Multicomponent Polymerization toward Poly(BODIPY‐sulfonamide)s as Unique SO2 Generators for Sonodynamic and Gas Combination Therapy

In this work, a multicomponent polymerization (MCP) approach involving bipyrroles, sulfonyl azides, and diynes was developed to afford a library of poly(bipyrrole‐sulfonylimide)s (PPSIs) in high yields and molecular weights, which were further modified to form unique sulfur dioxide (SO2) generators. Bipyrroles served as carbon‐based nucleophiles to undergo Cu‐catalyzed C‐C coupling during the MCP. Upon post‐MCP modification by transforming the bipyrrole unit to boron dipyrromethene (BODIPY) and the sulfonylimide moiety to sulfonamide, poly(BODIPY‐sulfonamide)s (PBSAs) were obtained as potent anticancer therapeutic agents. This study disclosed the decomposition and SO2‐releasing ability of PBSAs under ultrasound (US) irradiation. Furthermore, one of these polymers having a reactive oxygen species‐cleavable thioketal linker was modified with triethylene glycol chains to give PBSA‐EG, which was further studied for in vitro and in vivo US‐induced anti‐cancer therapy. Upon tail veil administration of PBSA‐EG nanoparticles into tumor‐bearing mice followed by US irradiation, remarkable tumor suppression was observed. This study demonstrates that the innovative and efficient MCP method can construct polymers bearing the BODIPY‐sulfonamide moieties, which show a great potential as safe and potent materials for combined gas and sonodynamic therapy against cancer.