Identification of a Novel AT1R-Targeted Near-Infrared Fluorescent Probe for Visualization and Imaging-Guided Surgery in Pancreatic Cancer.

Despite an evolving therapeutic landscape, pancreatic ductal adenocarcinoma (PDAC) remains associated with a poor prognosis and high mortality rates, primarily owing to its aggressive nature and high recurrence rates. Near-infrared fluorescence (NIRF)-guided surgery is a gold standard curative treatment for PDAC; however, its effectiveness is significantly limited by the scarcity of available PDAC-targeted NIRF probes. In this study, we developed a novel NIRF molecular probe, MPA-GGG-Ang-df, by conjugating the dye MPA and evaluated its targeting ability toward the angiotensin II type 1 receptor (AT1R), a protein whose expression is upregulated in PDAC. Biodistribution analysis revealed significant and specific tumor accumulation of MPA-GGG-Ang-df, with minimal nontarget tissue uptake. This resulted in tumor-to-pancreas ratio of 7.6 ± 0.5 and 6.0 ± 0.3 in SW1990 and CFPAC-1 subcutaneous tumor models, respectively, at 10 h postinjection. Additionally, quantitative analysis confirmed high tumor-to-background ratios (TBRs) of 5.8 ± 0.5, 4.2 ± 0.5, 3.1 ± 0.5, 2.9 ± 0.3, 4.7 ± 0.7, and 4.5 ± 0.5 for the tumor compared to the pancreas, liver, and colorectal tissue in orthotopic, liver, and intestine-metastasized SW1990 and CFPAC-1 tumor models, enabling precise tumor delineation to guide surgical resection. Furthermore, pathological analysis revealed well-defined tumor boundaries, underscoring the capacity of the probe to accurately visualize the AT1R protein at the molecular level. Considering its rapid targeting, durable retention, and precise delineation of tumor boundaries, MPA-GGG-Ang-df represents a promising AT1R-targeted fluorescence contrast agent, potentially expanding the options for fluorescence-guided surgery in PDAC.