Peptide-Based Probe Targeting Angiotensin Type‑1 Receptor Identifies Pancreatic Ductal Adenocarcinoma Using
Rohit Singh1, Happy Agarwal1, Ryan C Bynum1
1Stephenson Cancer Center, Department of Surgery, University of Oklahoma, Oklahoma City, Oklahoma 73104, United States.
Abstract:
Purpose 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. Methods 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. Results 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, P < 0.0004; S2O13 25.30 ± 1.53 a.u. at 3 h and 17.33 ± 0.58 a.u. at 24 h, P = 0.05). Biodistribution analysis revealed tumor uptake and confirmed the renal excretion of the probe. Conclusions The data suggest successful tumor uptake of the Angio1-750 probe and detection using MSOT in PDAC xenografts.
Insights
A novel near-infrared (NIR) fluorescent probe, Angio1-750, successfully targets and visualizes pancreatic ductal adenocarcinoma (PDAC) cells. This imaging agent aids in detecting residual tumor foci, potentially improving surgical outcomes for this aggressive cancer.
Area of Science:
- Oncology
- Medical Imaging
- Biotechnology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with poor treatment options.
- Complete surgical resection (R0) is often hindered by microscopic residual tumor foci, leading to high recurrence rates.
- Improved intraoperative visualization of tumor margins is critical for enhancing surgical success in PDAC patients.
Purpose of the Study:
- To engineer and evaluate a peptide-based fluorescent imaging probe for visualizing angiotensin type-1 receptor (AT1R)-positive PDAC.
- To assess the probe's ability to detect residual tumor foci and improve surgical resection outcomes.
- To validate the probe's efficacy in preclinical models of PDAC.
Main Methods:
- Engineered a peptide-based imaging probe targeting AT1R, conjugated with 750 nm reporter dyes (Angio1-750).
- Assessed probe binding and uptake in AT1R-positive PDAC cells versus control cells using immunofluorescence and NIR imaging.
- Evaluated probe performance in orthotopic PDAC mouse models using multispectral optoacoustic tomography (MSOT) and ex vivo biodistribution studies.
Main Results:
- PDAC cells exhibited significant membranous AT1R expression, unlike control cells.
- Angio1-750 demonstrated specific binding to AT1R and higher uptake in PDAC cells.
- MSOT successfully detected Angio1-750 in PDAC tumors in vivo, with significant signals observed over time.
- Biodistribution studies confirmed tumor accumulation and renal clearance of the probe, with no observed toxicity.
Conclusions:
- The Angio1-750 probe shows promise for intraoperative visualization of PDAC.
- Successful tumor uptake and detection via MSOT in PDAC xenografts were demonstrated.
- This imaging approach could enhance the completeness of surgical resection for PDAC.
