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.

Noninvasive assessment and therapeutic monitoring of drug-resistant colorectal cancer by MR molecular imaging of extradomain-B fibronectin

“…Literature studies show that even within the same cancer type, EDB-FN is preferentially upregulated in the more invasive cell and tumor subtypes, compared to the indolent ones 40 , 44 , 45 . This specific spatial and temporal expression of EDB-FN in malignancies and its absence in healthy tissues renders it an attractive target for molecular imaging and targeted therapy 46 - 50 . We previously designed and developed an EDB-FN-targeted GBCA, ZD2-N 3 -Gd(HP-DO3A) (MT218), by conjugating the EDB-FN-specific peptide ZD2 to the clinical GBCA Gadoteridol 51 , 52 , and demonstrated its ability to facilitate efficient MRMI for risk-stratification of EDB-FN-rich prostate and breast cancers, even at doses as low as 20 µmol/kg (1/5 th of the clinical dose), highlighting its translational applications and superior safety profile 51 , 53 .…”

Repurposing Clinical Agents for Chemical Exchange Saturation Transfer Magnetic Resonance Imaging: Current Status and Future Perspectives

“…From the MRI contrast agent perspective, while being very safe, glucose has the drawback to be rapidly metabolized inside most cells, making the contrast disappearing completely in several minutes. To overcome this inherent drawback, a number of glucose derivatives, including 2-deoxy- d -glucose (2-DG) [ 74 , 75 , 76 ], 3- O -methyl- d -glucose (3OMG) [ 71 , 72 ], glucosamine [ 81 ] and dextrans [ 77 , 78 , 118 , 119 ], have been reported. Those compounds have similar CEST contrast as glucose, but different transport and metabolic properties ( Figure 5 ).…”

“…Non-labeled dextrans of different MW can be directly used as MRI agents to probe tissue permeability in different size ranges [ 77 ] as well as the changes in tumor vascular permeability in response to anti-vascular treatment [ 118 ]. Dextrans can also be easily conjugated with targeting ligands for targeted imaging of tumor specific biomarkers, for example, prostate-specific membrane antigen (PSMA) in prostate tumor cells [ 78 ] and extradomain-B fibronectin (EDB-FN), a tumor microenvironmental biomarker overexpressed in pancreatic tumors [ 119 ].…”

Overexpression of Extradomain-B Fibronectin is Associated with Invasion of Breast Cancer Cells

“…This differential expression of EDB-FN was exploited for differentially diagnosing invasive prostate and breast cancer tumors from the non-invasive ones using EDB-FN-targeted MRI contrast agents [ 23 , 24 , 25 ]. Other independent groups have also used EDB-FN as a molecular marker for targeted imaging and therapeutic delivery for various types of cancers [ 26 , 27 , 28 ].…”