Nanoparticles coupled to a fluorescent dye can be used to target tumor-specific molecules in breast cancer, providing a way to track the particles by NIR spectroscopy, to enhance magnetic resonance imaging (MRI) and to deliver an anticancer payload only to diseased cells, as reported by SpectroscopyNOW.
Mohanraja Kumar, Mehmet Yigit, Guangping Dai, Anna Moore and Zdravka Medarova of the Molecular Imaging Laboratory at Massachusetts General Hospital and Harvard Medical School, in Boston, MA, explain how iron oxide nanoparticles could be used in combined imaging of tumors and delivery of a therapeutic agent at the same time. They describe details of the system in the journal Cancer Research this month.
Medarova and colleagues synthesized nanoparticles that bind to the tumor-specific molecule, uMUC-1. This structure is almost ubiquitous on the surface of human breast tumor cells, being present in 90% of cases. The team loaded the particles with a small interfering ribonucleic acid (siRNA) molecule, which can deactivate a specific gene, BIRC5, in the tumor cells. This gene is responsible for blocking normal apoptosis, which allows the cells to replicate uncontrollably. When tested against breast cancer cells growing in culture, the team found that the nanoparticles had a significant impact on reducing expression of the BIRC5 gene.
In addition, the team added a third trait to their agent, a fluorescent dye (Cy5.5) that would allow them to track the particles in the body. Moreover, given that the iron oxide nanoparticles are intrinsically superparamagnetic, they were also able to observe them using a magnetic resonance imaging (MRI) system. The team carried out tests, fluorescence imaging and MRI, and showed that the nanoparticles were rapidly taken up by the breast cancer cells in the laboratory. A follow-up experiment with human pancreatic cancer cells and colon cancer cells showed similar positive effects.
The next step was to test the nanoparticles in-vivo. They injected the nanoparticles intravenously into a mouse model of human breast cancer. The drug was administered on two separate occasions, seven days apart. The MRI scans and fluorescence imaging revealed that the nanoparticles accumulated in the tumors in preference to healthy tissue and that concentrations stayed high over the course of the two-week experiment. Importantly, very few nanoparticles accumulated in the surrounding muscle tissue.
Examination of the tumors showed that the siRNA payload had caused a five-fold increase in apoptosis compared to control nanoparticles that carried a dummy nucleic acid payload. Critically, this demonstrates that the therapeutic effect of the nanoparticles is due to the siRNA rather than the tumor-targeting properties of the peptides (EPPT) on the nanoparticles themselves.
"RNA interference (RNAi) holds considerable potential as a molecular therapeutic tool due to its broad applicability and exquisite specificity," the team explains. Their work has now overcome main obstacles in the way of siRNA therapy in that achieving efficient delivery is commonly precluded by RNase degradation, interaction with blood components, and inefficient translocation across the cell membrane.
The modular nature of the new agent, which combines imaging, targeting and therapy, means that it should be adaptable to other forms of cancer relatively easily, especially given that related iron oxides are already in clinical use. "Our strategy permits the simultaneous tumor-specific delivery of siRNA to tumors and the imaging of the delivery process. More generally, it illustrates the potential to apply this approach to many human cancer studies, including for basic tumor biology and therapy," the team concludes.
The US National Cancer Institute partly supported this work.
Posted by Lee Mather
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