Stability and Trapping of Magnetic Resonance Imaging Contrast Agents During High-Intensity Focused Ultrasound Ablation Therapy Nicole M. Hijnen, MSc,* Aaldert Elevelt, MSc,Þ and Holger Gru ¨ll, PhD*Þ Objectives: The purpose of this study was to investigate the use of Gd-DTPA shortly before magnetic resonance guided high-intensity focused ultrasound MR-HIFU thermal ablation therapy with respect to dissociation, trapping, and long-term deposition of gadolinium (Gd) in the body. Materials and Methods: Magnetic resonanceYHIFU ablation treatment was conducted in vivo on both rat muscle and subcutaneous tumor (9L glioma) using a clinical 3T MR-HIFU system equipped with a small-animal coil setup. A human equivalent dose of gadopentetate dimeglumine (Gd-DTPA) (0.6 mmol/kg of body weight) was injected via a tail vein catheter just before ablation (e5 minutes). Potential trapping of the contrast agent in the ablated area was visualized through the acquisition of R1 maps of the target location before and after therapy. The animals were sacrificed 2 hours or 14 days after the injection (n = 4 per group, a total of 40 animals). Subsequently, the Gd content in the tissue and carcass was determined using inductively coupled plasma techniques to investigate the biodistribution. Results: Temporal trapping of Gd-DTPA in the coagulated tissue was observed on the R1 maps acquired within 2 hours after the ablation, an effect confirmed by the inductively coupled plasma analysis (3 times more Gd 3+ was found in the treated muscle volume than in the control muscle tissue). Two weeks after the therapy, the absolute amount of Gd 3+ present in the coagulated tissue was low compared with the amount present in the kidneys 14 days after the injection (ab- lated muscle, 0.009% T 0.002% ID/g; kidney, 0.144% T 0.165% ID/g). There was no significant increase in Gd content in the principal target organs for translocated Gd 3+ ions (liver, spleen, and bone) or in the entire carcasses between the HIFU- and sham-treated animals. Finally, an in vivo relaxivity of 4.6 mmol j1 s j1 was found in the HIFU-ablated volume, indicating intact Gd-DTPA. Conclusions: Magnetic resonanceYHIFU treatment does not induce the dis- sociation of Gd-DTPA. In small-tissue volumes, no significant effect on the long-term in vivo Gd retention was found. However, care must be taken with the use of proton resonance frequency shiftYbased MR thermometry for HIFU guidance in combination with Gd 3+ because the susceptibility artifact induced by Gd 3+ can severely influence treatment outcome. Key Words: Gd-DTPA stability, ablation, contrast agent trapping, HIFU (Invest Radiol 2013;48: 517Y524) H igh-intensity focused ultrasound using magnetic resonance guid- ance (MR-HIFU) is currently studied as a truly noninvasive, clinical method for thermal ablation of tumor tissue. 1 By focusing ultrasound waves, pathological tissue deep inside the human body can be locally heated to lethal temperatures. 2,3 Because the mecha- nism of action is not tissue-specific, a wide range of tumors can be targeted. 4 In this process, MR is used to spatially map the tempera- ture changes that are induced in the targeted location. 5,6 In advance, MR imaging provides a tool for planning of the HIFU treatment. Herein, the use of MR contrast agents could aid the radiologist in tumor detection and is, in some cancers such as breast cancer, almost essential for MR tumor delineation. Because MR-HIFU is emerging for treatment of malignant can- cers, complete tumor coverage becomes critical for successful treatment. Magnetic resonance contrast agents are frequently used in clinical oncology to enhance tumor sites, thereby providing a clear tumor de- lineation on MR images. 7,8 All together, T1 contrast agents based on chelates of the paramagnetic gadolinium ion (Gd) are used in almost 30 % of all MR examinations, for example, Gd-DTPA (gadopentetate dimeglumine, MAGNEVIST), Gd-DOTA (gadoterate meglumine, DOTAREM), Gd-BT-DO3A (gadobutrol, GADOVIST), 9 or Gd-HP- DO3A (gadoteridol, PROHANCE). 10 Despite advantages, there are concerns against the use of Gd- based contrast agents (Gd-CAs) just before or during HIFU ablation. These concerns apply to the potential decomposition of the Gd chelate leading to free Gd 3+ and the entrapment of the contrast agent inside the ablated tissue, followed by redistribution into other tissues. In current clinical practice, risks regarding the combined use of Gd-CA and HIFU are minimized by performing the contrast-enhanced MR examinations 1 day or multiple days before the actual treatment, ensuring clearance of the Gd-CA at the time of HIFU treatment. 11 This approach has ob- vious drawbacks such as a larger patient burden, the need for patient repositioning, and costs. When a patient comes back for the actual treatment, the contrast-enhanced MR images have to be matched to the newly acquired noncontrast enhanced images. Matching of the images has to be precise (especially in case of blood vessel targeting 11 ), is prone to errors, and is sometimes difficult to perform (especially in case of fast- growing or displaceable tumors 12 ). At clinical doses, Gd-CAs are generally safe to use and rapidly eliminated from the body through the kidneys. 13 However, both the ligand (eg, DTPA, DOTA) and the Gd 3+ ions are toxic in free form. The ionic radius of Gd 3+ (108 picometer) is close to that of calcium (114 picometer), causing the Gd 3+ ion to block calcium channels and in- hibit calcium-dependent physiological processes. 13 Furthermore, Gd 3+ may be deposited as insoluble salts in bones, liver, and spleen, resulting in long-term retention of the Gd 3+ in the body. 14 The presence of free Gd 3+ ions has been strongly associated with the development of nephrogenic systemic fibrosis disease. 15,16 Chelation dramatically reduces the acute toxicity of the Gd 3+ and its ligand. Several compounds involving che- lated Gd have been approved for clinical use, including both linear (eg, DTPA) 17 and macrocyclic ligands (eg, DOTA, HP-DO3A). 8 From these, the linear ligands generally have lower stability constants, making them more sensitive to transmetalation (ie, substitution of Gd 3+ by en- dogenous metal ions such as Zn 2+ ) and decomplexation. 10,18 However, the effect of HIFU therapy on the stability of such chelates and the risk for CA entrapment have not yet been investigated. ORIGINAL ARTICLE Investigative Radiology & Volume 48, Number 7, July 2013 www.investigativeradiology.com 517 Received for publication June 5, 2012; and accepted for publication, after revision, December 14, 2012. From the *Department of Biomedical Engineering, Eindhoven University of Technology; and †Department of Minimally Invasive Healthcare, Philips Re- search Eindhoven, Eindhoven, the Netherlands. Conflicts of interest and source of funding: Authors Aaldert Elevelt, MSc, and Holger Gru ¨ll, PhD, are employed by Philips. Nicole Hijnen, MSc, is currently receiving a grant (grant 05T-201) from the Center for Translational Molecular Medicine (www.ctmm.nl), project VOLTA. Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.investigativeradiology.com). Reprints: Holger Gru ¨ll, PhD, Biomedical NMR, Department of Biomedical Engi- neering, Eindhoven University of Technology, High Tech Campus 11.p 261, 5656 AE Eindhoven, the Netherlands. E-mail: h.gruell@tue.nl. Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0020-9996/13/4807Y0517 Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.