Strategies for Target-Specific Contrast Agents for Magnetic Resonance Imaging

Abstract

This review describes recent research efforts focused on increasing the specificity of contrast agents for proton magnetic resonance imaging (MRI). Contrast agents play an indispensable role in MRI by enhancing the inherent contrast of images; however, the non-specific nature of current clinical contrast agents limits their usefulness. This limitation can be addressed by conjugating contrast agents or contrast-agent-loaded carriers-including polymers, nanoparticles, dendrimers, and liposomes-to molecules that bind to biological sites of interest. An alternative approach to conjugation is synthetically mimicking biological structures with metal complexes that are also contrast agents. In this review, we describe the advantages and limitations of these two targeting strategies with respect to translation from in vitro to in vivo imaging while focusing on advances from the last ten years.

Fig. 1

Schematic representation of the basic units of targeted contrast agents synthesized using the conjugation strategy.

Fig. 2

Monomeric targeted contrast agents synthesized using the conjugation strategy. Contrast agent 8 is adapted with permission from Qiao J, Li S, Wei L, et al. HER2 Targeted molecular MR imaging using a de novo designed protein contrast agent. PLoS ONE 2011; 6(3): e18103. Copyright 2011 Qiao et al.

Fig. 3

Representative in vivo images of targeted contrast agents: contrast enhancement of progesterone-receptor (PR)-positive and PR-negative tumors using monomeric conjugated contrast agent 1. Scale bars represent 5 mm, and arrows point to tumors. Adapted with permission from Sukerkar PA, MacRenaris KW, Meade TJ, Burdette JE. A steroid-conjugated magnetic resonance probe enhances contrast in progesterone receptor expressing organs and tumors in vivo. Mol Pharmaceutics 2011; 8(4): 1390–400. Copyright 2011 American Chemical Society.

Fig. 4

Multimeric targeted contrast agents synthesized using the conjugation strategy. Contrast agents 23, 24, 26, 30, and 32 were adapted with permission from Tan M, Wu X, Jeong E-K, Chen Q, Lu Z-R. Peptide-targeted nanoglobular Gd-DOTA monoamide conjugates for magnetic resonance cancer molecular imaging. Biomacromolecules 2010; 11(3): 754–61. Copyright 2010 American Chemical Society; Nam T, Park S, Lee S-Y, et al. Tumor targeting chitosan nanoparticles for dual-modality optical/MRI cancer imaging. Bioconjugate Chem 2010; 21(4): 578–82. Copyright 2010 American Chemical Society; Tan M, Wu X, Jeong E-K, Chen Q, Parker DL, Lu Z-R. An effective targeted nanoglobular manganese(II) chelate conjugate for magnetic resonance molecular imaging of tumor extracellular matrix. Mol Pharmaceutics 2010; 7(4): 936–43. Copyright 2010 American Chemical Society; Elias DR, Cheng Z, Tsourkas A. An intein-mediated site-specific click conjugation strategy for improved tumor targeting of nanoparticle systems. Small 2010; 6(21): 2460–8. Copyright 2010 Wiley-VCH verlag GmbH & Co. KGaA, Weinheim; and Zou P, Yu Y, Wang A, et al. Superparamagnetic iron oxide nanotheranostics for targeted cancer cell imaging and pH-dependant intracellular drug release. Mol Pharmaceutics 2010; 7(6): 1974–84. Copyright 2010 American Chemical Society, respectively.

Fig. 5

Representative in vivo images of targeted contrast agents: contrast enhancement of fibronectin–fibrin complex in tumor tissues using multimeric conjugated contrast agent 23. Arrows point to tumors. Reprinted with permission from Tan M, Wu X, Jeong E-K, Chen Q, Lu Z-R. Peptide-targeted nanoglobular Gd-DOTA monoamide conjugates for magnetic resonance cancer molecular imaging. Biomacromolecules 2010; 11(3): 754–61. Copyright 2010 American Chemical Society.

Fig. 6

Representative in vivo images of targeted contrast agents: contrast enhancement of HER2-positive tumors using conjugated SPIO nanoparticle 30. Arrows point to tumors. Adapted with permission from Elias DR, Cheng Z, Tsourkas A. An intein-mediated site-specific click conjugation strategy for improved tumor targeting of nanoparticle systems. Small 2010; 6(21): 2460–8. Copyright 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Fig. 7

Targeted contrast agents synthesized using the structure mimicking strategy. Contrast agents 40, 41, and 44 were adapted with permission from Frias JC, Williams KJ, Fisher EA, Fayad ZA. Recombinant HDL-like nanoparticles: A specific contrast agent for MRI of atherosclerotic plaques. J Am Chem Soc 2004; 126(50): 16316–17. Copyright 2004 American Chemical Society; Cormode DP, Skajaa T, van Schooneveld MM, et al. Nanocrystal core high-density lipoproteins: A multimodality contrast agent platform. Nano Lett 2008; 8(11): 3715–23. Copyright 2008 American Chemical Society; and Yang JJ, Yang J, Wei L, et al. Rational design of protein-based MRI contrast agents. J Am Chem Soc 2008; 130(29): 9260–7. Copyright 2008 American Chemical Society; respectively.

Fig. 8

Representative in vivo images of targeted contrast agents: contrast enhancement of atherosclerotic plaques using high-density lipoprotein mimic 40. Arrows point to abdominal aorta. Adapted with permission from Frias JC, Williams KJ, Fisher EA, Fayad ZA. Recombinant HDL-like nanoparticles: A specific contrast agent for MRI of atherosclerotic plaques. J Am Chem Soc 2004; 126(50): 16316–7. Copyright 2004 American Chemical Society.