Intracellular Hyperbranched Polymerization for Circumventing Cancer Drug Resistance.

Polymerization inside living cells provides chemists with a multitude of possibilities to modulate cell activities. Considering the advantages of hyperbranched polymers, such as a large surface area for target sites and multilevel branched structures for resistance to the efflux effect, we reported a hyperbranched polymerization in living cells based on the oxidative polymerization of organotellurides and intracellular redox environment. The intracellular hyperbranched polymerization was triggered by reactive oxygen species (ROS) in the intracellular redox microenvironment, effectively disrupting antioxidant systems in cells by an interaction between Te (+4) and selenoproteins, thus inducing selective apoptosis of cancer cells. Importantly, the obtained hyperbranched polymer aggregated into branched nanostructures in cells, which could effectively evade drug pumps and decrease drug efflux, ensuring the polymerization for persistent treatment. Finally, in vitro and in vivo studies confirmed that our strategy presented selective anticancer efficacy and well biosafety. This approach provides a way for intracellular polymerization with desirable biological applications to regulate cell activities.

CO/chemosensitization/antiangiogenesis synergistic therapy with H2O2-responsive diselenide-containing polymer.

Carbon monoxide (CO) therapy and antiangiogenesis therapy (AAT) are regarded as promising approaches for cancer treatment. However, the poor tumor targeting ability and inevitable side effects prevent their clinical application. In this study, we developed H2O2-responsive diselenide-containing micelles that combined CO therapy with chemosensitization therapy and AAT in a single system. Under the interaction of intratumoral H2O2, CO and gemcitabine (GEM) were released in situ from the micelles to reduce side effects, and CO significantly sensitized the chemotherapeutic effect of GEM by elevating the level of reactive oxygen species (ROS) in human gastric cancer AGS cells. Furthermore, diselenide bonds in the micelles were oxidized to seleninic acid in organic form, which suppressed the expressions of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP-2) to realize AAT. This study provides an integrated solution to combine CO therapy with chemosensitization therapy and AAT together with good biocompatibility.