Oxime Linked Doxorubicin Glycoconjugates Improve the Specific Targeting of Glioblastoma in High-Grade Glioma Therapy
Year: 2024
Authors: Iorio A.L., Lenci E., Marzano C., Bucaletti E., Tirinnanzi B., Casati G., Giunti L., Dallari C., Credi C., Sardi I., Trabocchi A.
Autors Affiliation: Meyer Childrens Hosp IRCCS, Neurooncol Unit, I-50139 Florence, Italy; Univ Florence, Dept Hlth Sci, Clin Pharmacol & Oncol Sect, I-50139 Florence, Italy; Univ Florence, Dept Chem Ugo Schiff, I-50019 Florence, Italy; Univ Florence, European Lab Nonlinear Spect LENS, I-50019 Florence, Italy; CNR, Natl Inst Opt, I-50019 Florence, Italy.
Abstract: 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 7 as compared to 4 and to conventional DOX. These data were confirmed in an in vitro coculture BBB model in which DOX glycoconjugate 7 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.
Journal/Review: ACS MEDICINAL CHEMISTRY LETTERS
More Information: This work was supported by Ministero della Salute, Ricerca Finalizzata, Project Code: NET-2019-12371188 and by MUR – Dipartimenti di Eccellenza 2023-2027 (DICUS 2.0) to the Department of Chemistry Ugo Schiff of the University of Florence.KeyWords: CNS tumors; blood-brain barrier; bioconjugation; GLUT receptors; organic synthesisDOI: 10.1021/acsmedchemlett.4c00398