External‐Radiation‐Induced Local Hydroxylation Enables Remote Release of Functional Molecules in Tumors

• Published in: Angewandte Chemie International Edition Vol. 59; no. 48; pp. 21546 - 21552
• Main Authors: Fu, Qunfeng, Li, Hongyu, Duan, Dongban, Wang, Changlun, Shen, Siyong, Ma, Huimin, Liu, Zhibo
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 23-11-2020
• Edition: International ed. in English
• Subjects: Animals; Cell Line, Tumor; Controlled release; Fluorescent Dyes - chemistry; Fluorescent Dyes - metabolism; fluorescent probes; Free radicals; Humans; Hydroxyl Radical - chemistry; Hydroxyl Radical - metabolism; Hydroxyl radicals; Hydroxylation; Mice; Molecular Structure; Neoplasms - chemistry; Neoplasms - metabolism; Neoplasms, Experimental - chemistry; Neoplasms, Experimental - metabolism; Penetration depth; prodrug activation; Radiation; radiation-induced cleavage; Tumors; Xanthones - chemistry; Xanthones - metabolism; Xenografts; Xenotransplantation; controlled release; prodrug activation; radiation-induced cleavage; fluorescent probes; hydroxyl radicals
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202005612

Radiation‐induced cleavage for controlled release in vivo is yet to be established. We demonstrate the use of 3,5‐dihydroxybenzyl carbamate (DHBC) as a masking group that is selectively and efficiently removed by external radiation in vitro and in vivo. DHBC reacts mainly with hydroxyl radicals produced by radiation to afford hydroxylation at para/ortho positions, followed by 1,4‐ or 1,6‐elimination to rescue the functionality of the client molecule. The reaction is rapid and can liberate functional molecules under physiological conditions. This controlled‐release platform is compatible with living systems, as demonstrated by the release of a rhodol fluorophore derivative in cells and tumor xenografts. The combined benefits of the robust caging group, the good release yield, and the independence of penetration depth make DHBC derivatives attractive chemical caging moieties for use in chemical biology and prodrug activation.
A masking group that is selectively and efficiently removed by external radiation was developed based on a unique aromatic hydroxylation and .OH from the radiolysis of H2O. This radiation‐induced cleavage was demonstrated in living systems by switching on an .OH‐responsive fluorescent probe in cells and tumor xenografts.