Fibronectin-targeting and metalloproteinase-activatable smart imaging probe for fluorescence imaging and image-guided surgery of breast cancer

Abstract

Residual lesions in the tumor bed have been a challenge for conventional white-light breast-conserving surgery. Meanwhile, lung micro-metastasis also requires improved detection methods. Intraoperative accurate identification and elimination of microscopic cancer can improve surgery prognosis. In this study, a smart fibronectin-targeting and metalloproteinase-activatable imaging probe CREKA-GK8-QC is developed. CREKA-GK8-QC possesses an average diameter of 21.7 ± 2.5 nm, excellent MMP-9 protein responsiveness and no obvious cytotoxicity. In vivo experiments demonstrate that NIR-I fluorescence imaging of CREKA-GK8-QC precisely detects orthotopic breast cancer and micro-metastatic lesions (nearly 1 mm) of lungs with excellent imaging contrast ratio and spatial resolution. More notably, fluorescence image-guided surgery facilitates complete resection and avoids residual lesions in the tumor bed, improving survival outcomes. We envision that our newly developed imaging probe shows superior capacity for specific and sensitive targeted imaging, as well as providing guidance for accurate surgical resection of breast cancer. Graphical Abstract

Recent Progress in Peptide-Based Molecular Probes for Disease Bioimaging

“…The combination of the two strategies can further improve the imaging contrast. For instance, a fibronectin-targeting peptide can be conjugated to a matrix metalloproteinase-9 (MMP-9)-cleavable peptide (GPVGLIGK) with fluorophore Cy5.5 and quencher QSY21 at the two ends, which is sensitive to detect both an orthotopic breast tumor and micrometastatic lesions (nearly 1 mm in diameter) . To realize multiplex and real-time imaging, Zhang and colleagues have developed a novel rare earth fluorescent probe designed for the near-infrared II (NIR-II) window .…”

Unfolded Protein-Based Sandwich AIE Probe Imparts High Fluorescent Contrast for Pan-Cancer Surgical Navigation

“…Fluorescence imaging-guided surgery (FGS) provides a new solution for precise resection of solid tumors due to its advantages of immediacy, high resolution, high specificity, and low cost compared with traditional clinical imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), ultrasonography (US), etc. − Fluorescent probes are mainly categorized into targeted imaging probes and activated imaging probes . For targeted imaging probes, the basis of their design cannot be separated from the markers that are highly expressed in the lesion, such as integrins, epidermal growth factor receptor, vascular endothelial growth factor receptor, folate receptor, and so on. − Activatable imaging probes, also known as “turn-on” probes, can be activated by chemical reactions with enzymes highly expressed in the tumor microenvironment or other conditions that turn on fluorescence and contrast with normal tissue, − such as CB enzyme, MMP-2 enzyme, and other things. − All of these targeted imaging probes and activated imaging probes have achieved good results in FGS, and a number of probes have even entered clinical trials, but their use is subject to certain prerequisites; i.e., the tumor needs to be highly expressive of a specific protein or enzyme. − However, many proteins or enzymes are not fully highly expressed in pan-cancer; for example, integrins are only 50% expressed in breast cancer, and the expression of folate receptor α in endometrial cancers is 20–50%, which means that there is currently no specific protein or enzyme that can be employed as a universal biomarker of fluorescent probes for pan-cancer surgical navigation. In short, the heterogeneity of pan-cancer hinders the clinical application of fluorescent probes, which forebodes that developing a universal fluorescent probe remains a challenge.…”

JS-K Combined with a Melanin-Based Theranostic Agent: A Novel Sequential Delivery Strategy to Enhance the Near-Infrared Fluorescence Imaging of Pancreatic Ductal Adenocarcinoma

“…Different kinds of nanoagents have been investigated for the surgical navigation of tumor resection and for the detection of lymph node and peritoneal micrometastases. − A variety of nanoagents enhance the efficacy of tumor visualization, while attempts at targeting PDAC via nanoagents have rarely been reported, possibly because it is difficult for nanoagents to accumulate in the tumor area and provide reliable surgical margins due to the hypovascular TME of PDAC.…”