Danhier Fabienne, Messaoudi Khaled, Lemaire Laurent, Benoit Jean-Pierre, Lagarce Frédéric
Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Avenue Mounier, 73, bte B1 73.12, B-1200 Brussels, Belgium.
L'Universit Nantes Angers Le Mans, INSERM U1066, Micro et nanomédecines biomimétiques, IBS-CHU Angers, 4 rue Larrey, 49933 Angers, Cedex 9, France.
Int J Pharm. 2015 Mar 15;481(1-2):154-61. doi: 10.1016/j.ijpharm.2015.01.051. Epub 2015 Jan 30.
Glioblastoma is the most frequent primary malignant brain tumor in adults. Despite treatments including surgery, radiotherapy and chemotherapy by oral Temozolomide (TMZ), the prognosis of patients with glioblastoma remains very poor. This is partly due to the resistance of malignant cells to therapy particularly TMZ. Overexpression of epidermal growth factor receptor (EGFR) and Galectin-1 by tumor cells significantly contributes to TMZ resistance. The purpose of this study was to evaluate in vivo, the effect of local administration by convection enhanced delivery (CED) of the anti-EGFR and anti-Galectin-1 siRNAs administered separately or in combination on (i) the survival of nude mice-bearing orthotopic U87MG glioblastoma cells and on (ii) the EGFR and Galectin-1 expression in excised U87MG tumor tissue. Both siRNAs were carried by chitosan lipid nanocapsules (LNCs). Survival of mice treated 14 days after tumor implantation by the combination of anti-EGFR and anti-Galectin-1 siRNAs and TMZ (40 mg/kg) was significantly increased compared to animals treated by single anti-EGFR or anti-Galectin-1 siRNAs carried by chitosan-LNCs. This was confirmed by a decreased EGFR and Galectin-1 expression at the protein level in excised U87MG tumor tissue, 8 days post-transfection, visualized by immunofluorescence. This study demonstrates the potential of our strategy in glioblastoma therapy.
胶质母细胞瘤是成人中最常见的原发性恶性脑肿瘤。尽管采用了包括手术、放疗和口服替莫唑胺（TMZ）化疗在内的治疗方法，但胶质母细胞瘤患者的预后仍然很差。这部分是由于恶性细胞对治疗尤其是TMZ产生耐药性。肿瘤细胞中表皮生长因子受体（EGFR）和半乳糖凝集素-1的过表达显著导致了TMZ耐药。本研究的目的是在体内评估通过对流增强递送（CED）分别或联合局部给予抗EGFR和抗半乳糖凝集素-1小干扰RNA（siRNAs）对（i）携带原位U87MG胶质母细胞瘤细胞的裸鼠存活情况以及（ii）切除的U87MG肿瘤组织中EGFR和半乳糖凝集素-1表达的影响。两种siRNAs均由壳聚糖脂质纳米胶囊（LNCs）携带。与接受壳聚糖-LNCs携带的单一抗EGFR或抗半乳糖凝集素-1 siRNAs治疗的动物相比，在肿瘤植入后14天接受抗EGFR和抗半乳糖凝集素-1 siRNAs及TMZ（40 mg/kg）联合治疗的小鼠存活时间显著延长。转染8天后，通过免疫荧光观察发现，切除的U87MG肿瘤组织中EGFR和半乳糖凝集素-1在蛋白水平的表达降低，这证实了上述结果。本研究证明了我们的策略在胶质母细胞瘤治疗中的潜力。
