Galassi Lucrezia, Rossi Martina, Lodeserto Pietro, Lenzi Monia, Borsetti Francesca, Voltattorni Manuela, Farruggia Giovanna, Blasi Paolo, Orienti Isabella
Department of Pharmacy and Biotechnology, University of Bologna, Via San Donato 19/2, 40127 Bologna, Italy.
Center for Applied Biomedical Research (CRBA), University of Bologna, 40126 Bologna, Italy.
Pharmaceutics. 2023 Feb 15;15(2):648. doi: 10.3390/pharmaceutics15020648.
Neuroblastoma cells highly express the disialoganglioside GD2, a tumor-associated carbohydrate antigen, which is also expressed in neurons, skin melanocytes, and peripheral nerve fibers. Immunotherapy with monoclonal anti-GD2 antibodies has a proven efficacy in clinical trials and is included in the standard treatment for children with high-risk neuroblastoma. However, the strong neuro-toxicity associated with anti-GD2 antibodies administration has hindered, until now, the possibility for dose-escalation and protracted use, thus restraining their therapeutic potential. Strategies to increase the efficacy of anti-GD2 antibodies are actively sought, with the aim to enable chronic treatments that could eradicate minimal residual disease and subsequent relapses, often occurring after treatment. Here, we report that Nanofenretinide and Nanospermidine improved the expression of GD2 in neuroblastoma cells (CHP-134) and provided different effects in combination with the anti-GD2 antibody naxitamab. In particular, Nanofenretinide significantly increased the cytotoxic effect of naxitamab while Nanospermidine inhibited cell motility at extents proportional to naxitamab concentration. In neuroblastoma cells characterized by a low and heterogeneous basal expression of GD2, such as SH-SY5Y, which may represent the cell heterogeneity in tumors after chemotherapy, both Nanofenretinide and Nanospermidine increased GD2 expression in approximately 50% of cells, thus shifting the tumor population towards improved sensitivity to anti-GD2 antibodies.
神经母细胞瘤细胞高度表达双唾液酸神经节苷脂GD2，一种肿瘤相关碳水化合物抗原，其在神经元、皮肤黑素细胞和外周神经纤维中也有表达。用单克隆抗GD2抗体进行免疫治疗在临床试验中已被证明有效，并且被纳入高危神经母细胞瘤儿童的标准治疗方案。然而，迄今为止，与抗GD2抗体给药相关的强烈神经毒性阻碍了剂量递增和长期使用的可能性，从而限制了它们的治疗潜力。人们正在积极寻求提高抗GD2抗体疗效的策略，目的是实现能够根除微小残留病和后续复发（通常在治疗后发生）的长期治疗。在此，我们报告纳米维甲酸和纳米亚精胺改善了神经母细胞瘤细胞（CHP-134）中GD2的表达，并与抗GD2抗体那昔妥单抗联合使用时产生了不同的效果。特别是，纳米维甲酸显著增强了那昔妥单抗的细胞毒性作用，而纳米亚精胺则以与那昔妥单抗浓度成比例的程度抑制细胞运动。在以GD2低水平且异质性基础表达为特征的神经母细胞瘤细胞中，如SH-SY5Y，其可能代表化疗后肿瘤中的细胞异质性，纳米维甲酸和纳米亚精胺均使约50%的细胞中GD2表达增加，从而使肿瘤群体对抗GD2抗体的敏感性提高。
