Comparison of Redox Responsiveness and Antitumor Capability of Paclitaxel Dimeric Nanoparticles with Different Linkers

Because of the high expression of glutathione (GSH) and reactive oxygen species (ROS) in cancer cells, nanoparticles formed by various redox-responsive linkers have been widely developed. However, the differences in the sensitivity of different linkers to a redox-heterogeneous intracellular environment have not been systematically studied. Herein, four kinds of paclitaxel dimeric nano-prodrug with different linkers, including mono-thioether, disulfide with one methylene, and disulfide with two methylene and ester, were designed and synthesized to explore the differences in redox responsiveness and antitumor capability. We find that the mono-thioether bond with one methylene on both sides is the most sensitive to reduction, while the disulfide bond with one methylene is the most sensitive to oxidation. The sensitivity to redox response is not only related to the redox bond but also to the length of the carbon chain, which has an important impact on drug release, cytotoxicity, and antitumor capability. Our research provides a reference for the rational design of subsequent redox-responsive prodrugs or carriers, which is significant for cancer treatment.