Molecular imaging brings the vision of personalized medicine into focus

Why patients with the same disease can have different fates has stymied physicians for centuries. Diet, genetics, and environment play a role, but more subtle factors are at work.

"We need to describe diseases by their characteristic molecular errors, to figure out the changes that reprogrammed the cells into causing disease and treat them specifically," said Michael Phelps, Ph.D., director of the Crump Institute for Molecular Imaging at the University of California, Los Angeles.

The concept that Phelps describes-tailoring therapy to the way a disease presents in an individual-is known as personalized medicine. Tailored therapy offers promise to both patients and the healthcare system as a whole. Physicians who can pinpoint the precise location, extent, status, and susceptibilities of a patient's disease will be better able to choose effective treatments, deliver appropriate therapeutic dosages, and monitor patient health. At the same time, such detailed information can reduce unnecessary drug prescriptions and avoid some invasive procedures or expensive scans altogether.

Molecular imaging is at the forefront of this new medical paradigm. FDG-PET, SPECT, MRI, and nanotechnologies are bridging the gap between the dream of personalized medicine and its clinical application. MI helps characterize the biomarkers of disease, provides tools for early diagnosis, ensures better treatment delivery, monitors therapy performance, profiles disease progression, and accelerates drug development.

One promising new molecular imaging technique involves conjugated nanoparticles. Tiny and versatile, these can link to molecules such as antibodies or peptides that will bind target cells and carry imaging agents directly to tissues of interest.

Patrick Winter, Ph.D., an assistant professor of medicine at Washington University in St. Louis, and colleagues have engineered perfluorocarbon nanoparticles coated in a lipid shell like M&Ms dipped in chocolate. As long as a molecule is lipid-soluble and relatively small, it can be added as a component to the shell to bind to different cell receptors or deliver new drugs. The researchers have developed particles carrying a ligand that binds to integrin aVb3, a protein expressed in tumors during angiogenesis. Using gadolinium as the imaging agent, they have injected the particles into mice. Though tiny, this construct is spotlight bright on MR scans. Each nanoparticle can be loaded with about 80,000 gadolinium atoms. In the mouse study, the scientists were able to highlight melanoma tumors just 3 to 5 mm in size.

"Even if you bind only a few of the particles, each one is bringing enough gadolinium that you can actually see it when you take an MRI," Winter said.

The team has also bound antibodies against fibrin or tissue factor as targeting molecules to highlight the location of blood clots.

Similar particles can ferry drugs to tumors, atherosclerotic plaques, or other tissues. When a particle encounters a cell, its outer layer of lipids and medication will meld with the cell membrane. As the medication is being deposited directly onto cells, smaller doses need to be administered. This ability is particularly appealing in diseases such as cancer, where drug toxicity alone can kill patients. The same system can be used to quantify effective drug dosages: The brighter the image appears, the more drug has reached the site. Clinical trials of the nanoparticles could begin within a year.

STEM CELLS

Stem cell therapy promises to manipulate cell division to repair damaged muscles, nerves, bones, and organs. Molecular imaging plays a crucial role in stem cell therapy by identifying how many cells reach the desired target and if they survive, divide, and differentiate to fulfill their intended function. Radiotracer-assisted reporter gene techniques exquisitely track these processes for as few as 1000 cells, but they tend to be short-lived because of radioactive decay.

MRI shows promise for long-term cell tracking, especially when stem cells are labeled with ultrasmall iron oxide nanoparticles. Recent research has resolved some questions about the potential toxicity of these agents. Still, at the current stage of development, MRI can track stem cells only when millions of cells are producing signal.

At Johns Hopkins University, Jeff Bulte, Ph.D., and Dara Kraitchman, Ph.D., are studying how labeled stem cells behave in vivo. Previous research has established that stem cells can restore heart function in animals within two months, but regions of damaged heart that potentially benefit from stem cell therapy were not identified. To find those regions, Bulte and Kraitchman injected iron oxide-labeled bone marrow stem cells into dogs with surgically induced cardiac injuries, then tracked the location of the stem cells for two months with MRI. They found that cells injected into the area near the infarct, as opposed to cells delivered to dead or undamaged tissue, were most likely to be incorporated into the heart itself. Pumping in the peri-infarct zone improved as well.

Though MRI can provide exquisitely detailed anatomic images, it cannot tell the difference between living and dead tissue. That distinction is critical in cancer, where physicians need to determine tumor viability.

Residual mass depicted with CT after chemo- or radiotherapy could be either residual tumor or scar, according to Dr. Malik Juweid, a professor of radiology at the University of Iowa. The standard approach is invasive biopsy or serial CT to monitor possible tumor growth. By measuring tumor metabolism, FDG-PET/CT offers a clearer prognosis.

"In cases of aggressive lymphoma, the chance that you are cured if you have a negative PET/CT scan is above 85%. So everybody can relax, and the patient can be safely observed without a need for aggressive biopsies or surgical intervention," Juweid said.

MONITORING TREATMENT

With better instrumentation and targeted radiopharmaceutical agents, PET/CT will routinely measure early responses and nonresponses to cancer treatment.

FDG-PET/CT has shown spectacular early responses for 30% of patients with gastrointestinal stromal tumors treated with Gleevec, but it also identified the 70% who responded poorly, Phelps said. Making the determination quickly and definitively is medically good for the patient because it offers the possibility of alternative therapy.

The National Cancer Institute is sponsoring a multicenter study to determine PET/CT's impact on the treatment of Hodgkin's disease. Patients will receive a PET/CT scan after one cycle of chemotherapy. Those whose scans are negative will receive either two or five additional cycles of chemo (six cycles is conventional practice). When the outcomes are compared, Juweid suspects that patients with negative scans will likely fare just as well with less treatment.

PET/CT is also fine-tuning radiation therapy. Edema often obscures tumor borders on standard MR and CT scans, complicating radiation therapy planning, but the extent of active tumor is crystal clear with PET/CT.

"Based on the amount of viable tumor seen in the scan, the radiologist may be able to narrow the radiation field. That will help decrease toxicity to normal tissues and better focus radiation to the tumor," Juweid said.

Treating Alzheimer's disease became a possibility when FDG-PET provided the first definitive test to diagnose the disease. New radiopharmaceutical tracers such as carbon-11 Pittsburgh compound B bind to beta-amyloid plaque, and fluorine-18 FDDNP binds to amyloid plaque and neurofibrillary tangles, thought to be associated with the neurological damage caused by Alzheimer's disease. These tracers may be key to physiologically tracking disease progression and its response to proposed drug treatment.