Intracellular Radical Polymerization of Paclitaxel-Bearing Acrylamide for Self-Inflicted Apoptosis of Cancer Cells

Polymerization inside living cells presents a straightforward approach to synthesize functional macromolecules in situ, but available protocols are limited by the cytotoxicity of reaction ingredients and the lack of coordination with the cellular environment. In this work, we report intracellular radical polymerizations that are promoted by the redox response of the tumor microenvironment. In the presence of endogenous glutathione (GSH) and supplementary sodium ascorbate (NaAsc), a low dose of the Cu(II)–histidine complex could be continuously reduced into an active Cu(I) catalyst inside living cells to initiate the polymerization of N-hydroxyethyl acrylamide with 97% conversion within 2 h. This method exhibited selectivity toward cells with redox imbalance and proved that the critical factors of intracellular polymerization are related to the redox status of GSH/GSSG. The tumor cells could initiate the polymerization of acryloyl paclitaxel (Acr-PTX) into a paclitaxel-bearing polymer (poly-PTX), which induces the apoptosis of these tumor cells far more efficiently than monomeric forms of PTX. Our work demonstrates an innovative approach to synthesize functional polymers inside living tumor cells by taking advantage of the local microenvironment of cells and also to direct the fate of tumor cells using the in situ synthesized polymers. This work will motivate the design of radical polymerization of acrylamide inside cells toward solving challenges of tumor therapy with high spatial and temporal resolution.