Rationale: Precise diagnosis and effective
therapy of the tumor microenvironment (TME) remains a challenge. Fluorescence tracers for monitoring primary
tumors are currently reported; however, they face challenges in accurately delineating
tumors in real-time during surgery, including interference from the background and insufficient accumulation of imaging
reagents at
tumor sites. Additionally, although the natural product
podophyllotoxin (PPT) had potent and broad anti-
tumor activity, the poor
tumor target specificity and high toxicity of PPT extremely limited its clinical application. Methods: In the current study, a novel
theranostic agent PBB was designed and synthesized by coupling the natural chemotherapeutic drug PPT with a near-infrared (NIR) fluorescence probe
hemicyanine (CyOH) via redox-responsive thiolactate linker and introducing
biotin to CyOH to enhance the active target ability. The activation mechanism of PBB was characterized by absorption spectra, fluorescence spectra, and HPLC. Subsequently, we investigated its imaging action, anti-
tumor activity, and toxicity in vitro and in vivo. Results:In vitro experiments, PBB was verified to possess a ROS/GSH-responsive molecular switch, impelling PBB to release a fluorescent fragment and active drug PPT and selectively lighting up
tumor cells but not the normal cells. As such, PBB was demonstrated to selectively inhibit the growth of
tumor cells by inducing intracellular accumulation of ROS and
MMP depolarization. More importantly, PBB significantly suppressed hepatic
tumor growth and minimized the adverse effects caused by PPT, including acute toxicity and impaired liver function. Finally, the NIR fluorescence accumulated in the
tumor tissue and stayed continuous for over 24h, and PBB provided precise visualization and highly selective fluorescence diagnosis to guide
tumor resection. Conclusions: Therefore, the multilevel targeting
theranostic agent provided a novel tool for precise diagnosis, real-time monitoring, and efficient
tumor chemotherapy with high safety.