Two-in-one combination therapy of fluoronucleoside analogues and triplex forming oligonucleotides

• Published in: Nano today Vol. 48; p. 101699
• Main Authors: Ni, Dongqi, Huang, Kang, Wang, Hui, Zhou, Weixian, Guo, Mengyu, Baimanov, Didar, Xue, Yueguang, Chen, Yandong, Liu, Ying
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.02.2023
• Subjects: Cancer therapy; Floxuridine; Fluoronucleoside analogues; Molecular dynamics simulations; Triplex-forming oligonucleotide; Lipo2000; Fluoronucleoside analogues; Triplex-forming oligonucleotide; F; F-TFO; H&E; chemo-TFO; Molecular dynamics simulations; Floxuridine; FdUMP; Cancer therapy; MD; F-dU; TFO; 5-FU; TS
• ISSN: 1748-0132; 1878-044X
• DOI: 10.1016/j.nantod.2022.101699

Antigene technology based on triplex-forming oligonucleotide (TFO) has been widely used in gene-specific regulation, serving as a potential gene therapy method. The optimization of TFO backbone and base can significantly improve the formation and stability of the triplex DNA. Fluorination is widely used in small molecule drug development, but its application in TFO optimization has not been well characterized. Herein, we developed a ‘in silico-in vitro-in vivo’ screening strategy to optimize fluorine atom (F) substitution of TFO. Molecular dynamics simulations are applied to screen single-site F substitutions in the TFO bases that retained stable triplex formation ability with the Ets2-targeted duplex DNA. Combining existing nucleotide analogue floxuridine, the synergistic effect is realized via a two-in-one chemo-TFO including gene regulation and chemotherapeutic functions, which is verified through in vitro and in vivo anti-tumor experiments. [Display omitted] •A two-in-one chemo-triplex-forming oligonucleotide (chemo-TFO) with both gene regulation and chemotherapy function is designed.•Single-site fluorine atom substitutions that have no effect on the triplex formation ability of TFO are screened by molecular dynamics simulation.•Chemo-TFO is delivered into tumor cells to achieve a synergistic effect of gene regulation and FdUMP-based chemotherapy.