Peptide‐Modified AIEgen Probe for Selective Imaging and Killing of Drug‐Resistant Cancer Cells Based on Cell‐Cycle‐Dependent Uptake

Abstract Distinguishing the precise phases of cells in the cell cycle is important for elucidation of their regulatory mechanisms and exploiting cell‐cycle‐targeted drugs. Here, a simple but efficient strategy is established based on a peptide‐modified aggregation‐induced emission luminogen (AIEgen) probe PKK–TTP by utilizing its differential cellular uptake amounts for specific cell cycle recognition and targeted therapy. After incubating the probe in cells with different phases, maximal fluorescence and reactive oxygen species (ROS) generation are observed in S phase, middle in G0/G1 phase, and the minimum in G2/M phase. The cell‐cycle‐dependent fluorescent intensity is proven to be related to variable uptake routes of PKK–TTP. The maximized uptake of PKK–TTP in S phase relies on three simultaneously working endocytic routes, including macro‐pinocytosis and clathrin‐ and caveolin‐dependent endocytosis, while decreased uptake in the G0/G1 and G2/M phases mainly depends on the single route. Furthermore, the uptake of PKK–TTP is further verified in normal cells and drug‐resistant cancer cells (S). Bright fluorescence of PKK–TTP is observed in drug‐resistant cancer cells in S phase, while a little fluorescence is observed in paclitaxel (PTX)‐treated cancer cells due to G2/M phase. Collectively, PKK–TTP can be applied to distinguish cancer cells, evaluating the drug resistance and exerting its therapeutic efficiency downstream.