Enzyme-responsive disulfide polymerization inside cells for selective removal of aging cells

Abstract

The intracellular biomacromolecules including proteins, DNA, and polysaccharides, play an important role to perform cellular function. Theses macromolecules are synthesized by the polymerization of small molecules such as amino acids, nucleotides, and monossacharides, but they have distinct properties that the small molecules do not have. From this perspective, the potential use of intracellular polymerization could be new strategy in cancer theranostics. However, the regulation of polymerization has been still challenging due to spatiotemporal control. Unexpected polymerization can cause cellular damage on normal cells, decrease efficiency of intra-mitochondrial polymerization. Hence, we developed enzyme responsive polymerization inside cells to precisely control the polymerization in living cells using thiophosphate group as a substrate of alkaline phosphatase (ALP). In this approach, the thiophosphate undergoes ALP-catalyzed dephosphorylation to form thiol group that can activate disulfide polymerization in presence of oxidative agent. The elevated level of ROS provides effective condition to occur polymerization inside mitochondria of aging cells. The oxidative agents catalyze production of a larger amount of polymer, which generates more oxidative agent as autocatalytic emergency, leading to dysfunction of mitochondria.