Tumor Inhibition Achieved by Targeting and Regulating Multiple Key Elements in EGFR Signaling Pathway Using a Self‐Assembled Nanoprodrug

Comprehensive understanding of signaling pathways regulating cancer progression has led to tremendous advances of molecularly targeted therapies. The epidermal growth factor receptor (EGFR) pathway is an attractive target for cancer therapy, and targeting multiple key elements in the pathway may further facilitate therapeutic efficacy. Here, an EGFR‐targeted nanoprodrug is demonstrated for in vivo imaging and tumor inhibition, which is assembled by a disulfide‐bridged quercetin (QSSQ) and an EGFR inhibitor erlotinib. QSSQ is synthesized via chemical manipulation of multiple phenolic hydroxyl groups on quercetin; and the nanoprodrug is then fabricated through the disulfide‐facilitated assembly of QSSQ and erlotinib. The nanoprodrug is of high drug loading (87.3%) since its only inert component is the disulfide linker. The nanoprodrug is stable in physiological environment, whereas overexpressed glutathione in tumor tissue breaks the disulfide bridge, thereby disrupting the nanostructure and releasing active drugs quercetin and erlotinib. Upon release, erlotinib serves as an active drug blocking the EGFR tyrosine kinase, and quercetin generates strong aggregation‐induced emission of fluorescence for imaging drug release and acts as another drug inhibiting the downstream EFGR signaling, as evidenced by Western blotting analyses. The combined action thereof results in remarkable antitumor efficacy toward xenograft tumor‐bearing mice. An epidermal growth factor receptor (EGFR)‐targeted nanoprodrug is fabricated through self‐assembly of a disulfide‐bridged quercetin and an EGFR inhibitor erlotinib, which features high drug loading, GSH‐triggered drug release, and fluorescence imaging. The released erlotinib and quercetin respectively regulate the upstream and downstream proteins in EFGR signaling pathway and thereby effectively inhibit tumor growth in tumor‐bearing mice.