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.