Dataset Information

Extradomain-B Fibronectin-Targeted Dextran-Based Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Probe for Detecting Pancreatic Cancer.

ABSTRACT: A dextran-peptide conjugate was developed for magnetic resonance (MR) molecular imaging of pancreatic ductal adenocarcinoma (PDAC) through its overexpressed microenvironment biomarker, extradomain-B fibronectin (EDB-FN). This new agent consists of diamagnetic and biocompatible dextran and a targeting peptide. Dextrans can be directly detected by chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) without the need for radionuclide or metallic labeling. In addition, large molecular weight dextran, dextran 10 (MW ? 10 kDa), provides an approximately 50 times higher sensitivity per molecule than a single glucose unit. The potential of this highly biocompatible diamagnetic probe is demonstrated in a murine syngeneic allograft PDAC tumor model. The biocompatibility and sensitivity of this new agent clearly show potential for a path to clinical translation.

SUBMITTER: Han Z

PROVIDER: S-EPMC6896991 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Extradomain-B Fibronectin-Targeted Dextran-Based Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Probe for Detecting Pancreatic Cancer.

Han Zheng Z Zhang Shuixing S Fujiwara Kenji K Zhang Jia J Li Yuguo Y Liu Jing J van Zijl Peter C M PCM Lu Zheng-Rong ZR Zheng Lei L Liu Guanshu G

Bioconjugate chemistry 20190415 5

A dextran-peptide conjugate was developed for magnetic resonance (MR) molecular imaging of pancreatic ductal adenocarcinoma (PDAC) through its overexpressed microenvironment biomarker, extradomain-B fibronectin (EDB-FN). This new agent consists of diamagnetic and biocompatible dextran and a targeting peptide. Dextrans can be directly detected by chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) without the need for radionuclide or metallic labeling. In addition, large m ...[more]

PMID: 30938983

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Project description: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.

Project description:Background:Encephalitis is a common central nervous system inflammatory disease that seriously endangers human health owing to the lack of effective diagnostic methods, which leads to a high rate of misdiagnosis and mortality. Glutamate is implicated closely in microglial activation, and activated microglia are key players in encephalitis. Hence, using glutamate chemical exchange saturation transfer (GluCEST) imaging for the early diagnosis of encephalitis holds promise. Methods:The sensitivity of GluCEST imaging with different concentrations of glutamate and other major metabolites in the brain was validated in phantoms. Twenty-seven Sprague-Dawley (SD) rats with encephalitis induced by Staphylococcus aureus infection were used for preclinical research of GluCEST imaging in a 7.0-Tesla scanner. For the clinical study, six patients with encephalitis, six patients with lacunar infarction, and six healthy volunteers underwent GluCEST imaging in a 3.0-Tesla scanner. Results:The number of amine protons on glutamate that had a chemical shift of 3.0 ppm away from bulk water and the signal intensity of GluCEST were concentration-dependent. Under physiological conditions, glutamate is the main contributor to the GluCEST signal. Compared with normal tissue, in both rats and patients with encephalitis, the encephalitis areas demonstrated a hyper-intense GluCEST signal, while the lacunar infarction had a decreased GluCEST signal intensity. After intravenous immunoglobulin therapy, patients with encephalitis lesions showed a decrease in GluCEST signal, and the results were significantly different from the pre-treatment signal (1.34 ± 0.31 vs 5.0 ± 0.27%, respectively; p = 0.000). Conclusion:Glutamate plays a role in encephalitis, and the GluCEST imaging signal has potential as an in vivo imaging biomarker for the early diagnosis of encephalitis. GluCEST will provide new insight into encephalitis and help improve the differential diagnosis of brain disorders.

Dataset Information

Extradomain-B Fibronectin-Targeted Dextran-Based Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Probe for Detecting Pancreatic Cancer.

Publications

Extradomain-B Fibronectin-Targeted Dextran-Based Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Probe for Detecting Pancreatic Cancer.

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