Enabling AIEgens close assembly in tumor-overexpressed protein cluster for boosted image-guided cancer surgery

Development of efficient fluorescent probes that can realize precise fluorescence image-guided cancer surgery(FIGCS)with extremely high tumor-to-normal tissue(T/NT)ratio is urgently desirable.Herein,we report the design and synthesis of an aggregation-induced emission(AIE)-active,peptide-based fluorescence turn-on probe MPA-Ph-R-FFGYSAYPDSVPMMS(MPA-Ph-R-FFGYSA for short),which consists of a new near-infrared emissive AIE luminogen(AIEgen)MPA-Ph-R,a self-assembling peptide sequence“FFG”,and an“active”targeting peptide YSAYPDSVPMMS that can selectively bind to EphA2 protein cluster overexpressed in many cancers.As compared to the control probe MPA-Ph-R-YSA without“FFG”,MPA-Ph-R-FFGYSA exhibits much higher fluorescent brightness and sensitivity in both cellular and in vivo studies on EphA2 cluster detection/imaging,as“FFG”is beneficial to closer assembly of AIEgens in EphA2 cluster,leading to more effective restriction of the intramolecular motion of AIEgen.In vivo studies demonstrate that MPA-Ph-R-FFGYSA is a safe bioprobe and gives excellent performance in FIGCS with a rather high T/NT ratio of^13.4 upon intravenous administration into peritoneal carcinomatosis-bearing mice.This study provides a new strategy of utilizing the close assembly of tumor microenvironment-responsive AIE probes for boost FIGCS.