Peptide-Based Probe Targeting Angiotensin Type-1 Receptor Identifies Pancreatic Ductal Adenocarcinoma Using Multispectral Optoacoustic Tomography

<b>Purpose</b> Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and aggressive malignancies with limited treatment options. Curative surgical resection of the primary pancreatic mass is frequently limited by residual microscopic tumor foci, leading to a high recurrence rate in patients. To improve surgical outcomes, visualizing remaining tumor foci with fluorescent probes is crucial to achieve complete (R0) resection. <b>Methods</b> A peptide-based imaging probe targeting the angiotensin type-1 receptor was engineered with either 555 or 750 nm reporter dyes. Immunofluorescence and NIR imaging analyses were performed to assess receptor interactions and binding probes in AT1R-positive PDAC cells and low (HT-29) control cells. Probe uptake in the complex PDAC microenvironment of orthotopic mouse models (S2VP10 and S2O13) was evaluated using multispectral optoacoustic tomography (MSOT). Ex vivo biodistribution was confirmed, and toxicity was measured in the treated mice. <b>Results</b> PDAC cells demonstrated membranous expression of angiotensin type-1 receptor, which was absent in the HT-29 control cells. An engineered NIR probe, Angio1-750, was synthesized and characterized. Docking analysis of the engineered peptide with the targeted receptor demonstrated binding. PDAC cells treated with Angio1-750 probe showed a higher signal than the HT-29 cells. The PDAC tumor had a detectable signal in MSOT (S2VP10 61 ± 7.64 a.u. at 3 h and 43.18 ± 4.51 a.u. at 24 h, <i>P</i> < 0.0004; S2O13 25.30 ± 1.53 a.u. at 3 h and 17.33 ± 0.58 a.u. at 24 h, <i>P</i> = 0.05). Biodistribution analysis revealed tumor uptake and confirmed the renal excretion of the probe. <b>Conclusions</b> The data suggest successful tumor uptake of the Angio1-750 probe and detection using MSOT in PDAC xenografts.