Reactive Oxygen Species-Responsive Protein Modification and Its Intracellular Delivery for Targeted Cancer Therapy

• Published in: Angewandte Chemie International Edition Vol. 53; no. 49; pp. 13444 - 13448
• Main Authors: Wang, Ming, Sun, Shuo, Neufeld, Caleb I., Perez-Ramirez, Bernardo, Xu, Qiaobing
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.12.2014; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Benzyl Compounds - chemistry; Benzyl Compounds - metabolism; Cancer; Cancer therapies; Carbonates; Carbonates - chemistry; Carbonates - metabolism; Cell Line, Tumor; Conjugation; Cytotoxicity; drug delivery; Enzyme Therapy; Humans; Hydrogen peroxide; Lysine; Modulation; nanoparticles; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - metabolism; Oxygen; protein engineering; Proteins; Reactive Oxygen Species - metabolism; Ribonuclease, Pancreatic - chemistry; Ribonuclease, Pancreatic - metabolism; Ribonuclease, Pancreatic - pharmacology; Ribonuclease, Pancreatic - therapeutic use; ROS-responsive; targeted cancer therapy; Therapy; Tumors; targeted cancer therapy; protein engineering; ROS-responsive; nanoparticles; drug delivery
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.201407234

Herein we report a convenient chemical approach to reversibly modulate protein (RNase A) function and develop a protein that is responsive to reactive oxygen species (ROS) for targeted cancer therapy. The conjugation of RNase A with 4‐nitrophenyl 4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl) benzyl carbonate (NBC) blocks protein lysine and temporarily deactivates the protein. However, the treatment of RNase A–NBC with hydrogen peroxide (one major intracellular ROS) efficiently cleaves the NBC conjugation and restores the RNase A activity. Thus, RNase A–NBC can be reactivated inside tumor cells by high levels of intracellular ROS, thereby restoring the cytotoxicity of RNase A for cancer therapy. Due to higher ROS levels inside tumor cells compared to healthy cells, and the resulting different levels of RNase A–NBC reactivation, RNase A–NBC shows a significant specific cytotoxicity against tumor cells. Reversible protein function modulation was achieved by a convenient chemical approach. RNase A was equipped with a boronic acid group (RNase A–NBC) that responds to reactive oxygen species (ROS). This complex shows cytotoxicity in the presence of ROS, as for example in cancer cells, whereas healthy cells are only affected at significantly higher concentrations.