A dendritic polyamidoamine supramolecular system composed of pillar[5]arene and azobenzene for targeting drug-resistant colon cancer

Abstract

Fusobacterium nucleatum caused drug-resistant around tumor sites often leads to the failure of chemotherapy during colorectal cancer (CRC) treatment. Multifunctional cationic quaternary ammonium materials have been widely used as broad-spectrum antibacterial agents in antibacterial and anticancer fields. Herein, we design a smart supramolecular quaternary ammonium nanoparticle, namely quaternary ammonium PAMAM–AZO@CP[5]A (Q-P–A@CP[5]A), consisting of azobenzene (AZO)-conjugated dendritic cationic quaternary ammonium polyamidoamine (PAMAM) as the core and carboxylatopillar[5]arene (CP[5]A)-based switch, for antibacterial and anti-CRC therapies. The quaternary ammonium-PAMAM–AZO (Q-P–A) core endows the supramolecular system with enhanced antibacterial and anticancer properties. –N⁺CH₃ groups on the surface of Q-P–A are accommodated in the CP[5]A cavity under normal conditions, which significantly improves the biocompatibility of Q-P–A@CP[5]A. Meanwhile, the CP[5]A host can be detached from –N⁺CH₃ groups under pathological conditions, achieving efficient antibacterial and antitumor therapies. Furthermore, azoreductase in the tumor site can break the –NN– bonds of AZO in Q-P–A@CP[5]A, leading to the morphology recovery of supramolecular nanoparticles and CRC therapy through inducing cell membrane rupture. Both in vitro and in vivo experiments demonstrate that Q-P–A@CP[5]A possesses good biocompatibility, excellent antibacterial effect, and CRC treatment capability with negligible side effects. This supramolecular quaternary ammonium system provides an effective treatment method to overcome chemotherapy-resistant cancer caused by bacteria.