an improved therapeutic effect against intra-cerebrally growing tumors.
Our results identify the IGF-Trap as a potent inhibitor of intracerebral glioma growth and show that encapsulation in nanoparticles can improve delivery of biologics such as the IGF-Trap to the brain, thereby enhancing the therapeutic response.
胶质母细胞瘤是一种侵袭性脑癌，5年生存率为5%-10%。目前的治疗选择有限，部分原因是血脑屏障会排除药物，限制了靶向药物进入肿瘤。1型胰岛素样生长因子受体（IGF-1R）被确定为胶质母细胞瘤的治疗靶点。我们之前报道过，IGF-1R水平降低的胶质瘤细胞在脑内的生长受到抑制。本研究的目的是评估胶质瘤细胞对一种新型IGF轴抑制剂IGF-Trap的敏感性，并优化其向脑部的递送。
我们使用皮下和原位植入方法，测试了IGF-Trap对人胶质瘤干细胞MES-1123和U87 MG细胞以及小鼠GL261细胞体内生长的影响。
我们发现，分别通过全身给药和直接脑内给药，IGF-Trap可抑制皮下或脑内原位植入的胶质瘤细胞的生长，从而提高生存率。为了提高全身给药至脑部的效率，我们在静脉注射前将IGF-Trap包裹在三甲基壳聚糖（TRIOZAN™）纳米颗粒中。我们发现纳米颗粒包裹增加了IGF-Trap在脑内的摄取和保留，并对脑内生长的肿瘤产生了更好的治疗效果。
我们的结果表明IGF-Trap是脑内胶质瘤生长的有效抑制剂，并表明包裹在纳米颗粒中可以改善生物制剂如IGF-Trap向脑部的递送，从而增强治疗反应。
