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WIREs Nanomed Nanobiotechnol
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Design of a novel class of protein‐based magnetic resonance imaging contrast agents for the molecular imaging of cancer biomarkers

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Abstract Magnetic resonance imaging (MRI) of disease biomarkers, especially cancer biomarkers, could potentially improve our understanding of the disease and drug activity during preclinical and clinical drug treatment and patient stratification. MRI contrast agents with high relaxivity and targeting capability to tumor biomarkers are highly required. Extensive work has been done to develop MRI contrast agents. However, only a few limited literatures report that protein residues can function as ligands to bind Gd3+ with high binding affinity, selectivity, and relaxivity. In this paper, we focus on reporting our current progress on designing a novel class of protein‐based Gd3+ MRI contrast agents (ProCAs) equipped with several desirable capabilities for in vivo application of MRI of tumor biomarkers. We will first discuss our strategy for improving the relaxivity by a novel protein‐based design. We then discuss the effect of increased relaxivity of ProCAs on improving the detection limits for MRI contrast agent, especially for in vivo application. We will further report our efforts to improve in vivo imaging capability and our achievement in molecular imaging of cancer biomarkers with potential preclinical and clinical applications. WIREs Nanomed Nanobiotechnol 2013, 5:163–179. doi: 10.1002/wnan.1205 This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Biology-Inspired Nanomaterials > Peptide-Based Structures

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Immunofluoresence imaging of ProCA1.affi (left) or HER‐2 antibody (right) in SKOV‐3 xenograft tumors in mice after IV injection. ProCA1.affi and HER‐2 antibody are stained with red color. Blood vessel is stained with green color. ProCA1.affi is evenly distributed in tumor 24‐h postinjection, whereas HER‐2 antibody only accumulated in near the blood vessel. (Reprinted with permission from Ref 69. Copyright 2011 PloS ONE)

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Design (a, b) and binding test (c) of ProCA1.GRP for the molecular imaging of gastrin‐releasing peptide receptor (GRPR). GRP peptide was linked either at C‐terminal (a, named ProCA1.GRPC) and in the middle of ProCA1 with grafting approach (b, named ProCA1.GRP(52)). (c) Radioactive binding test of ProCA1, ProCA1.GRPC, and ProCA1.GRP(52) to GRPR high‐expression cells (PC3 and DU154) and GRPR low‐expression cells (H441). ProCA1.GRP(52) shows the best binding among three contrast agents. (Reprinted with permission from Ref 90. Copyright 2010 Springer)

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Molecular imaging of HER‐2 by ProCA1.affi. (a) Model structure of ProCA1.Affi. (b) Magnetic resonance imaging (MRI) of HER‐2 xenograft tumor (SKOV‐3 and MDA‐MB‐231) before and after injection of ProCA1.affi. (c) Tumor intensity changes over time postinjection of ProCA1.affi. SKOV‐3 has much higher HER‐2 expression and SOKV‐3 has more MRI signal enhancement than that of MDA‐MB‐231. The MRI signal intensities of SKOV‐3 or MDA‐MB‐231 tumor regions from six adjacent slides were quantified by Image J software. The average signal intensities and the standard derivation were then calculated from these six adjacent slides. (d) MRI of the mouse SKOV3 tumor pre‐blocked by affibody ZHER2:342 (bottom) and without blocking (top). (Reprinted with permission from Ref 69. Copyright 2011 PloS ONE)

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Multiple organ enhancement of magnetic resonance imaging (MRI) of mice after injection of ProCA1 for 20 min (b), 3 h (c), 24 h (d) compared with pre‐scan (a). (e) MRI intensity changes of kidney (black) and liver (gray) before and after injection of ProCA1. (Reprinted with permission from Ref 32. Copyright 2012 Elsevier)

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(a) Schematic representation of a Gd3+ chelate surrounded by bulk water with one inner sphere and three second sphere water molecules and several outer sphere water molecules. Modification of contrast agents by PEG could change the water properties which could further influence relaxivity. (b) Simulated magnetic field‐dependent relaxivity r1 of clinical MRI contrast agents and ProCA based on the given τR, τm, τv, and Δ2 and Solomon‐Bloembergen‐Morgan (SBM) theory using combinations of τR (100 ps for clinical MRI contrast agents and 10 ns for ProCA), τm (0.1, 1, 10, and 100 ns), τv (10 ps), and Δ2 (5 × 1019 s−2) under a magnetic field strength from 0.01 MHz to 10,000 MHz. (c) Model structure of ProCA1 with PEG modification. (Reprinted with permission from Ref 32. Copyright 2012 Elsevier)

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Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Biology-Inspired Nanomaterials > Peptide-Based Structures

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