Low-Molecular-Weight Iron Chelates May Be an Alternative to Gadolinium-based Contrast Agents for T1-weighted Contrast-enhanced MR Imaging

Abstract

Purpose To synthesize two low-molecular-weight iron chelates and compare their T1 contrast effects with those of a commercial gadolinium-based contrast agent for their applicability in dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging. Materials and Methods The animal experiments were approved by the local ethics committee. Two previously described iron (Fe) chelates of pentetic acid (Fe-DTPA) and of trans-cyclohexane diamine tetraacetic acid (Fe-tCDTA) were synthesized with stability constants several orders of magnitude higher than those of gadolinium-based contrast agents. The T1 contrast effects of the two chelates were compared with those of gadopentetate dimeglumine in blood serum phantoms at 1.5 T, 3 T, and 7 T. For in vivo studies, a human breast cancer cell line (MDA-231) was implanted in five mice per group. The dynamic contrast effects of the chelates were compared by performing DCE MR imaging with intravenous application of Fe-DTPA or Fe-tCDTA on day 1 and DCE MR imaging in the same tumors with gadopentetate dimeglumine on day 2. Quantitative DCE maps were generated with software and were compared by means of a one-tailed Pearson correlation test. Results Relaxivities in serum (0.94 T at room temperature) of Fe-tCDTA (r1 = 2.2 mmol · sec, r2 = 2.5 mmol · sec) and Fe-DTPA (r1 = 0.9 mmol · sec, r2 = 0.9 mmol · sec) were approximately twofold and fivefold lower, respectively, compared with those of gadopentetate dimeglumine (r1 = 4.1 mmol · sec, r2 = 4.8 mmol · sec). Used at moderately higher concentrations, however, iron chelates generated similar contrast effects at T1-weighted MR imaging in vitro in serum, in vivo in blood, and for DCE MR imaging of breast cancer xenografts. The volume transfer constant values for Fe-DTPA and Fe-tCDTA in the same tumors correlated well with those observed for gadopentetate dimeglumine (Fe-tCDTA Pearson R, 0.99; P = .0003; Fe-DTPA Pearson R, 0.97; P = .003). Conclusion Iron-based contrast agents are promising as alternatives for contrast enhancement at T1-weighted MR imaging and have the potential to contribute to the safety of MR imaging. RSNA, 2017 Online supplemental material is available for this article.

MRI contrast enhancement of liver pre-neoplasia using iron–tannic nanoparticles

“…10,11 Iron (Fe 3+ ) complex can be also used as a contrast agent instead of Gd 3+ because Fe 3+ is also a paramagnetic material having less toxicity. [12][13][14] The iron-tannic nanoparticles (Fe-TA NPs), which have been produced by the interaction of Fe 3+ and tannic acid (TA), have shown benecial properties. Examples of their benecial properties are that they have small size, high MRI relaxivity, high stability, good water solubility, and demonstrate high uptake efficiency in tumor cells with capability of being responsive to abnormal microenvironments.…”

Fe-HBED Analogs: A Promising Class of Iron-Chelate Contrast Agents for Magnetic Resonance Imaging

“…It has recently been observed in humans and preclinical models that low levels of Gd can be detected in tissue, particularly in the central nervous system following administration of multiple doses of gadoliniumbased contrast agents (GBCA) [2][3][4]. While adverse health outcomes have not been associated with this retention, the observation has revived interest in MRI active chelates of biotic metals; candidates include manganese [5,6] and iron [7][8][9][10]. Manganese [11] and iron [12] are essential to living organisms, which have consequently developed dedicated biological pathways for achieving homeostasis.…”

“…ere are two key challenges for IBCA, both of which can be addressed via appropriate design of the chelate structure. Iron chelates typically provide less signal than gadolinium chelates on a per metal atom basis [7,8,16]. Lower signal per chelate molecule can be addressed by dosing more iron chelate.…”

“…Lower signal per chelate molecule can be addressed by dosing more iron chelate. However, signal can be strongly in uenced by chelate structure [7,17], and so the performance of iron chelates may be improved by modifying the chelate structure to improve their relaxivity properties. It should also be noted that the contrast advantage of gadolinium over iron chelates may be partially mitigated at the higher eld strengths that are more commonly used today than when the rst MRI CAs were developed and commercialized; indeed, that is one reason why Gd was selected over Mn or Fe some 30 years ago [7,8].…”

Effect of Neodymium Doping on MRI Relaxivity of Gadolinium Oxide Nanoparticles

“…Magnetic resonance imaging (MRI) has an important role in diagnosis of different diseases involving body soft tissues [ 1 ]. To obtain better diagnosis and differentiation of the lesions, using of MRI contrast media is essential in many cases [ 2 , 3 ]. Contrast agents in MRI influence image contrast by changing longitudinal (T1) and transverse (T2) relaxation times of the protons.…”