Abstract
The survival of pancreatic cancer patients can be greatly improved if their disease is detected at an early, potentially curable stage. Magnetic resonance molecular imaging (MRMI) of oncoproteins is a promising strategy for accurate, early detection of the disease. Here, we test the hypothesis that MRMI of extradomain-B fibronectin (EDB-FN), an abundant oncoprotein in the tumor extracellular matrix, can overcome the stromal barriers of pancreatic cancer to facilitate effective molecular imaging and detection of small tumors. Specimens of normal, premalignant, and malignant human pancreatic tissues were stained with a peptide-fluorophore conjugate (ZD2-Cy5.5) to assess EDB-FN binding and expression. MRMI with ZD2-N3-Gd(HP-DO3A) (MT218) specific to EDB-FN and MRI with Gd(HP-DO3A) were performed in three murine models bearing human pancreatic cancer xenografts, including a Capan-1 flank model, a BxPC3-GFP-Luc and a PANC-1-GFP-Luc intrapancreatic xenograft model. Tumor enhancement of the contrast agents was analyzed and compared. Staining of human tissue samples with ZD2-Cy5.5 revealed high EDB-FN expression in pancreatic tumors, moderate expression in premalignant tissue, and little expression in normal tissue. MRMI with MT218 generated robust intratumoral contrast, clearly detected and delineated small tumors (smallest average size: 6.1 mm2), and out-performed conventional contrast enhanced MRI with Gd(HP-DO3A). Quantitative analysis of signal enhancement revealed that MT218 produced 2.7, 2.1, and 1.6 times greater contrast-to-noise ratio (CNR) than the clinical agent in the Capan-1 flank, BxPC3-GFP-Luc and PANC-1-GFP-Luc intrapancreatic models, respectively (p < 0.05). MRMI of the ECM oncoprotein EDB-FN with MT218 is able to generate superior contrast enhancement in small pancreatic tumors and provide accurate tumor delineation in animal models. Early, accurate detection and delineation of pancreatic cancer with high-resolution MRMI has the potential to guide timely treatment and significantly improve the long-term survival of pancreatic cancer patients.
Highlights
Pancreatic cancer (PaCa) is responsible for a large and rapidly growing number of cancer deaths [1]
Pancreatic cancer (PaCa) is highly fibrotic with a dense extracellular matrix (ECM), which limits the access of contrast agents to the inner tumor tissues [25]
By exploiting oncospecific expression of extradomain B fibronectin (EDB-FN) in the tumor ECM as a target for molecular imaging (MRMI), we found that the imaging of PaCa could be substantially improved
Summary
Pancreatic cancer (PaCa) is responsible for a large and rapidly growing number of cancer deaths [1]. Patients often present with advanced-stage PaCa that has metastasized or cannot be surgically resected [1]. Current strategies for PaCa diagnosis are not sensitive for early-stage disease. Contrast enhanced computed tomography (CE-CT) is the most commonly utilized for imaging of PaCa [5], but has difficulty for diagnosing small and potentially curable tumors, lymph node metastasis, and liver metastasis [5,6,7,8]. Contrast enhanced magnetic resonance imaging presents superior soft tissue contrast and excellent spatial resolution, and is increasingly utilized in PaCa diagnosis [5, 9]. The existing clinical contrast agents are not tumor-specific, and suffer from poor sensitivity in detecting small tumors [10].
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