Nanoparticle imaging research focuses on diagnostic, therapeutic possibilities

Michael J. Welch, Ph.D.; image courtesy of RSNA.
CHICAGO—The utilization of nanometer-size compounds in medicine offers the potential for a new era of diagnostic imaging as well as the promise of new capabilities for delivering therapies tailored and targeted for a specific disease, according to Michael J. Welch, PhD, who delivered the Eugene P. Pendergrass New Horizons Lecture at the 94th annual meeting of the Radiological Society of North America (RSNA).

In a somber moment, RSNA president Theresa C. McCloud, MD, dedicated this year’s oration to the memory of imaging informatics luminary Samuel J. Dwyer, PhD, who died earlier this year.

Welch is a professor of radiology, chemistry and molecular biology and pharmacology at the Mallinckrodt Institute of Radiology at Washington University in St. Louis.  He is head of the radiochemistry laboratory at the facility, teaches biomedical engineering at the university, and is a past president of the SNM.

His work on rapid synthesis of positron-labeled organic chemicals was of vital importance in the development of PET at the Mallinckrodt Institute in the early 1970s and in the technology’s subsequent application to diagnostic medicine.

Applying modern organic chemistry to the preparation of radioactive elements used in medical imaging, he developed rapid methods to synthesize positron-labeled organic chemicals, a process essential in making PET into a practical clinical modality.

In the late 1980s, he and colleagues demonstrated that PET scans using radiolabeled estrogen could locate human receptors for the hormone. Subsequent PET studies with radiolabeled compounds provided a rapid and sensitive way to study biological processes in the nervous system. These and other efforts also helped PET gain acceptance for detecting breast and other cancers and for making beneficial choices in patient management.

Welch also is principal investigator for Washington University's longest continuous National Institutes of Health grant, “Cyclotron Isotopes in Biology and Medicine,” which was renewed through 2008—the grant's 44th year of operation.

It previously focused on studies of imaging agents useful for neuroscience, but now is directed toward the development of imaging agents that can help researchers better understand the connections between diabetes and heart disease.

Welch focused the bulk of his lecture on recent developments in nanoparticle research for cancer and cardiac disease imaging and therapy.

He noted that researchers have found that particles less than 100 nanometers (nm) have less chance for detection by the immune system; while particles larger than 10nm are delayed from excretion by the kidneys.

“Long-circulating nanoparticles functionalized with ligands for receptors over-expressed by tumor cells have promising applications for active and passive tumor targeting,” he said.

These findings have allowed scientists to attach nanoparticles to radionuclides for MR, SPECT, PET and near-infrared optical imaging that function as probes for specific disease or inflammation.

The pharmacokinetics of the nanoparticle can even be altered to suit the requirements of the imaging technology being used, Welch said.

“If utilizing an imaging technology where longer imaging times can be used, the pharmacokinetics can be lengthened so that there is longer blood retention of the agent and greater uptake is likely to occur in the target site,” he said.

In a seminal Journal of Nuclear Medicine publication (July 2005), Welch and fellow scientists demonstrated that long-circulating nanoparticles are ideal vehicles for targeted drug delivery as their surface can be functionalized with a variety of ligands and proteins in a multivalent configuration, increasing the capability of interaction with the target.

Furthermore, they found that functional groups on the nanoparticle surface may be conjugated with metal-chelating systems for radiolabeling, thus providing effective tools for imaging and radiotherapy. They also observed that the nanoparticle composition may be optimized to effectively encapsulate and release drugs, thus allowing both imaging and therapy with one vehicle.

Currently, he noted that there is exciting and promising work being conducted by Ralph Weissleder MD, PhD, on nanoparticle-based PET/CT imaging of macrophages in inflammatory atherosclerosis.

Citing work published this year in Circulation (January 2008), Welch reported that Weissleder’s work establishes the capability of a novel tri-modality nanoparticle to directly detect macrophages in atherosclerotic plaques.

The advantages include improved sensitivity; direct correlation of the PET signal with an established biomarker; and the capability to readily quantify the PET signal, perform whole-body vascular surveys, and spatially localize and follow the tri-reporter by microscopy. In addition, the clinical translatability of the agent looks to provide given similarities to magnetic resonance imaging probes in clinical trials.

Development on nanoparticle agents seems to be confined to small start-up firms and academic institutions, Welch noted. In part, he believes that this may be due to concern over the possibility of toxic effects of nanoparticles; although he stated that his group has been—and continues to—test for cytotoxicity in their compounds.

He forecast that initial breakthroughs in clinical utilization of nanoparticle-based agents will be in the cardiac field, due to the prevalence of cardiac disease in the population. “My prediction is that translation will occur with agents targeting cardiovascular function or with dual-use agents with imaging and drug delivery properties,” he said.