Abstract
MR molecular imaging (MRMI) of abundant oncogenic biomarkers in tumor microenvironment has the potential to provide precision cancer imaging in high resolution. Extradomain-B fibronectin (EDB-FN) is an oncogenic extracellular matrix protein, highly expressed in aggressive triple negative breast cancer. A targeted macrocyclic gadolinium-based contrast agent (GBCA) ZD2-N3-Gd(HP-DO3A) (MT218), specific to EDB-FN, was developed for MRMI of aggressive breast cancer. The effectiveness of different doses of MT218 for MRMI was tested in MDA-MB-231 and Hs578T human triple negative breast cancer models. At clinical dose of 0.1 and subclinical dose of 0.04 mmol Gd/kg, MT218 rapidly bound to the extracellular matrix EDB-FN and produced robust tumor contrast enhancement in both the tumor models, as early as 1–30 min post-injection. Substantial tumor enhancement was also observed in both the models with MT218 at doses as low as 0.02 mmol Gd/kg, which was significantly better than the clinical agent Gd(HP-DO3A) at 0.1 mmol Gd/kg. Little non-specific enhancement was observed in the normal tissues including liver, spleen, and brain for MT218 at all the tested doses, with renal clearance at 30 min. These results demonstrate that MRMI with reduced doses of MT218 is safe and effective for sensitive and specific imaging of aggressive breast cancers.
Highlights
MRI is a powerful non-invasive imaging modality that provides high resolution, three-dimensional images of soft tissues, including cancerous lesions
Since Extradomain-B fibronectin (EDB-FN) is secreted into the tumor extracellular matrix (ECM), the expression of EDB-FN was evaluated in 3D tumor spheroids of MDA-MB-231 and Hs578T cells incubated with ZD2-Cy5.5, a fluorescent peptide probe specific to EDBFN
To determine if the uptake of MT218 is correlated with the endogenous EDB-FN expression in different tumor xenografts, we evaluated the changes in signal to noise ratio (SNR) in the MDA-MB-231 and Hs578T tumor models at 20 min post-injection of MT218 at 0.1, 0.04, and 0.02 mmol Gd/kg (Figure 5)
Summary
MRI is a powerful non-invasive imaging modality that provides high resolution, three-dimensional images of soft tissues, including cancerous lesions. Gadolinium (III)-based contrast agents (GBCAs) are routinely used to enhance the contrast between cancerous lesions and surrounding normal tissues for accurate cancer detection and diagnosis [1]. The use of clinical GBCAs for diagnosis and therapeutic monitoring is limited due to the lack of disease-specific contrast agents, and concerns of potential Gd toxicity [2,3,4]. Used clinical GBCAs are non-specific to tumor tissues and are unable to accurately detect and differentiate aggressive malignancies from benign lesions. High dosages of GBCAs are often used for detectable contrast enhancement in tumors. Frequent use of GBCAs at high doses may lead to adverse side effects such as nephrogenic systemic fibrosis (NSF) caused by the retention of Gd in tissues in patients
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