Iorio Anna Lisa, Lenci Elena, Marzano Chiara, Bucaletti Elisabetta, Tirinnanzi Bianca, Casati Giacomo, Giunti Laura, Dallari Caterina, Credi Caterina, Sardi Iacopo, Trabocchi Andrea
Neuro-Oncology Unit, Meyer Children's Hospital IRCCS, 50139 Florence, Italy.
Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, 50139 Florence, Italy.
ACS Med Chem Lett. 2024 Oct 23;15(11):1953-1960. doi: 10.1021/acsmedchemlett.4c00398. eCollection 2024 Nov 14.
The treatment of glioblastoma (GBM) represents an urgent challenge for public health due to the inability to effectively deliver anticancer agents, such as doxorubicin (DOX), through the blood-brain barrier (BBB). Herein we report the synthesis of two novel DOX glycoconjugates using an oxime linkage that maintained the intercalation capability of the planar anthracycline ring of DOX, as demonstrated by UV-vis and fluorescence experiments in the presence of DNA. The biological effect of DOX glycoconjugates was evaluated in GBM cell lines, showing an enhanced cytotoxic and pro-apoptotic effect of as compared to and to conventional DOX. These data were confirmed in an coculture BBB model in which DOX glycoconjugate showed high capability to cross a cellular monolayer and exert its cytotoxic effect on GBM cells. The results show that conjugation with glucose may represent a helpful tool to increase chemotherapy effectiveness in poor-responding GBM patients.
由于无法有效通过血脑屏障（BBB）递送抗癌药物，如阿霉素（DOX），胶质母细胞瘤（GBM）的治疗对公共卫生构成了紧迫挑战。在此，我们报告了两种新型DOX糖缀合物的合成，它们通过肟键连接，保持了DOX平面蒽环的嵌入能力，这在DNA存在下的紫外可见和荧光实验中得到了证明。在GBM细胞系中评估了DOX糖缀合物的生物学效应，结果显示与DOX和传统DOX相比，其细胞毒性和促凋亡效应增强。这些数据在GBM-脑微血管内皮细胞共培养血脑屏障模型中得到了证实，其中DOX糖缀合物表现出穿过细胞单层并对GBM细胞发挥细胞毒性作用的高能力。结果表明，与葡萄糖缀合可能是提高对治疗反应不佳的GBM患者化疗效果的有用工具。
