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Fluorescent Orthotopic Mouse Model of Pancreatic Cancer
Published on: September 20, 2016
Revolutionizing Solid Tumor Surgery with Fibroblast Activation Protein (FAP)-Targeted Imaging Probes for a
Hanyue Ma1,2, Lysanne D A N de Muynck3, Ruben D Houvast3
1Departments of Radiology & Nuclear Medicine, Erasmus Medical Center, Rotterdam 3015 GD, The Netherlands.
Abstract:
The development of fluorescent probes that target the tumor stroma to help surgeons detect and remove malignant lesions using near-infrared fluorescence (NIRF)-guided surgery is advancing rapidly. Such advancements show promise for a range of malignancies, expanding the eligibility of patients for surgical intervention and offering improved surgical outcomes. Fibroblast activation protein (FAP), expressed by cancer-associated fibroblasts (CAFs), is highly upregulated within the tumor stroma of nearly all solid tumors. It is a promising tumor target for NIRF-guided surgery, especially in solid tumors with dense tumor stroma, such as pancreatic cancer. In this study, we aimed to develop FAP-targeting fluorescent probes with enhanced pharmacokinetics for the NIRF-guided surgery of pancreatic cancer. Three novel FAP-targeted probes (eFAPs) based on a (4-quinolinoyl)-glycyl-2-cyanopyrrolidine (QCP) structure equipped with the NIRF dye IRDye800CW were designed and synthesized. All of the probes displayed excellent inhibition potency and selectivity to FAP. The probes consistently exhibited strong inhibition and specific uptake in FAP-expressing U87 glioblastoma cells. In in vivo optical imaging studies, eFAP-24 showed a tumor-to-background ratio (TBR) of 3.1 ± 0.6 at 24 h postinjection, enabling the clear delineation of tumors using the clinical Quest Spectrum NIRF imaging system. A strong fluorescence signal in the tumor and a negligible uptake in nontarget tissues were confirmed by biodistribution analyses. The successful development and validation of FAP-targeting fluorescent probes, especially eFAP-24, offers promising prospects for enhancing the visualization of FAP-rich stromal compartments improving surgical outcomes through NIRF-guided surgery, particularly in solid tumors with dense stroma such as pancreatic cancer.
Insights
New fluorescent probes targeting fibroblast activation protein (FAP) enhance tumor visualization for near-infrared fluorescence (NIRF)-guided surgery. eFAP-24 specifically targets FAP-rich tumors, improving detection and surgical outcomes in pancreatic cancer.
Area of Science:
- Oncology
- Surgical Innovation
- Molecular Imaging
Background:
- Near-infrared fluorescence (NIRF)-guided surgery is advancing for improved detection and removal of malignant lesions.
- Fibroblast activation protein (FAP), highly expressed by cancer-associated fibroblasts (CAFs) in tumor stroma, is a promising target for NIRF imaging.
- Pancreatic cancer, with its dense tumor stroma, presents a significant challenge for surgical visualization.
Purpose of the Study:
- To develop novel FAP-targeting fluorescent probes with optimized pharmacokinetics for NIRF-guided surgery.
- To evaluate the efficacy of these probes in preclinical models of pancreatic cancer.
Main Methods:
- Design and synthesis of three novel FAP-targeted fluorescent probes (eFAPs) based on a (4-quinolinoyl)-glycyl-2-cyanopyrrolidine (QCP) structure and the NIRF dye IRDye800CW.
- In vitro assessment of probe inhibition potency and selectivity against FAP, and cellular uptake studies in FAP-expressing U87 glioblastoma cells.
- In vivo optical imaging studies in animal models to evaluate tumor delineation, tumor-to-background ratio (TBR), and biodistribution.
Main Results:
- All synthesized eFAP probes demonstrated potent and selective inhibition of FAP, with significant uptake in FAP-expressing cells.
- eFAP-24 achieved a notable tumor-to-background ratio (TBR) of 3.1 ± 0.6 at 24 hours post-injection, enabling clear tumor delineation.
- Biodistribution analysis confirmed strong fluorescence signal within tumors and minimal uptake in non-target tissues.
Conclusions:
- The developed FAP-targeting fluorescent probes, particularly eFAP-24, show significant promise for enhancing the visualization of FAP-rich tumor stroma.
- These probes offer potential for improved surgical guidance in FAP-positive solid tumors, including pancreatic cancer.
- Successful validation supports the advancement of eFAP-24 for clinical translation in NIRF-guided surgical applications.
