Alliance draws Siemens into heart of nano-universe

Siemens Medical Solutions and Schering are collaborating with industry and academic institutions to develop a new diagnostic procedure to detect the earliest signs of heart disease.

The German firms and their collaborators are developing an innovative MR contrast agent that, when appropriately applied, will visualize so-called vulnerable plaques in blood vessels.

Researchers in the collaborative project, called Nano-Ag, are developing an integrated molecular imaging diagnostic technique to detect these plaques. The agent at the center of the work is a nanoscale citrate-coated very small iron oxide particle (VSOP) specific for vulnerable plaques. The nonfunctionalized VSOP is taken up selectively by macrophages within vulnerable plaques.

The research is a big step in a new direction for Siemens. According to Arne Hengerer, Ph.D., director of molecular MRI at Siemens, it is the first time the company has become actively involved in preclinical MRI contrast agent development.

"We see this as an investment in the future of our business," he said.

The technique promises to hone the assessment of cardiac risk to an unprecedented level. Rather than look at just the anatomic markers of disease, as is currently done with angiography, a sufficiently advanced MR technology using contrast would visualize the inflammatory activity believed to be a critical part of myocardial infarction. Even a low-grade stenosis may have inflammatory activity, but this inflammation can easily elude current methods of detection.

"The aim, therefore, is to not only detect the stenosis, but also to detect the inflammatory activity in the vessel wall," said Dr. Matthias Taupitz, M.D., of Charité Universitätsmedizin Berlin, the German academic partner in the interdisciplinary consortium. "If we can find this, the patient might be treated with anti-inflammatory therapy before these plaques rupture and produce an acute cardiovascular event."

The consortium brings together members of the pharmaceutical industry, medium-sized medical companies, and leading international academic centers. Ferropharm, a start-up pharmaceutical company, and the radiology department of Charité Universitätsmedizin Berlin have been developing the new contrast agent and accompanying MR techniques. Other developmental work has involved MeVis, the German Cancer Research Institute of Heidelberg, and the radiology department of the University of Freiburg. The project also continues Siemens' longstanding partnership with Schering.

"We've managed to bring together the key expertise needed for this solution for cardiovascular imaging in a very interdisciplinary team," Hengerer said.

The project is jointly funded by industry and the German Federal Ministry of Education and Research's initiative "NanoforLife," a government program designed to aid researchers in developing nanotechnology in the field of diagnostic imaging.

"This was an open call for any application of nanoparticles in clinical diagnostics. Our consortium chose cardiovascular diagnostics," Taupitz said.

"Our goal is to functionalize this citrate-coated particle by adding peptides to the iron particles to make them more specific for markers in cardiovascular disease, in particular for vulnerable plaques," he said.

The results could have profound importance for the earlier detection for cardiac infarction. A growing body of evidence indicates that vulnerable plaques produce changes in the vascular wall. Those changes may be the chief cause of the acute vascular occlusions associated with myocardial infarction.

Definitive verification of the presence of plaques is not yet possible with existing imaging techniques. Chemical modification of the super paramagnetic VSOP is expected to provide new opportunities for noninvasive verification. Tests will help determine whether this developing VSOP is suitable as a contrast agent for MR.

Formulations for nanoparticles have already been approved in clinical testing or have found clinical application. Those particles, however, are coated with polymers.

The new nanoparticle the consortium is working is coated with a monomeric substance, specifically a citrate. The particle was invented by Herbert Pilgrimm, Ph.D, of Ferropharm. Its development as a contrast agent was conducted by Ferropharm in cooperation with the radiological department at Charité Berlin. The agent has undergone successful preclinical characterization and a clinical phase I trial. It is now undergoing clinical phase II trials as a blood pool agent.

Monomer-coated particles have clearly defined chemical surface properties and a favorable ratio of iron core to total particle size, according to Taupitz.

"The diameter is about 7 nanometers, and this favorably influences the pharmokinetics for cardiovascular indications," he said. "These are the first electrostatically stabilized particles that have gone into clinical trials."

Electrostatic stabilization is based on the principle of binding charged monomeric molecules (citrate) to the particles, Hengerer said.

"The coat not only must ensure adequate stability of the particles against aggregation, but it must also be biocompatible," he said.

Over the course of the project, the researchers plan to functionalize the nanoparticle by adding peptides. The aim is for these peptides to improve specificity, as they bind selectively to molecular disease markers for vulnerable plaques.

"The choice of peptides is still under discussion," Hengerer said.

In application, the contrast would be injected into the patient, enriching the affected regions. MR would visualize the agent and the source of potential danger. MR measurement procedures would quantitate the risk. These procedures, like many of the other elements of the research, must be adapted to the specialized requirements of cardiac imaging.

"There are challenges in developing the contrast agent, but there are large challenges on the device side as well," Hengerer said. "Because we intend to visualize very small lesions, we need much better spatial resolution. We need new MR sequences, protocols, and postprocessing tools to come up with quantitative analyzers of VSOP enrichment."

Clinical MR systems currently being developed will serve as the platforms for this development, accelerating transfer of these methods to the clinical routine. That transfer is still a long way off, however. Hengerer has set 2015 as a tentative date for market launch.