TME-targeting theranostic agent uses NIR tracking for tumor diagnosis and surgical resection and acts as chemotherapeutic showing enhanced efficiency and minimal toxicity

Abstract

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.

Tumor imaging and photothermal therapy in second near infrared window: A systematic review and meta-analysis

“…The massive accumulation of NIR-II probes at the tumor cell proclaimed intensive signal than that of surrounding tissue, which is conducive to the effective identification of tumors. Acknowledgedly, the local interactions between tumor cells and their adjacent tissues make tumor microenvironment (TME) slight acidity and overexpression of H 2 O 2 ( 69 ). In the circumstances, Ag 2 S-GOx@BHS NYs, a TME specific activated probe, accumulated and ignited heterogeneous tumor ( 15 ).…”

Redox-Activatable Theranostic Co-Prodrug for Precise Tumor Diagnosis and Selective Combination Chemotherapy

“…The fluorescence spectrum was measured on a fluorescence spectrophotometer (RF-5301PC, Shimadzu, Japan). Compounds 6 , 9–11 , and 14 were prepared according to the literature. , 4-(bromomethyl)­phenol was obtained from p -hydroxybenzyl alcohol according to the previously reported method . All tested compounds are ≥95% pure based on HPLC analysis (Waters 1525 Binary HPLC Pump equipped with the Waters 2998 Photodiode Array Detector on the XBridge-C18 Analyt-ic Column, 5 μm, 4.6 mm × 150 mm).…”

Advanced NIR-II Fluorescence Imaging Technology for Precise Evaluation of Nanomedicine Delivery in Cancer Therapy

“…Moreover, these imaging modalities usually involve lengthy image acquisition and post-processing processes, making real-time imaging unachievable. Fluorescence imaging with high sensitivity, fast feedback, multiplexing, and the absence of ionizing radiation overcomes the abovementioned limitations and exhibits great potential for the evaluation of nanomedicine delivery in vivo [9,10]. Especially notable is deep-tissue fluorescence imaging in the second near-infrared window (NIR-II, 1000 -1700 nm), a new optical transparency window for biological tissues (Figure 1) [11].…”