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ICP-MS: Biomedical Advances and Experimental Applications

Inductively coupled plasma mass spectrometry (ICP-MS) is a powerful technique for the trace and ultra-trace elemental analysis of a variety of sample types. As the name indicates, this technology makes use of a high-energy argon plasma to break down nebulized samples into individual atoms, which are then ionized and channeled into a mass spectrometer for separation, detection, and quantification. In this way, multiple constituent elements can be detected and measured simultaneously from heterogenous samples. This capacity has made ICP-MS particularly suitable for drug discovery and development applications, which often require the highly sensitive detection of specific components from complex biological mixtures. Across the therapeutic landscape, ICP-MS has facilitated preclinical and clinical advances by enabling researchers to analyze sample composition with superior accuracy and comprehensive coverage.

One of the most well-established biomedical applications of ICP-MS is for the detection of metals or other elements from human blood, urine, or tissue samples. This approach can be used to quantify environmental or occupational exposure to a variety of toxic or potentially toxic compounds across a particular cohort, enabling population biomonitoring to improve public health. In the context of a specific disease, ICP-MS can be a powerful biomarker discovery tool. By using ICP-MS to compare patient and control samples, researchers have identified potential biomarkers for a diverse list of diseases, including ovarian cancer, inflammatory bowel disease, and amyotropic lateral sclerosis (ALS). These biomarkers can be used to guide treatment decisions, monitor disease progression, and predict clinical outcomes, ultimately improving patient care.

ICP-MS also facilitates the investigation of metalloproteins, or proteins that bind one or more metal ions. These proteins play a variety of critical biological roles and include many targets of compelling therapeutic interest. Indeed, as many as 40-50% of enzymes are metalloenzymes – meaning that their catalytic activity requires a metal ion – while zinc-binding proteins alone may comprise as much as 10% of the human proteome. Despite this vast clinical relevance, metalloenzyme inhibitors currently represent only ~4% of FDA-approved small-molecule drugs, indicating considerable opportunity for future innovation in this space. In support of metalloenzyme studies, ICP-MS enables researchers to confirm the elemental identity of bound ions and quantify binding stoichiometry with excellent precision.  Furthermore, ICP-MS can be used to analyze and compare metalloprotein levels or binding capacities across a range of samples to gain functional and mechanistic insights. Researchers have used ICP-MS to compare the binding specificities of different myoglobin variants, to determine whether antibiotic treatment alters the zinc-binding ability of an essential bacterial enzyme, and to elucidate the relationship between a mutated metalloprotein (SOD1) and downstream neurodegeneration, highlighting the broad applicability of this technology to the study of metalloproteins in human disease.

Another effective application of ICP-MS is to the discovery, development, and evaluation of metallodrugs. Metallodrugs are commonly known for their use as chemotherapeutic agents. Indeed, the platinum-containing drug cisplatin was first approved by the FDA in 1978 and remains in widespread use for the treatment of ovarian, testicular, lung, and many other cancers. Development of novel cancer metallotherapeutics continues to this day, with the ruthenium-based small-molecule drug BOLD-100 (Bold Therapeutics; NCT04421820) currently undergoing phase 2 clinical trials for the treatment of gastrointestinal cancers. Beyond their anti-cancer applications, metallodrugs have demonstrated efficacy in a host of other clinical contexts. Lithium carbonate and other lithium-based drugs have been used since the 1950s to treat bipolar disorder, with more recent research suggesting broader neuroprotective effects for these and other metal-based compounds. In addition to their well-established antibiotic activity, metallodrugs can be potent anti-virals, anti-fungals, and anti-protozoals. The gold compound auranofin has been used for over 40 years to treat rheumatoid arthritis, while exciting ongoing research harnesses metal complexes for the effective stabilization and delivery of non-metallic drugs.

Across these areas of therapeutic interest and more, ICP-MS can provide critical information to support all stages of the metallodrug development process. Following metallodrug synthesis, ICP-MS can be used to verify the elemental composition of the obtained product. Mechanistic insight can be obtained by using ICP-MS to characterize binding interactions between a metallodrug and its protein or DNA target, or to detect and quantify adducts formed between metallodrugs and plasma/serum proteins. One of the most common uses of ICP-MS is to measure cellular uptake of a metallodrug or metal of interest following treatment or exposure. Metal bioaccumulation can be analyzed over time to establish a metallodrug’s pharmacokinetic profile, across different tissue types to characterize biodistribution patterns, or between different cell lines (e.g., drug-resistant and drug-sensitive) to elucidate underlying mechanisms of action.

In addition to its high sensitivity and quantitative accuracy, the ability of ICP-MS to simultaneously analyze multiple elements provides a significant advantage to the investigation of complex biological systems. For example, uptake of the aforementioned platinum-based drug cisplatin is largely mediated by the membrane copper transporters CTR1 and CTR2, and the relationship between cisplatin accumulation, intracellular copper levels, and CTR1/2 expression is controlled by a complex network of regulatory interactions. In this context, ICP-MS provides a powerful experimental benefit by allowing the simultaneous quantification of both cisplatin and copper levels, enabling cellular responses to cisplatin treatment to be characterized holistically. In another example, ICP-MS revealed a reduction in selenium levels following treatment of Clostridium difficile with the gold-based metallodrug auranofin, leading researchers to propose a novel antimicrobial strategy targeting selenium metabolism.

Beyond metallodrug development, ICP-MS is well-suited to support the development of treatments for diseases associated with defective metal metabolism. Perhaps the most widely known of these disorders is Wilson’s disease, an autosomal recessive condition in which mutation of the copper transporter ATP7B leads to aberrant copper accumulation. These effects are most prominent in brain and liver tissues, where they are associated with a range of neurological, psychiatric, and hepatic symptoms. ICP-MS can be used to measure copper levels in serum and urine samples for diagnostic purposes, as well as to monitor treatment efficacy and therapeutic outcomes. In a preclinical context, ICP-MS has been leveraged to quantify copper levels in animal models of Wilson’s disease, as well as to confirm the selective reduction of copper levels in mouse fibroblasts following treatment with a novel chelator. One research group used ICP-MS to quantify copper accumulation in cell lines carrying distinct ATP7B mutations, providing valuable mechanistic insight into the relationship between genotype and phenotype in Wilson’s disease. ICP-MS has been harnessed in analogous ways to improve the understanding and treatment of many other metal-associated disorders – including hereditary hemochromatosis, hypermanganesemia, and Menkes disease – while still more disorders of this type await the experimental attentions of future investigators.

Since its invention and initial commercialization over 40 years ago, ICP-MS has proven its value as a rapid, accurate, and sensitive analysis method with a broad range of preclinical and clinical applications. This technology has been of particular benefit to the study of metalloproteins and metallodrugs, enabling their absolute quantification from complex biological samples, and has facilitated the ongoing investigation of metal metabolism and associated diseases. Despite this clear demonstration of utility, however, ICP-MS has remained inaccessible to many researchers for a number of reasons, including the level of technical expertise required and the high equipment, set-up, and operating costs associated with these experiments. By partnering with specialized service providers who have extensive ICP-MS experience (including running ICP-MS experiments, optimizing assay protocols, and troubleshooting technical issues), more researchers than ever before can take advantage of the powerful analytic capacity of inductively coupled plasma mass spectrometry, accelerating drug development research for a wide range of therapeutic targets.

To connect with our expert scientific team and explore how ICP-MS could advance your preclinical research program, visit http://momentum.bio/contact

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