A single compound with dual function – the ability to deliver a diagnostic and therapeutic agent – may one day be used to enhance the diagnosis, imaging, and treatment of brain tumors, according to findings from Virginia Commonwealth University and Virginia Tech.
The research is published in the August 2011 issue of Radiology (ahead of print on Aug. 3) in the article, "Metallofullerene-based Nanoplatform for Brain Tumor Brachytherapy and Longitudinal Imaging in a Murine Orthotopic Xenograft Model," by Michael D. Shultz, John D. Wilson, Dr. Christine E. Fuller, Jianyuan Zhang, Harry C. Dorn, and Panos P. Fatouros.
Glioblastomas are the most common and aggressive brain tumor in humans, with a high rate of relapse. These tumor cells often extend beyond the well-defined tumor margins making it extremely difficult for clinicians and radiologists to visualize with current imaging techniques. Researchers have been investigating enhanced methods of attacking these cells in order to possibly delay or prevent brain tumor relapse.
In the study, the research team led by Panos Fatouros, a former professor and chair of the Division of Radiation Physics and Biology in the VCU School of Medicine, now retired, demonstrated that a nanoparticle containing an MRI diagnostic agent can effectively be imaged within the brain tumor and provide radiation therapy in an animal model. Survival of the treated mice was 2.5 times longer than the untreated mice (52 days compared to 20.7 days).
The nanoparticle filled with gadolinium, a sensitive MRI contrast agent for imaging, and coupled with radioactive lutetium 177 to deliver brachytherapy, is known as a theranostic agent – a single compound capable of delivering simultaneously effective treatment and imaging. The lutetium 177 is attached to the outside of the carbon cage of the nanoparticle.
The researchers report three advances in knowledge reported in the Radiology article. A functionalized endohedral gadolinium metallofullerene showed extended tumor distribution and prolonged retention when administered by means of convection-enhanced delivery to provide longitudinal imaging. A radiolabeled chelate can be successfully coupled to the (enhanced fullerene), producing a single theranostic nanoplatform with multimodal properties for imaging and therapy. The tumor retention characteristics of the nanoplatform provide sufficient time for decay and extensive radionuclide distribution to yield effective therapy.
"We believe the clustering properties of this nanoplatform prolong its retention within the tumor, thereby allowing a higher radiation dose to be delivered locally," said Michael Shultz, a research fellow in Fatouros' lab in the Department of Radiology in the VCU School of Medicine.
"This theranostic agent could potentially provide critical data about tumor response to therapy by means of longitudinal imaging without further contrast administration," said Fatouros.
The molecular platform is based on a fullerene – a hollow carbon cage that Harry Dorn, professor of chemistry in the College of Science at Virginia Tech, discovered how to fill with atoms of useful metals. One filling is gadolinium, a particularly sensitive MRI contrast agent, which proved 40 times more effective in imaging the brain than commercial MRI agents (reported in Radiology in 2006). In 2009, Dorn's team developed a hands-off way to fill fullerenes with radioactive material.
"Although this is a limited animal study, it shows great promise and hopefully this metallofullerene platform will be extended to humans," said Dorn, who is the Dr. A.C. Lilly Jr. Faculty Fellow in Nanoscience at Virginia Tech.
Of the other co-authors on the August article in Radiology, John D. Wilson is associate professor in the VCU Department of Radiology; Christine E. Fuller is professor and director of neuropathology and autopsy pathology at VCU; and Jianyuan "Jason" Zhang of Bejing, China, is a graduate student in chemistry at Virginia Tech. Fatouros is the corresponding author.
The study was funded by grants to Dorn and Fatouros from the National Science Foundation and the National Institutes of Health.
The researchers are now working on adding specific targeting compounds to the molecule to increase the retention of the nanoparticles within the tumor or tissue-specific retention. "The lutetium 177 has a penetration depth of less than one millimeter; therefore the agent must be delivered in the immediate vicinity of the tumor. We have reported in Nanomedicine (H. L. Fillmore et al in the April 2011 issue) that we can target the theranostic fullerene directly to malignant glioma cells by attaching a peptide (IL-13), which binds to an overexpressed receptor in glioma brain tumor cells," said Fatouros.
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