Abstract
The application of magnetic resonance imaging (MRI) to non-invasively assess disease biomarkers has been hampered by the lack of desired contrast agents with high relaxivity, targeting capability, and optimized pharmacokinetics. We have developed a novel MR imaging probe targeting to HER2, a biomarker for various cancer types and a drug target for anti-cancer therapies. This multimodal HER20targeted MR imaging probe integrates a de novo designed protein contrast agent with a high affinity HER2 affibody and a near IR fluorescent dye. Our probe can differentially monitor tumors with different expression levels of HER2 in both human cell lines and xenograft mice models. In addition to its 100-fold higher dose efficiency compared to clinically approved non-targeting contrast agent DTPA, our developed agent also exhibits advantages in crossing the endothelial boundary, tissue distribution, and tumor tissue retention over reported contrast agents as demonstrated by even distribution of the imaging probe across the entire tumor mass. This contrast agent will provide a powerful tool for quantitative assessment of molecular markers, and improved resolution for diagnosis, prognosis and drug discovery.
Highlights
Molecular imaging probes the molecular abnormalities of diseases to allow earlier detection, monitoring of disease progression, and molecular assessment of treatments [1]
Metal binding affinity and relaxivity We have developed a novel multimodal molecular imaging probe to target cancer marker HER2/neu using magnetic resonance and near infrared imaging (Fig. 1)
The designed probe was further modified by a tri-branched polyethylene glycol (PEG) with 40 PEG subunits (ProCA1-affi-m). (B) The metal binding affinity for Gd3+ with Kd of 1.86610212 M was measured by competitive method using Fluo5N [10] (C) The relaxivity of ProCA1-affi with and without PEGylation (ProCA1-affi-m, black) and clinically used Gd-DTPA were measured under the magnetic field of 1.41 T at 37uC (*P,0.05)
Summary
Molecular imaging probes the molecular abnormalities of diseases to allow earlier detection, monitoring of disease progression, and molecular assessment of treatments [1]. Developing contrast agents that can be targeted to various biomarkers allowing real-time imaging of biological events at the molecular level will have great clinical importance [4,5,6]. To achieve molecular imaging by MRI, especially to quantitatively monitor the expression level of the disease biomarkers, it is essential to develop contrast agents with high relaxivity, target capability, optimized pharmacokinetics, tissue penetration and low or no toxicity [7]. Current diagnosis of HER-2 positive tumor relies mostly on the use of fine needle biopsies with subsequent immunohistochemistry (IHC) analysis and/or fluorescent in situ hybridization (FISH). These methods suffer from several drawbacks including sampling errors, misinterpretation due to lack of quantization, and discordance between primary tumors and metastases. Assessment of HER2/neu levels by non-invasive MR imaging will provide a tremendous tool for cancer diagnosis/prognosis, design of treatment strategies, and monitoring the effectiveness of the treatment
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