Bioanalysis

ICP-MS, A Key Technology Applied by QPS to Support the Development of Imaging Agents

Capabilities in clinical diagnostics have increased significantly over the last decade, not only by upgraded diagnostics systems but also by improved or newly developed contrast agents. These contrast agents enable highly detailed viewing of structures inside the body, such as organs, tissue, and veins. Some imaging techniques that make use of contrast media are CT, MRI, X-ray, PET and ultra-sound. It is clear that improved image quality facilitates earlier disease diagnosis, with subsequent economic and health benefits.

QPS` ICP-MS facility in the Netherlands has supported preclinical and clinical studies to develop numerous imaging compounds encompassing a wide range of elements, including Yttrium (Y), Technetium (Tc), Iodine (I), Gadolinium (Gd) and Iron (Fe).

Here, the role of ICP-MS in developing the formulation for two of these elements is demonstrated.

Iron: used to increase organ and tumor contrast in MRI

Iron oxide micro- or nanoparticles show great promise for medical applications because these particles respond to the magnetic fields applied in MRI. The particles can be coated with various marker molecules which bind selectively to tumors or other targets within the body. One example is Resovist™, a liver-specific MRI contrast medium containing iron oxide microparticles. High serum iron levels resulting from iron particle administration are toxic and may lead to serious complications. Therefore, finding the right composition for iron particle formulations is critical, to optimize imaging characteristics and minimize side effects. To evaluate the pharmacokinetics of one dose of an iron formulation  (10 µmol Fe/kg body weight) in healthy volunteers, assays were developed to determine total iron (serum levels of free iron plus protein-bound iron plus the iron from the micro-particle contrast agent) and serum iron (only transferrin-bound iron). Total iron was determined by ICP-MS and serum iron by Spectrometry (Ferrozine method). The results for one subject shown in Figure 1 indicate that the solid iron microparticles are stable, since the serum iron is not significantly increased in the presence of the microparticles.

Figure 1. Iron concentration in one subject, measured by ICP-MS (total iron) and by Spectrometry (serum iron, ferrozine method) at different times after dosing with a microparticle iron formulation. The results show that the serum iron is not significantly influenced by dosage with the iron microparticle formulation.

Gadolinium: used to increase MRI contrast

Gadolinium-based contrast agents (GBCA’s) are very popular in MRI applications, mainly because of the large paramagnetic moment of Gd. Since free Gadolinium (Gd3+) may lead to serious side effects, such as nephrogenic systemic fibrosis (NSF), Gadolinium is commonly administered as a chelating complex, for example Gd-DPTA.

To measure clinical samples accurately and to develop new stable contrast agents and formulations, we developed a highly accurate and precise bioanalytical ICP-MS assay at our laboratory (CV% < 5%), as demonstrated in Figure 2. In addition to this assay, we developed an LC-ICP-MS assay for human plasma samples, to simultaneously analyze free and complex-bound Gd in one analytical run. We use ratios of [Gd bound] / [Gd free] ≤ 10000 with an LLOQ for free Gd3+ on the order of 1 – 10 ng/mL, as shown in Figure 3. This assay was developed for a linear type Gd contrast agent (Primovist™) and a cyclic type (Dotarem™).

Figure 2. For accurate measurement of clinical samples and for the development of new, stable contrast agents and formulations, QPS has developed a highly accurate and precise bioanalytical ICP-MS assay. Precision and accuracy of Gd levels in human EDTA plasma is validated with a bias of ± 5% at 4 validation levels.

Figure 3. LC-ICP-MS of gadolinium in human plasma. Shown is the separation of Dotarem™, Primovist™ (both at 250 µg/mL) and free Gd (50 ng/mL) spikes in human plasma. A 1 : 10000 concentration ratio of free to bound gadolinium, with an LLOQ of 10 ng/mL, can be obtained in this way.

Conclusion

The various combinations of LC with ICP-MS and UV detection techniques provide powerful tools  to investigate new or existing contrast media. Methodologies we have developed provide fast, accurate, highly selective and sensitive methods for quantifying common contrast elements such as Fe and Gd. Elements like Ba, I, Y or radiopharmaceuticals like 198Au, 99mTc, 51Cr, 45/47Ca, 59Fe, 75Se, 131I, 169Yb, not illustrated in this newsletter, are also particularly suited for analysis by ICP-MS.

ICP-MS, whether or not extended with HPLC-UV, can be used either quantitative or qualitative, as dictated by GLP, and may therefore contribute to the development of reliable and safe contrast media.

Authors:

QPS Netherlands
Fred van Heuveln, PhD; Manager Elemental Spectrometry;fred.van.heuveln@qps.com 

QPS Austria Jaap Wieling, PhD; Sr. Vice President, Bioanalysis and Technology R&D and General Manager QPS Austria; jaap.wieling@qps.com

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